CN113226297A - 大麻素类似物及其制备方法 - Google Patents
大麻素类似物及其制备方法 Download PDFInfo
- Publication number
- CN113226297A CN113226297A CN201980087003.4A CN201980087003A CN113226297A CN 113226297 A CN113226297 A CN 113226297A CN 201980087003 A CN201980087003 A CN 201980087003A CN 113226297 A CN113226297 A CN 113226297A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- formula
- alkyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229930003827 cannabinoid Natural products 0.000 title claims abstract description 161
- 239000003557 cannabinoid Substances 0.000 title claims abstract description 161
- 238000000034 method Methods 0.000 title claims description 100
- 150000001875 compounds Chemical class 0.000 claims description 161
- -1 isoprenyl moieties Chemical group 0.000 claims description 111
- 108091033319 polynucleotide Proteins 0.000 claims description 65
- 102000040430 polynucleotide Human genes 0.000 claims description 65
- 239000002157 polynucleotide Substances 0.000 claims description 65
- 239000002253 acid Substances 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 44
- 101710095468 Cyclase Proteins 0.000 claims description 41
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 claims description 41
- 238000004519 manufacturing process Methods 0.000 claims description 36
- NZFANILBSUFMQB-UHFFFAOYSA-N 2-(5,5-dihydroxypentyl)benzoic acid Chemical compound OC(CCCCC1=C(C(=O)O)C=CC=C1)O NZFANILBSUFMQB-UHFFFAOYSA-N 0.000 claims description 35
- 150000007970 thio esters Chemical class 0.000 claims description 35
- SEEZIOZEUUMJME-FOWTUZBSSA-N cannabigerolic acid Chemical class CCCCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1C(O)=O SEEZIOZEUUMJME-FOWTUZBSSA-N 0.000 claims description 34
- QXACEHWTBCFNSA-SFQUDFHCSA-N cannabigerol Chemical class CCCCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1 QXACEHWTBCFNSA-SFQUDFHCSA-N 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 31
- 108010011449 Long-chain-fatty-acid-CoA ligase Proteins 0.000 claims description 26
- 102000005870 Coenzyme A Ligases Human genes 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 239000011541 reaction mixture Substances 0.000 claims description 22
- YKKHSYLGQXKVMO-HZPDHXFCSA-N (6ar,10ar)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydrobenzo[c]chromene-2-carboxylic acid Chemical compound C([C@H]1C(C)(C)O2)C=C(C)C[C@H]1C1=C2C=C(CCCCC)C(C(O)=O)=C1O YKKHSYLGQXKVMO-HZPDHXFCSA-N 0.000 claims description 21
- HRHJHXJQMNWQTF-UHFFFAOYSA-N cannabichromenic acid Chemical class O1C(C)(CCC=C(C)C)C=CC2=C1C=C(CCCCC)C(C(O)=O)=C2O HRHJHXJQMNWQTF-UHFFFAOYSA-N 0.000 claims description 21
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 claims description 20
- QXACEHWTBCFNSA-UHFFFAOYSA-N cannabigerol Natural products CCCCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(O)=C1 QXACEHWTBCFNSA-UHFFFAOYSA-N 0.000 claims description 20
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- UVOLYTDXHDXWJU-UHFFFAOYSA-N Cannabichromene Chemical class C1=CC(C)(CCC=C(C)C)OC2=CC(CCCCC)=CC(O)=C21 UVOLYTDXHDXWJU-UHFFFAOYSA-N 0.000 claims description 16
- 239000005792 Geraniol Substances 0.000 claims description 16
- 229940071221 dihydroxybenzoate Drugs 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 16
- 229940113087 geraniol Drugs 0.000 claims description 16
- 239000007858 starting material Substances 0.000 claims description 16
- GVVPGTZRZFNKDS-JXMROGBWSA-N geranyl diphosphate Chemical group CC(C)=CCC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O GVVPGTZRZFNKDS-JXMROGBWSA-N 0.000 claims description 15
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 claims description 14
- GVVPGTZRZFNKDS-YFHOEESVSA-N Geranyl diphosphate Natural products CC(C)=CCC\C(C)=C/COP(O)(=O)OP(O)(O)=O GVVPGTZRZFNKDS-YFHOEESVSA-N 0.000 claims description 14
- 229940093530 coenzyme a Drugs 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 14
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- KXKOBIRSQLNUPS-UHFFFAOYSA-N 1-hydroxy-6,6,9-trimethyl-3-pentylbenzo[c]chromene-2-carboxylic acid Chemical class O1C(C)(C)C2=CC=C(C)C=C2C2=C1C=C(CCCCC)C(C(O)=O)=C2O KXKOBIRSQLNUPS-UHFFFAOYSA-N 0.000 claims description 13
- UCONUSSAWGCZMV-HZPDHXFCSA-N Delta(9)-tetrahydrocannabinolic acid Chemical class C([C@H]1C(C)(C)O2)CC(C)=C[C@H]1C1=C2C=C(CCCCC)C(C(O)=O)=C1O UCONUSSAWGCZMV-HZPDHXFCSA-N 0.000 claims description 13
- DXDWUVOURNLDAG-UHFFFAOYSA-N OC(CCCCOC(C1=CC=CC=C1)=O)O Chemical compound OC(CCCCOC(C1=CC=CC=C1)=O)O DXDWUVOURNLDAG-UHFFFAOYSA-N 0.000 claims description 13
- 229940043350 citral Drugs 0.000 claims description 13
- 238000012258 culturing Methods 0.000 claims description 13
- 108010006731 Dimethylallyltranstransferase Proteins 0.000 claims description 12
- 102000005454 Dimethylallyltranstransferase Human genes 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- WVOLTBSCXRRQFR-DLBZAZTESA-N cannabidiolic acid Chemical class OC1=C(C(O)=O)C(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 WVOLTBSCXRRQFR-DLBZAZTESA-N 0.000 claims description 12
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000005516 coenzyme A Substances 0.000 claims description 12
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical group NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 12
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 102000003960 Ligases Human genes 0.000 claims description 11
- 108090000364 Ligases Proteins 0.000 claims description 11
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical class OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 claims description 11
- ZNXZGRMVNNHPCA-VIFPVBQESA-N pantetheine Chemical group OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS ZNXZGRMVNNHPCA-VIFPVBQESA-N 0.000 claims description 11
- 150000007513 acids Chemical class 0.000 claims description 10
- VBGLYOIFKLUMQG-UHFFFAOYSA-N Cannabinol Chemical class C1=C(C)C=C2C3=C(O)C=C(CCCCC)C=C3OC(C)(C)C2=C1 VBGLYOIFKLUMQG-UHFFFAOYSA-N 0.000 claims description 9
- LTYOQGRJFJAKNA-KKIMTKSISA-N Malonyl CoA Natural products S(C(=O)CC(=O)O)CCNC(=O)CCNC(=O)[C@@H](O)C(CO[P@](=O)(O[P@](=O)(OC[C@H]1[C@@H](OP(=O)(O)O)[C@@H](O)[C@@H](n2c3ncnc(N)c3nc2)O1)O)O)(C)C LTYOQGRJFJAKNA-KKIMTKSISA-N 0.000 claims description 9
- LTYOQGRJFJAKNA-DVVLENMVSA-N malonyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-DVVLENMVSA-N 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- HCAWPGARWVBULJ-IAGOWNOFSA-N delta8-THC Chemical compound C1C(C)=CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 HCAWPGARWVBULJ-IAGOWNOFSA-N 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 7
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 230000001131 transforming effect Effects 0.000 claims description 6
- 102000013404 Geranyltranstransferase Human genes 0.000 claims description 5
- 108010026318 Geranyltranstransferase Proteins 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- 102000018208 Cannabinoid Receptor Human genes 0.000 claims description 4
- 108050007331 Cannabinoid receptor Proteins 0.000 claims description 4
- 230000000911 decarboxylating effect Effects 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000005817 fluorobutyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 3
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000002989 phenols Chemical class 0.000 claims description 3
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 210000004027 cell Anatomy 0.000 abstract description 86
- 230000014509 gene expression Effects 0.000 abstract description 26
- 210000005253 yeast cell Anatomy 0.000 abstract description 22
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000036961 partial effect Effects 0.000 abstract description 5
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 57
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 56
- 239000000047 product Substances 0.000 description 44
- 229920001184 polypeptide Polymers 0.000 description 30
- 102000004196 processed proteins & peptides Human genes 0.000 description 30
- 108090000765 processed proteins & peptides Proteins 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000002609 medium Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 102000004190 Enzymes Human genes 0.000 description 20
- 108090000790 Enzymes Proteins 0.000 description 20
- 235000001014 amino acid Nutrition 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 18
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 18
- 125000005843 halogen group Chemical group 0.000 description 18
- 239000008103 glucose Substances 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229940065144 cannabinoids Drugs 0.000 description 15
- 241000218236 Cannabis Species 0.000 description 14
- 150000001413 amino acids Chemical class 0.000 description 14
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 14
- 150000007523 nucleic acids Chemical group 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- QDVPGZOKFHEOIW-UHFFFAOYSA-N 6-fluorohexanoic acid Chemical compound OC(=O)CCCCCF QDVPGZOKFHEOIW-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- UVOLYTDXHDXWJU-NRFANRHFSA-N Cannabichromene Natural products C1=C[C@](C)(CCC=C(C)C)OC2=CC(CCCCC)=CC(O)=C21 UVOLYTDXHDXWJU-NRFANRHFSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
- 239000002243 precursor Substances 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 108091000080 Phosphotransferase Proteins 0.000 description 11
- 241000187747 Streptomyces Species 0.000 description 11
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 11
- 150000001735 carboxylic acids Chemical class 0.000 description 11
- 102000020233 phosphotransferase Human genes 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- SEEZIOZEUUMJME-VBKFSLOCSA-N Cannabigerolic acid Natural products CCCCCC1=CC(O)=C(C\C=C(\C)CCC=C(C)C)C(O)=C1C(O)=O SEEZIOZEUUMJME-VBKFSLOCSA-N 0.000 description 10
- SEEZIOZEUUMJME-UHFFFAOYSA-N cannabinerolic acid Natural products CCCCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(O)=C1C(O)=O SEEZIOZEUUMJME-UHFFFAOYSA-N 0.000 description 10
- 238000000855 fermentation Methods 0.000 description 10
- 230000004151 fermentation Effects 0.000 description 10
- 125000001153 fluoro group Chemical group F* 0.000 description 10
- 230000012010 growth Effects 0.000 description 10
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- ORKZJYDOERTGKY-UHFFFAOYSA-N Dihydrocannabichromen Natural products C1CC(C)(CCC=C(C)C)OC2=CC(CCCCC)=CC(O)=C21 ORKZJYDOERTGKY-UHFFFAOYSA-N 0.000 description 9
- 125000003275 alpha amino acid group Chemical group 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 229950011318 cannabidiol Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 239000013604 expression vector Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 230000037353 metabolic pathway Effects 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 8
- 150000004985 diamines Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 230000007935 neutral effect Effects 0.000 description 8
- 229920000642 polymer Polymers 0.000 description 8
- ASUAYTHWZCLXAN-UHFFFAOYSA-N prenol Chemical compound CC(C)=CCO ASUAYTHWZCLXAN-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 150000003573 thiols Chemical class 0.000 description 8
- 239000013598 vector Substances 0.000 description 8
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 7
- BBIISWIPDNMCNS-UHFFFAOYSA-N 2-(5-fluoropentyl)-4,6-dihydroxybenzoic acid Chemical compound OC1=C(C(=O)O)C(=CC(=C1)O)CCCCCF BBIISWIPDNMCNS-UHFFFAOYSA-N 0.000 description 7
- BDXSWIQVLYXSSU-UHFFFAOYSA-N 4-fluorobutanoic acid Chemical compound OC(=O)CCCF BDXSWIQVLYXSSU-UHFFFAOYSA-N 0.000 description 7
- WVOLTBSCXRRQFR-SJORKVTESA-N Cannabidiolic acid Natural products OC1=C(C(O)=O)C(CCCCC)=CC(O)=C1[C@@H]1[C@@H](C(C)=C)CCC(C)=C1 WVOLTBSCXRRQFR-SJORKVTESA-N 0.000 description 7
- 108020004705 Codon Proteins 0.000 description 7
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 7
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 7
- 125000002350 geranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 239000002773 nucleotide Substances 0.000 description 7
- 125000003729 nucleotide group Chemical group 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000223218 Fusarium Species 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- ZNXZGRMVNNHPCA-UHFFFAOYSA-N Pantetheine Natural products OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS ZNXZGRMVNNHPCA-UHFFFAOYSA-N 0.000 description 6
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000007822 coupling agent Substances 0.000 description 6
- 238000006114 decarboxylation reaction Methods 0.000 description 6
- 230000002255 enzymatic effect Effects 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- NUHSROFQTUXZQQ-UHFFFAOYSA-N isopentenyl diphosphate Chemical compound CC(=C)CCO[P@](O)(=O)OP(O)(O)=O NUHSROFQTUXZQQ-UHFFFAOYSA-N 0.000 description 6
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- NNKDBQZOEWXWDW-UHFFFAOYSA-N 2-(4-chlorobutyl)-4,6-dihydroxybenzoic acid Chemical compound ClCCCCC1=CC(=CC(=C1C(=O)O)O)O NNKDBQZOEWXWDW-UHFFFAOYSA-N 0.000 description 5
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 5
- 241000146399 Ceriporiopsis Species 0.000 description 5
- RIVVNGIVVYEIRS-UHFFFAOYSA-N Divaric acid Chemical compound CCCC1=CC(O)=CC(O)=C1C(O)=O RIVVNGIVVYEIRS-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 102000019337 Prenyltransferases Human genes 0.000 description 5
- 108050006837 Prenyltransferases Proteins 0.000 description 5
- 102100029437 Serine/threonine-protein kinase A-Raf Human genes 0.000 description 5
- 230000010933 acylation Effects 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 229960003453 cannabinol Drugs 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 5
- 235000011180 diphosphates Nutrition 0.000 description 5
- FRNQLQRBNSSJBK-UHFFFAOYSA-N divarinol Chemical compound CCCC1=CC(O)=CC(O)=C1 FRNQLQRBNSSJBK-UHFFFAOYSA-N 0.000 description 5
- 229960004242 dronabinol Drugs 0.000 description 5
- 235000019867 fractionated palm kernal oil Nutrition 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000010354 integration Effects 0.000 description 5
- 229960003151 mercaptamine Drugs 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 230000003362 replicative effect Effects 0.000 description 5
- 241000894007 species Species 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- ZROLHBHDLIHEMS-HUUCEWRRSA-N (6ar,10ar)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCC)=CC(O)=C3[C@@H]21 ZROLHBHDLIHEMS-HUUCEWRRSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- SNEOFJCRUHLAMV-UHFFFAOYSA-N 2-(4-fluorobutyl)-4,6-dihydroxybenzoic acid Chemical compound OC1=C(C(=O)O)C(=CC(=C1)O)CCCCF SNEOFJCRUHLAMV-UHFFFAOYSA-N 0.000 description 4
- AAXZFUQLLRMVOG-UHFFFAOYSA-N 2-methyl-2-(4-methylpent-3-enyl)-7-propylchromen-5-ol Chemical compound C1=CC(C)(CCC=C(C)C)OC2=CC(CCC)=CC(O)=C21 AAXZFUQLLRMVOG-UHFFFAOYSA-N 0.000 description 4
- NNMJZXNLJQLBPC-UHFFFAOYSA-N 2-pentylbenzene-1,3-diol Chemical class CCCCCC1=C(O)C=CC=C1O NNMJZXNLJQLBPC-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- YMQFZAGVJOGELX-UHFFFAOYSA-N 5-fluoropentanoic acid Chemical compound OC(=O)CCCCF YMQFZAGVJOGELX-UHFFFAOYSA-N 0.000 description 4
- 101000595405 Arabidopsis thaliana Stress-response A/B barrel domain-containing protein HS1 Proteins 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000020084 Bone disease Diseases 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 108090000489 Carboxy-Lyases Proteins 0.000 description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- POCUEOYYSJSKIZ-UHFFFAOYSA-N OC1=CC(O)=CC(CCCCCF)=C1 Chemical compound OC1=CC(O)=CC(CCCCCF)=C1 POCUEOYYSJSKIZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- CBIDRCWHNCKSTO-UHFFFAOYSA-N prenyl diphosphate Chemical compound CC(C)=CCO[P@](O)(=O)OP(O)(O)=O CBIDRCWHNCKSTO-UHFFFAOYSA-N 0.000 description 4
- 230000013823 prenylation Effects 0.000 description 4
- 208000020016 psychiatric disease Diseases 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OXACIWCDUSDAJP-UHFFFAOYSA-N 2-pentyl-2H-chromen-5-ol Chemical class C(CCCC)C1OC=2C=CC=C(C=2C=C1)O OXACIWCDUSDAJP-UHFFFAOYSA-N 0.000 description 3
- JCYPDKSGYHGCCY-UHFFFAOYSA-N 2-pentylbenzoic acid Chemical class CCCCCC1=CC=CC=C1C(O)=O JCYPDKSGYHGCCY-UHFFFAOYSA-N 0.000 description 3
- YSXDKDWNIPOSMF-UHFFFAOYSA-N 5-chloropentanoic acid Chemical compound OC(=O)CCCCCl YSXDKDWNIPOSMF-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 101710084186 Acetyl-coenzyme A synthetase Proteins 0.000 description 3
- 102100035709 Acetyl-coenzyme A synthetase, cytoplasmic Human genes 0.000 description 3
- 101710194784 Acetyl-coenzyme A synthetase, cytoplasmic Proteins 0.000 description 3
- 101710187573 Alcohol dehydrogenase 2 Proteins 0.000 description 3
- 101710133776 Alcohol dehydrogenase class-3 Proteins 0.000 description 3
- 102100034044 All-trans-retinol dehydrogenase [NAD(+)] ADH1B Human genes 0.000 description 3
- 101710193111 All-trans-retinol dehydrogenase [NAD(+)] ADH4 Proteins 0.000 description 3
- 241000228212 Aspergillus Species 0.000 description 3
- 108010075293 Cannabidiolic acid synthase Proteins 0.000 description 3
- 244000025254 Cannabis sativa Species 0.000 description 3
- 235000008697 Cannabis sativa Nutrition 0.000 description 3
- 102000004031 Carboxy-Lyases Human genes 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 241000221779 Fusarium sambucinum Species 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 241000235058 Komagataella pastoris Species 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 101100268917 Oryctolagus cuniculus ACOX2 gene Proteins 0.000 description 3
- 241000228143 Penicillium Species 0.000 description 3
- 241000589771 Ralstonia solanacearum Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 108700005078 Synthetic Genes Proteins 0.000 description 3
- UCONUSSAWGCZMV-UHFFFAOYSA-N Tetrahydro-cannabinol-carbonsaeure Natural products O1C(C)(C)C2CCC(C)=CC2C2=C1C=C(CCCCC)C(C(O)=O)=C2O UCONUSSAWGCZMV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000001177 diphosphate Substances 0.000 description 3
- 238000006911 enzymatic reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000002538 fungal effect Effects 0.000 description 3
- 125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 3
- 108010018534 isopentenyl monophosphate kinase Proteins 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 239000010450 olivine Substances 0.000 description 3
- 229910052609 olivine Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 229940035893 uracil Drugs 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- FQVLRGLGWNWPSS-BXBUPLCLSA-N (4r,7s,10s,13s,16r)-16-acetamido-13-(1h-imidazol-5-ylmethyl)-10-methyl-6,9,12,15-tetraoxo-7-propan-2-yl-1,2-dithia-5,8,11,14-tetrazacycloheptadecane-4-carboxamide Chemical compound N1C(=O)[C@@H](NC(C)=O)CSSC[C@@H](C(N)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C)NC(=O)[C@@H]1CC1=CN=CN1 FQVLRGLGWNWPSS-BXBUPLCLSA-N 0.000 description 2
- IQSYWEWTWDEVNO-ZIAGYGMSSA-N (6ar,10ar)-1-hydroxy-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]chromene-2-carboxylic acid Chemical compound C([C@H]1C(C)(C)O2)CC(C)=C[C@H]1C1=C2C=C(CCC)C(C(O)=O)=C1O IQSYWEWTWDEVNO-ZIAGYGMSSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- GLZPCOQZEFWAFX-JXMROGBWSA-N (E)-Geraniol Chemical compound CC(C)=CCC\C(C)=C\CO GLZPCOQZEFWAFX-JXMROGBWSA-N 0.000 description 2
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- CZXWOKHVLNYAHI-LSDHHAIUSA-N 2,4-dihydroxy-3-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-propylbenzoic acid Chemical compound OC1=C(C(O)=O)C(CCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 CZXWOKHVLNYAHI-LSDHHAIUSA-N 0.000 description 2
- MVQHQNPEUJISIX-UHFFFAOYSA-N 2-(3-fluoropropyl)-4,6-dihydroxybenzoic acid Chemical compound OC1=C(C(=O)O)C(=CC(=C1)O)CCCF MVQHQNPEUJISIX-UHFFFAOYSA-N 0.000 description 2
- TWKHUZXSTKISQC-UHFFFAOYSA-N 2-(5-methyl-2-prop-1-en-2-ylphenyl)-5-pentylbenzene-1,3-diol Chemical compound OC1=CC(CCCCC)=CC(O)=C1C1=CC(C)=CC=C1C(C)=C TWKHUZXSTKISQC-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- FBEZEHBDPIYPOT-UHFFFAOYSA-N 2-pentyl-2H-chromene-6-carboxylic acid Chemical class C(CCCC)C1OC2=CC=C(C=C2C=C1)C(=O)O FBEZEHBDPIYPOT-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- FAVCTJGKHFHFHJ-GXDHUFHOSA-N 3-[(2e)-3,7-dimethylocta-2,6-dienyl]-2,4-dihydroxy-6-propylbenzoic acid Chemical compound CCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1C(O)=O FAVCTJGKHFHFHJ-GXDHUFHOSA-N 0.000 description 2
- NHZMSIOYBVIOAF-UHFFFAOYSA-N 5-hydroxy-2,2-dimethyl-3-(3-oxobutyl)-7-pentyl-3h-chromen-4-one Chemical compound O=C1C(CCC(C)=O)C(C)(C)OC2=CC(CCCCC)=CC(O)=C21 NHZMSIOYBVIOAF-UHFFFAOYSA-N 0.000 description 2
- OIVPAQDCMDYIIL-UHFFFAOYSA-N 5-hydroxy-2-methyl-2-(4-methylpent-3-enyl)-7-propylchromene-6-carboxylic acid Chemical compound O1C(C)(CCC=C(C)C)C=CC2=C1C=C(CCC)C(C(O)=O)=C2O OIVPAQDCMDYIIL-UHFFFAOYSA-N 0.000 description 2
- KWJCQIJWHWOEJO-UHFFFAOYSA-N 6-(4-chlorobutyl)-3-(3,7-dimethylocta-2,6-dienyl)-2,4-dihydroxybenzoic acid Chemical compound ClCCCCC1=CC(=C(C(=C1C(=O)O)O)CC=C(CCC=C(C)C)C)O KWJCQIJWHWOEJO-UHFFFAOYSA-N 0.000 description 2
- SRIMXBUQPOAWIB-UHFFFAOYSA-N 7-(5-fluoropentyl)-2-methyl-2-(4-methylpent-3-enyl)chromen-5-ol Chemical compound FCCCCCC=1C=C(C=2C=CC(OC=2C=1)(CCC=C(C)C)C)O SRIMXBUQPOAWIB-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 2
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 102100034035 Alcohol dehydrogenase 1A Human genes 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 241000219194 Arabidopsis Species 0.000 description 2
- 241000219195 Arabidopsis thaliana Species 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000351920 Aspergillus nidulans Species 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- FAVCTJGKHFHFHJ-UHFFFAOYSA-N CBGVA Natural products CCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(O)=C1C(O)=O FAVCTJGKHFHFHJ-UHFFFAOYSA-N 0.000 description 2
- XIHNOHIMHVBHBT-UHFFFAOYSA-N CC(=CCC=1C(=C(C(=O)O)C(=CC=1O)CCCCCF)O)CCC=C(C)C Chemical compound CC(=CCC=1C(=C(C(=O)O)C(=CC=1O)CCCCCF)O)CCC=C(C)C XIHNOHIMHVBHBT-UHFFFAOYSA-N 0.000 description 2
- 101100327917 Caenorhabditis elegans chup-1 gene Proteins 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- REOZWEGFPHTFEI-JKSUJKDBSA-N Cannabidivarin Chemical compound OC1=CC(CCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 REOZWEGFPHTFEI-JKSUJKDBSA-N 0.000 description 2
- 101000712615 Cannabis sativa Tetrahydrocannabinolic acid synthase Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102100035882 Catalase Human genes 0.000 description 2
- 108010053835 Catalase Proteins 0.000 description 2
- 241000195597 Chlamydomonas reinhardtii Species 0.000 description 2
- 241001471082 Colocasia bobone disease-associated cytorhabdovirus Species 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 2
- ZROLHBHDLIHEMS-UHFFFAOYSA-N Delta9 tetrahydrocannabivarin Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCC)=CC(O)=C3C21 ZROLHBHDLIHEMS-UHFFFAOYSA-N 0.000 description 2
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010019686 Farnesol kinase Proteins 0.000 description 2
- 241000145614 Fusarium bactridioides Species 0.000 description 2
- 241000223195 Fusarium graminearum Species 0.000 description 2
- 241000146406 Fusarium heterosporum Species 0.000 description 2
- 241000223221 Fusarium oxysporum Species 0.000 description 2
- 101150094690 GAL1 gene Proteins 0.000 description 2
- 102100028501 Galanin peptides Human genes 0.000 description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 101100121078 Homo sapiens GAL gene Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- 235000014663 Kluyveromyces fragilis Nutrition 0.000 description 2
- 241001138401 Kluyveromyces lactis Species 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 235000004357 Mentha x piperita Nutrition 0.000 description 2
- 241001479543 Mentha x piperita Species 0.000 description 2
- 241000203407 Methanocaldococcus jannaschii Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000235395 Mucor Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- 241000221960 Neurospora Species 0.000 description 2
- DOTNPMPNOUVVQT-UHFFFAOYSA-N OC1=CC(O)=CC(CCCCCl)=C1 Chemical compound OC1=CC(O)=CC(CCCCCl)=C1 DOTNPMPNOUVVQT-UHFFFAOYSA-N 0.000 description 2
- SDTDZYDMSQUSDG-UHFFFAOYSA-N OC1=CC(O)=CC(CCCCF)=C1 Chemical compound OC1=CC(O)=CC(CCCCF)=C1 SDTDZYDMSQUSDG-UHFFFAOYSA-N 0.000 description 2
- PQIYFQKCTNXJRA-UHFFFAOYSA-N OC1=CC(O)=CC(CCCF)=C1 Chemical compound OC1=CC(O)=CC(CCCF)=C1 PQIYFQKCTNXJRA-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 241000320412 Ogataea angusta Species 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 239000001888 Peptone Substances 0.000 description 2
- 108010080698 Peptones Proteins 0.000 description 2
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 2
- 102000012288 Phosphopyruvate Hydratase Human genes 0.000 description 2
- 108010022181 Phosphopyruvate Hydratase Proteins 0.000 description 2
- 241000235648 Pichia Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010030975 Polyketide Synthases Proteins 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- 108020005115 Pyruvate Kinase Proteins 0.000 description 2
- 102000013009 Pyruvate Kinase Human genes 0.000 description 2
- 241000589194 Rhizobium leguminosarum Species 0.000 description 2
- 241000235070 Saccharomyces Species 0.000 description 2
- 101100386089 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) MET17 gene Proteins 0.000 description 2
- 244000253911 Saccharomyces fragilis Species 0.000 description 2
- 235000018368 Saccharomyces fragilis Nutrition 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- IQSYWEWTWDEVNO-UHFFFAOYSA-N THCVA Natural products O1C(C)(C)C2CCC(C)=CC2C2=C1C=C(CCC)C(C(O)=O)=C2O IQSYWEWTWDEVNO-UHFFFAOYSA-N 0.000 description 2
- 241000228341 Talaromyces Species 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102000005924 Triose-Phosphate Isomerase Human genes 0.000 description 2
- 108700015934 Triose-phosphate isomerases Proteins 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 241000235015 Yarrowia lipolytica Species 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 229930185621 benastatin Natural products 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 108010002861 cannabichromenic acid synthase Proteins 0.000 description 2
- REOZWEGFPHTFEI-UHFFFAOYSA-N cannabidivarine Natural products OC1=CC(CCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 REOZWEGFPHTFEI-UHFFFAOYSA-N 0.000 description 2
- YJYIDZLGVYOPGU-UHFFFAOYSA-N cannabigeroldivarin Natural products CCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(O)=C1 YJYIDZLGVYOPGU-UHFFFAOYSA-N 0.000 description 2
- 239000003556 cannabinoid 2 receptor agonist Substances 0.000 description 2
- 229930191614 cannabinolic acid Natural products 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 108091008053 gene clusters Proteins 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000006127 geranylation Effects 0.000 description 2
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229940031154 kluyveromyces marxianus Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- LTYOQGRJFJAKNA-VFLPNFFSSA-N malonyl-coa Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-VFLPNFFSSA-N 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 150000004712 monophosphates Chemical class 0.000 description 2
- 230000036651 mood Effects 0.000 description 2
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- IRMPFYJSHJGOPE-UHFFFAOYSA-N olivetol Chemical compound CCCCCC1=CC(O)=CC(O)=C1 IRMPFYJSHJGOPE-UHFFFAOYSA-N 0.000 description 2
- SXFKFRRXJUJGSS-UHFFFAOYSA-N olivetolic acid Chemical compound CCCCCC1=CC(O)=CC(O)=C1C(O)=O SXFKFRRXJUJGSS-UHFFFAOYSA-N 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 238000007243 oxidative cyclization reaction Methods 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 235000019319 peptone Nutrition 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229930001119 polyketide Natural products 0.000 description 2
- 150000003881 polyketide derivatives Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- MQCJHQBRIPSIKA-UHFFFAOYSA-N prenyl phosphate Chemical compound CC(C)=CCOP(O)(O)=O MQCJHQBRIPSIKA-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 150000003505 terpenes Chemical class 0.000 description 2
- 235000007586 terpenes Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- XSSYCIGJYCVRRK-RQJHMYQMSA-N (-)-carbovir Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1C[C@H](CO)C=C1 XSSYCIGJYCVRRK-RQJHMYQMSA-N 0.000 description 1
- VVJVMUUCGDSHBT-VXKWHMMOSA-N (1s,2s)-1,2-dinaphthalen-1-ylethane-1,2-diamine Chemical compound C1=CC=C2C([C@@H]([C@@H](N)C=3C4=CC=CC=C4C=CC=3)N)=CC=CC2=C1 VVJVMUUCGDSHBT-VXKWHMMOSA-N 0.000 description 1
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- JSCUZAYKVZXKQE-JXMROGBWSA-N (2e)-1-bromo-3,7-dimethylocta-2,6-diene Chemical compound CC(C)=CCC\C(C)=C\CBr JSCUZAYKVZXKQE-JXMROGBWSA-N 0.000 description 1
- WLAUCMCTKPXDIY-JXMROGBWSA-N (2e)-1-chloro-3,7-dimethylocta-2,6-diene Chemical compound CC(C)=CCC\C(C)=C\CCl WLAUCMCTKPXDIY-JXMROGBWSA-N 0.000 description 1
- UJCHIZDEQZMODR-BYPYZUCNSA-N (2r)-2-acetamido-3-sulfanylpropanamide Chemical compound CC(=O)N[C@@H](CS)C(N)=O UJCHIZDEQZMODR-BYPYZUCNSA-N 0.000 description 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- VCVPSRADUBPOKJ-NSHDSACASA-N 1-[[(2s)-1-methylpyrrolidin-2-yl]methyl]piperidine Chemical compound CN1CCC[C@H]1CN1CCCCC1 VCVPSRADUBPOKJ-NSHDSACASA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- DKCWQRKXTQSULZ-UHFFFAOYSA-N 1h-imidazole;urea Chemical compound NC(N)=O.C1=CNC=N1 DKCWQRKXTQSULZ-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- SBSKRVZFWQPJID-UHFFFAOYSA-N 2,2-difluorobutanoic acid Chemical compound CCC(F)(F)C(O)=O SBSKRVZFWQPJID-UHFFFAOYSA-N 0.000 description 1
- PKXVNCYLUCOREQ-UHFFFAOYSA-N 2,2-difluorohexanoic acid Chemical compound CCCCC(F)(F)C(O)=O PKXVNCYLUCOREQ-UHFFFAOYSA-N 0.000 description 1
- DIXONZOTEIIZKO-UHFFFAOYSA-N 2,2-difluoropentanoic acid Chemical compound CCCC(F)(F)C(O)=O DIXONZOTEIIZKO-UHFFFAOYSA-N 0.000 description 1
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- GFIWSSUBVYLTRF-UHFFFAOYSA-N 2-[2-(2-hydroxyethylamino)ethylamino]ethanol Chemical compound OCCNCCNCCO GFIWSSUBVYLTRF-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 description 1
- 102100032282 26S proteasome non-ATPase regulatory subunit 14 Human genes 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 101710186512 3-ketoacyl-CoA thiolase Proteins 0.000 description 1
- WTUCTMYLCMVYEX-UHFFFAOYSA-N 4,4,4-trifluorobutanoic acid Chemical compound OC(=O)CCC(F)(F)F WTUCTMYLCMVYEX-UHFFFAOYSA-N 0.000 description 1
- 108010060511 4-Aminobutyrate Transaminase Proteins 0.000 description 1
- 102100035923 4-aminobutyrate aminotransferase, mitochondrial Human genes 0.000 description 1
- GRHQDJDRGZFIPO-UHFFFAOYSA-N 4-bromobutanoic acid Chemical compound OC(=O)CCCBr GRHQDJDRGZFIPO-UHFFFAOYSA-N 0.000 description 1
- IPLKGJHGWCVSOG-UHFFFAOYSA-N 4-chlorobutanoic acid Chemical compound OC(=O)CCCCl IPLKGJHGWCVSOG-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- 229940006015 4-hydroxybutyric acid Drugs 0.000 description 1
- WNXNUPJZWYOKMW-UHFFFAOYSA-N 5-bromopentanoic acid Chemical compound OC(=O)CCCCBr WNXNUPJZWYOKMW-UHFFFAOYSA-N 0.000 description 1
- PHOJOSOUIAQEDH-UHFFFAOYSA-N 5-hydroxypentanoic acid Chemical compound OCCCCC(O)=O PHOJOSOUIAQEDH-UHFFFAOYSA-N 0.000 description 1
- NVRVNSHHLPQGCU-UHFFFAOYSA-N 6-bromohexanoic acid Chemical compound OC(=O)CCCCCBr NVRVNSHHLPQGCU-UHFFFAOYSA-N 0.000 description 1
- XWWKSLXUVZVGSP-UHFFFAOYSA-N 6-chlorohexanoic acid Chemical compound OC(=O)CCCCCCl XWWKSLXUVZVGSP-UHFFFAOYSA-N 0.000 description 1
- IWHLYPDWHHPVAA-UHFFFAOYSA-N 6-hydroxyhexanoic acid Chemical compound OCCCCCC(O)=O IWHLYPDWHHPVAA-UHFFFAOYSA-N 0.000 description 1
- MHNOXDQYBLSPIC-UHFFFAOYSA-N 7-(5-chloropentyl)-2-methyl-2-(4-methylpent-3-enyl)chromen-5-ol Chemical compound ClCCCCCC=1C=C(C=2C=CC(OC=2C=1)(CCC=C(C)C)C)O MHNOXDQYBLSPIC-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- MPORYQCGWFQFLA-ONPDANIMSA-N 7-[(7s)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid;trihydrate Chemical compound O.O.O.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 MPORYQCGWFQFLA-ONPDANIMSA-N 0.000 description 1
- IGNBKLCFKTYIRI-UHFFFAOYSA-N 7-chloroheptanoic acid Chemical compound OC(=O)CCCCCCCl IGNBKLCFKTYIRI-UHFFFAOYSA-N 0.000 description 1
- PNAJBOZYCFSQDJ-UHFFFAOYSA-N 7-hydroxyheptanoic acid Chemical compound OCCCCCCC(O)=O PNAJBOZYCFSQDJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 101150077996 AAE gene Proteins 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 241001019659 Acremonium <Plectosphaerellaceae> Species 0.000 description 1
- 101710146995 Acyl carrier protein Proteins 0.000 description 1
- 108010021809 Alcohol dehydrogenase Proteins 0.000 description 1
- 101710187578 Alcohol dehydrogenase 1 Proteins 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 101100319367 Arabidopsis thaliana At5g22580 gene Proteins 0.000 description 1
- 241001513093 Aspergillus awamori Species 0.000 description 1
- 241000892910 Aspergillus foetidus Species 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- 241001480052 Aspergillus japonicus Species 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 240000006439 Aspergillus oryzae Species 0.000 description 1
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000223651 Aureobasidium Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 108010018763 Biotin carboxylase Proteins 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 description 1
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 1
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 1
- CZXWOKHVLNYAHI-UHFFFAOYSA-N CBDVA Natural products OC1=C(C(O)=O)C(CCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 CZXWOKHVLNYAHI-UHFFFAOYSA-N 0.000 description 1
- 108091033409 CRISPR Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 244000197813 Camelina sativa Species 0.000 description 1
- 235000014595 Camelina sativa Nutrition 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 229940123368 Cannabinoid CB2 receptor agonist Drugs 0.000 description 1
- 235000011305 Capsella bursa pastoris Nutrition 0.000 description 1
- 240000008867 Capsella bursa-pastoris Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241001660259 Cereus <cactus> Species 0.000 description 1
- 241000221955 Chaetomium Species 0.000 description 1
- 108050001186 Chaperonin Cpn60 Proteins 0.000 description 1
- 102000052603 Chaperonins Human genes 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 241000123346 Chrysosporium Species 0.000 description 1
- 241001674013 Chrysosporium lucknowense Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108700010070 Codon Usage Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000222511 Coprinus Species 0.000 description 1
- 241000222356 Coriolus Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- 102000057412 Diphosphomevalonate decarboxylases Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 102100023431 E3 ubiquitin-protein ligase TRIM21 Human genes 0.000 description 1
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- 101100406563 Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) orsB gene Proteins 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 102100035111 Farnesyl pyrophosphate synthase Human genes 0.000 description 1
- 101710125754 Farnesyl pyrophosphate synthase Proteins 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 241000221207 Filobasidium Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000567163 Fusarium cerealis Species 0.000 description 1
- 241001112697 Fusarium reticulatum Species 0.000 description 1
- 241001014439 Fusarium sarcochroum Species 0.000 description 1
- 241000223192 Fusarium sporotrichioides Species 0.000 description 1
- 241001465753 Fusarium torulosum Species 0.000 description 1
- 241000567178 Fusarium venenatum Species 0.000 description 1
- 108700007698 Genetic Terminator Regions Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 101000892220 Geobacillus thermodenitrificans (strain NG80-2) Long-chain-alcohol dehydrogenase 1 Proteins 0.000 description 1
- OINNEUNVOZHBOX-XBQSVVNOSA-N Geranylgeranyl diphosphate Natural products [P@](=O)(OP(=O)(O)O)(OC/C=C(\CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)/C)O OINNEUNVOZHBOX-XBQSVVNOSA-N 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 238000010468 Hell-Volhard-Zelinsky reaction Methods 0.000 description 1
- 101710170207 High-affinity glucose transporter Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000590281 Homo sapiens 26S proteasome non-ATPase regulatory subunit 14 Proteins 0.000 description 1
- 101000780443 Homo sapiens Alcohol dehydrogenase 1A Proteins 0.000 description 1
- 101000710899 Homo sapiens Cannabinoid receptor 1 Proteins 0.000 description 1
- 101000958922 Homo sapiens Diphosphomevalonate decarboxylase Proteins 0.000 description 1
- 101000685877 Homo sapiens E3 ubiquitin-protein ligase TRIM21 Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 101001114059 Homo sapiens Protein-arginine deiminase type-1 Proteins 0.000 description 1
- 101000642268 Homo sapiens Speckle-type POZ protein Proteins 0.000 description 1
- 241000223198 Humicola Species 0.000 description 1
- 108010052919 Hydroxyethylthiazole kinase Proteins 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108010000775 Hydroxymethylglutaryl-CoA synthase Proteins 0.000 description 1
- 102100028888 Hydroxymethylglutaryl-CoA synthase, cytoplasmic Human genes 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- 108010065958 Isopentenyl-diphosphate Delta-isomerase Proteins 0.000 description 1
- 241000235649 Kluyveromyces Species 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 101710153103 Long-chain-fatty-acid-CoA ligase FadD13 Proteins 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102100026665 Malonate-CoA ligase ACSF3, mitochondrial Human genes 0.000 description 1
- 240000007228 Mangifera indica Species 0.000 description 1
- 235000014826 Mangifera indica Nutrition 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108700040132 Mevalonate kinases Proteins 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 241000218213 Morus <angiosperm> Species 0.000 description 1
- 101100390535 Mus musculus Fdft1 gene Proteins 0.000 description 1
- 208000029578 Muscle disease Diseases 0.000 description 1
- 241000226677 Myceliophthora Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 101000997933 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (2E,6E)-farnesyl diphosphate synthase Proteins 0.000 description 1
- 101001015102 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) Dimethylallyltranstransferase Proteins 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- AXFZADXWLMXITO-UHFFFAOYSA-N N-acetylcysteamine Chemical compound CC(=O)NCCS AXFZADXWLMXITO-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 241000233892 Neocallimastix Species 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 101100390536 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) erg-6 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241001120672 Noccaea Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001236817 Paecilomyces <Clavicipitaceae> Species 0.000 description 1
- 101000958925 Panax ginseng Diphosphomevalonate decarboxylase 1 Proteins 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 241000496307 Phaeomyces Species 0.000 description 1
- 241001542817 Phaffia Species 0.000 description 1
- 241000081271 Phaffia rhodozyma Species 0.000 description 1
- 241000222385 Phanerochaete Species 0.000 description 1
- 241000222393 Phanerochaete chrysosporium Species 0.000 description 1
- 241000222395 Phlebia Species 0.000 description 1
- 102100024279 Phosphomevalonate kinase Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000195887 Physcomitrella patens Species 0.000 description 1
- 241000222350 Pleurotus Species 0.000 description 1
- 244000252132 Pleurotus eryngii Species 0.000 description 1
- 235000001681 Pleurotus eryngii Nutrition 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- 241000183024 Populus tremula Species 0.000 description 1
- 241000218976 Populus trichocarpa Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000897024 Pseudomonas reinekei Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000231139 Pyricularia Species 0.000 description 1
- 241000205160 Pyrococcus Species 0.000 description 1
- 102000014128 RANK Ligand Human genes 0.000 description 1
- 108010025832 RANK Ligand Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 101100010928 Saccharolobus solfataricus (strain ATCC 35092 / DSM 1617 / JCM 11322 / P2) tuf gene Proteins 0.000 description 1
- 101100507956 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HXT7 gene Proteins 0.000 description 1
- 101000832889 Scheffersomyces stipitis (strain ATCC 58785 / CBS 6054 / NBRC 10063 / NRRL Y-11545) Alcohol dehydrogenase 2 Proteins 0.000 description 1
- 241000222480 Schizophyllum Species 0.000 description 1
- 241000235346 Schizosaccharomyces Species 0.000 description 1
- 241000235347 Schizosaccharomyces pombe Species 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 102100036422 Speckle-type POZ protein Human genes 0.000 description 1
- 241000579741 Sphaerotheca <fungi> Species 0.000 description 1
- 208000020339 Spinal injury Diseases 0.000 description 1
- 241001149962 Sporothrix Species 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 101100281395 Streptomyces cinnamonensis fnq26 gene Proteins 0.000 description 1
- 241000187432 Streptomyces coelicolor Species 0.000 description 1
- 241000187437 Streptomyces glaucescens Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 102000003691 T-Type Calcium Channels Human genes 0.000 description 1
- 108090000030 T-Type Calcium Channels Proteins 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 101150001810 TEAD1 gene Proteins 0.000 description 1
- 101150074253 TEF1 gene Proteins 0.000 description 1
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 1
- 241001136494 Talaromyces funiculosus Species 0.000 description 1
- 241001540751 Talaromyces ruber Species 0.000 description 1
- 241000228178 Thermoascus Species 0.000 description 1
- 241000223257 Thermomyces Species 0.000 description 1
- 241000204667 Thermoplasma Species 0.000 description 1
- 241000204673 Thermoplasma acidophilum Species 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 241001494489 Thielavia Species 0.000 description 1
- 241001495429 Thielavia terrestris Species 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- 108060008225 Thiolase Proteins 0.000 description 1
- 102000002932 Thiolase Human genes 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 241001149964 Tolypocladium Species 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000222354 Trametes Species 0.000 description 1
- 241000222355 Trametes versicolor Species 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 102100029898 Transcriptional enhancer factor TEF-1 Human genes 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 241000223259 Trichoderma Species 0.000 description 1
- 241000223260 Trichoderma harzianum Species 0.000 description 1
- 241000378866 Trichoderma koningii Species 0.000 description 1
- 241000223262 Trichoderma longibrachiatum Species 0.000 description 1
- 241000499912 Trichoderma reesei Species 0.000 description 1
- 241000223261 Trichoderma viride Species 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 238000003302 UV-light treatment Methods 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- 241001452678 Wickerhamomyces canadensis Species 0.000 description 1
- 241000235013 Yarrowia Species 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- KQNSPSCVNXCGHK-UHFFFAOYSA-N [3-(4-tert-butylphenoxy)phenyl]methanamine Chemical compound C1=CC(C(C)(C)C)=CC=C1OC1=CC=CC(CN)=C1 KQNSPSCVNXCGHK-UHFFFAOYSA-N 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000006241 alcohol protecting group Chemical group 0.000 description 1
- 208000029650 alcohol withdrawal Diseases 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 101150087698 alpha gene Proteins 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- 229940124325 anabolic agent Drugs 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 229920000080 bile acid sequestrant Polymers 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 208000016738 bone Paget disease Diseases 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000002617 bone density conservation agent Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 1
- 229960002495 buspirone Drugs 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 150000004652 butanoic acids Chemical class 0.000 description 1
- 108010005026 butyryl-CoA synthetase Proteins 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229930192457 cannabichromanone Natural products 0.000 description 1
- IGHTZQUIFGUJTG-UHFFFAOYSA-N cannabicyclol Chemical class O1C2=CC(CCCCC)=CC(O)=C2C2C(C)(C)C3C2C1(C)CC3 IGHTZQUIFGUJTG-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 230000035425 carbon utilization Effects 0.000 description 1
- 239000003575 carbonaceous material Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 108010079058 casein hydrolysate Proteins 0.000 description 1
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
- 229960004755 ceftriaxone Drugs 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- OSVXSBDYLRYLIG-UHFFFAOYSA-N chlorine dioxide Inorganic materials O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- NBRBXGKOEOGLOI-UHFFFAOYSA-N dasabuvir Chemical compound C1=C(C(C)(C)C)C(OC)=C(C=2C=C3C=CC(NS(C)(=O)=O)=CC3=CC=2)C=C1N1C=CC(=O)NC1=O NBRBXGKOEOGLOI-UHFFFAOYSA-N 0.000 description 1
- 229960001418 dasabuvir Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical class [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000000221 dopamine uptake inhibitor Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000007911 effervescent powder Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- QYDYPVFESGNLHU-UHFFFAOYSA-N elaidic acid methyl ester Natural products CCCCCCCCC=CCCCCCCCC(=O)OC QYDYPVFESGNLHU-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000009483 enzymatic pathway Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 101150116391 erg9 gene Proteins 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- ZRCVYEYHRGVLOC-HYARGMPZSA-N gemifloxacin Chemical compound C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 ZRCVYEYHRGVLOC-HYARGMPZSA-N 0.000 description 1
- 229960003170 gemifloxacin Drugs 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- FFOWJDCTFSWUMJ-JXMROGBWSA-N geranyl phosphate Chemical compound CC(C)=CCC\C(C)=C\COP(O)(O)=O FFOWJDCTFSWUMJ-JXMROGBWSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 125000004968 halobutyl group Chemical group 0.000 description 1
- 125000004969 haloethyl group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid group Chemical group C(CCCCCC)(=O)O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OEXFMSFODMQEPE-HDRQGHTBSA-N hexanoyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 OEXFMSFODMQEPE-HDRQGHTBSA-N 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- QVDTXNVYSHVCGW-ONEGZZNKSA-N isopentenol Chemical compound CC(C)\C=C\O QVDTXNVYSHVCGW-ONEGZZNKSA-N 0.000 description 1
- CPJRRXSHAYUTGL-UHFFFAOYSA-N isopentenyl alcohol Chemical compound CC(=C)CCO CPJRRXSHAYUTGL-UHFFFAOYSA-N 0.000 description 1
- QMZRXYCCCYYMHF-UHFFFAOYSA-N isopentenyl phosphate Chemical compound CC(=C)CCOP(O)(O)=O QMZRXYCCCYYMHF-UHFFFAOYSA-N 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- 229940041028 lincosamides Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 108010089734 malonyl-CoA synthetase Proteins 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000008897 memory decline Effects 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 239000001771 mentha piperita Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- QYDYPVFESGNLHU-KHPPLWFESA-N methyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC QYDYPVFESGNLHU-KHPPLWFESA-N 0.000 description 1
- 229940073769 methyl oleate Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 102000002678 mevalonate kinase Human genes 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229960000808 netilmicin Drugs 0.000 description 1
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000004957 nitroimidazoles Chemical class 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000001741 organic sulfur group Chemical group 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N pentanoic acid group Chemical group C(CCCC)(=O)O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 150000005603 pentanoic acids Chemical class 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- YPJUNDFVDDCYIH-UHFFFAOYSA-N perfluorobutyric acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)F YPJUNDFVDDCYIH-UHFFFAOYSA-N 0.000 description 1
- CXZGQIAOTKWCDB-UHFFFAOYSA-N perfluoropentanoic acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F CXZGQIAOTKWCDB-UHFFFAOYSA-N 0.000 description 1
- 125000005008 perfluoropentyl group Chemical group FC(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)* 0.000 description 1
- 125000005009 perfluoropropyl group Chemical group FC(C(C(F)(F)F)(F)F)(F)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 108091000116 phosphomevalonate kinase Proteins 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 230000037039 plant physiology Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000002675 polymer-supported reagent Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 229960001755 resorcinol Drugs 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229960003177 sitafloxacin Drugs 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- TUPFOYXHAYOHIB-WZGOVNIISA-M sodium;(2s,5r,6r)-6-[[(2s)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]h Chemical compound [Na+].C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 TUPFOYXHAYOHIB-WZGOVNIISA-M 0.000 description 1
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical compound [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 description 1
- 229960000497 trovafloxacin Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 230000024275 uncoating of virus Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
- C07C39/08—Dihydroxy benzenes; Alkylated derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
- C07C39/373—Halogenated derivatives with all hydroxy groups on non-condensed rings and with unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1003—Transferases (2.) transferring one-carbon groups (2.1)
- C12N9/1014—Hydroxymethyl-, formyl-transferases (2.1.2)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1025—Acyltransferases (2.3)
- C12N9/1029—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1085—Transferases (2.) transferring alkyl or aryl groups other than methyl groups (2.5)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
- C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/24—Preparation of oxygen-containing organic compounds containing a carbonyl group
- C12P7/26—Ketones
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
- C12P7/42—Hydroxy-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y203/00—Acyltransferases (2.3)
- C12Y203/01—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
- C12Y203/01206—3,5,7-Trioxododecanoyl-CoA synthase (2.3.1.206)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y205/00—Transferases transferring alkyl or aryl groups, other than methyl groups (2.5)
- C12Y205/01—Transferases transferring alkyl or aryl groups, other than methyl groups (2.5) transferring alkyl or aryl groups, other than methyl groups (2.5.1)
- C12Y205/01102—Geranyl-pyrophosphate—olivetolic acid geranyltransferase (2.5.1.102)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y401/00—Carbon-carbon lyases (4.1)
- C12Y401/01—Carboxy-lyases (4.1.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y404/00—Carbon-sulfur lyases (4.4)
- C12Y404/01—Carbon-sulfur lyases (4.4.1)
- C12Y404/01026—Olivetolic acid cyclase (4.4.1.26)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y602/00—Ligases forming carbon-sulfur bonds (6.2)
- C12Y602/01—Acid-Thiol Ligases (6.2.1)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/04—Monocyclic monocarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本文提供了大麻素类似物,包括卤代大麻素类似物、羟基化大麻素类似物,氘代大麻素类似物和氚代大麻素类似物。大麻素类似物可通过在修饰的宿主细胞(例如重组修饰的酵母细胞)中部分或全部表达来制备,任选地结合化学合成步骤。
Description
相关申请的交叉引用
本申请要求2018年10月31日提交的美国临时专利申请No.62/753,708和于2018年11月14日提交的美国临时专利申请No.62/767,447的优先权,其全部内容通过引用合并于此。
背景技术
大麻(Cannabis sativa)品种已在世界范围内被广泛地栽培并应用于许多领域。茎,枝和叶用于纤维和基于纤维的产品。芽和种子作为食物;种子可获得廉价油;花用于芳香,娱乐,仪式和药用目的;以及花和根用于营养以及其他医药和制药用途。实际上,已经记录了许多人体内受控的临床研究以及传闻或开放标签的研究,这些研究证明了植物提取物和纯化的大麻植物化合物在许多人类医学疾病中均具有有益作用。人体研究中描述的大麻素类化合物的有益活性涵盖神经系统疾病,情绪/行为疾病,胃肠道疾病以及睡眠,食欲和疲劳问题。其他用途或潜在用途包括治疗各种微生物和病毒感染以及治疗多种癌症。
发明内容
本文提供了根据式I的化合物及其盐和大麻素衍生物:
其中:R1选自由C1-C20卤代烷基,C1-C20羟基烷基,氘代的C1-C20烷基,氚代的C1-C20烷基和C2-C20烯基组成的组,R2选自由COOR2a和H组成的组,R2a选自由C1-C6烷基和H组成的组,并且R3选自由H和异戊二烯基部分组成的组。
在一些实施方案中,大麻素衍生物是大麻二酚酸类似物,大麻二酚类似物,Δ9-四氢大麻酚酸类似物,Δ8-四氢大麻酚酸类似物,大麻环萜酚酸类似物,大麻环萜酚类似物,大麻酚类似物,脱氢大麻二酚类似物,大麻酚酸类似物,次大麻酚类似物,次大麻酚酸类似物,Δ9-四氢次大麻酚类似物,Δ8-四氢次大麻酚类似物,Δ9-四氢次大麻酚酸类似物,Δ8-四氢次大麻酚酸类似物,次大麻萜酚类似物,次大麻萜酚酸类似物,次大麻环萜酚类似物,次大麻环萜酚酸类似物,次大麻二酚类似物,次大麻二酚酸类似物,二羟基大麻酚类似物,或大麻环酚类似物。
本文还提供了制备式IV的化合物或其盐的方法:
其中R1选自C1-C20卤代烷基,C1-C20羟基烷基,氘代的C1-C20烷基,氚代的C1-C20烷基和C2-C20烯基。该方法包括在包含根据式II的硫酯的培养基中培养修饰的重组宿主细胞;
其中R4选自由辅酶A(CoA)部分,泛酰巯基乙胺部分和半胱胺部分组成的组,其中修饰的重组宿主细胞包含:
i.编码合成酶的第一多核苷酸,所述合成酶将式II的硫酯和丙二酰辅酶A转化为式III的四酮:
ii.第二多核苷酸,其编码将式III的四酮转化为式IV的化合物的2-烷基-4,6-二羟基苯甲酸环化酶,
以及其中修饰的重组宿主细胞在第一和第二多核苷酸编码的产物被表达以及式IV的化合物被产生的条件下培养。
式IV的化合物可以通过本文所述的方法转化为许多中性和酸性的大麻素类似物。
附图说明
图1显示了用于制备本公开所述大麻素类似物的酶促途径的一个实例。
发明详述
本公开提供了新的大麻素类化合物,其可用于多种人类治疗适应症,包括神经系统疾病,情绪/行为障碍,感染和癌症。还提供了使用可持续的现代生物药物制备方法生产药用级大麻素的方法。
I.定义
除非另有定义,否则本文中使用的所有技术术语,符号和其他科学术语旨在具有本申请所属领域的普通技术人员通常理解的含义。在某些情况下,为了清楚和/或便于参考,本文定义了具有通常理解的含义的术语,并且本文中包含此类定义的内容不必然被解释为与本领域通常的理解具有实质性区别。
如本文所用,术语“大麻素”,“大麻素类化合物”和“大麻素产物”可互换使用,是指含有聚酮部分(例如,二羟基戊基苯甲酸或另一种2-烷基-4,6-二羟基苯甲酸)和萜烯衍生的异戊二烯基部分(例如,香叶基)的分子。香叶基基团衍生自香叶醇的二磷酸酯(称为香叶基焦磷酸或香叶基二磷酸酯),其可以与二羟基戊基苯甲酸型化合物反应形成酸性大麻素大麻萜酚酸(CBGA)和CBGA类似物,如图1所示。CBGA可通过酶促方式(例如,通过体内或体外酶处理的脱羧作用以形成中性大麻素大麻萜酚)和化学方式(例如通过加热)转化为其他生物活性的大麻素。
术语大麻素包括酸性大麻素和中性大麻素。术语“酸性大麻素”是指具有羧酸部分的大麻素。羧酸部分可以质子化形式(即,作为-COOH)或以去质子化形式(即作为羧酸根-COO-)存在。酸性大麻素的实例包括但不限于大麻萜酚酸(cannabigerolic acid),大麻二酚酸(cannabidiolic acid),大麻环萜酚酸(cannabichromenic acid)和Δ9-四氢大麻酚酸。术语“中性大麻素”是指不包含羧酸部分(即,不包含-COOH或-COO-部分)的大麻素。中性大麻素的实例包括但不限于大麻萜酚,大麻二酚,大麻环萜酚和Δ9-四氢大麻酚。
术语“2-烷基-4,6-二羟基苯甲酸”是指具有以下结构的化合物:
其中R是C1-C20烷基,其可以如本文所述被卤代,羟基化,氘代和/或氚代。2-烷基-4,6-二羟基苯甲酸的实例包括但不限于二羟基戊基苯甲酸(即2-戊基-4,6-二羟基苯甲酸;CAS登记号491-72-5)和divarinic酸(即2-丙基-4,6-二羟基苯甲酸;CAS登记号4707-50-0)。二羟基戊基苯甲酸类似物包括其他的2-烷基-4,6-二羟基苯甲酸和取代的间苯二酚,包括但不限于5-卤代甲基间苯二酚类,5-卤代乙基间苯二酚类,5-卤代丙基间苯二酚类,5-卤代己基间苯二酚类,5-卤代庚基间苯二酚类,5-卤代辛基间苯二酚类和5-卤代壬基间苯二酚类。
术语“烷基”本身或作为另一取代基的一部分,是指直链或支链的饱和脂族基团。烷基可以包括任何数目的碳,例如C1-2,C1-3,C1-4,C1-5,C1-6,C1-7,C1-8,C1-9,C1-10,C2-3,C2-4,C2-5,C2-6,C3-4,C3-5,C3-6,C4-5,C4-6和C5-6。例如C1-6烷基包括但不限于甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,戊基,异戊基,己基等。烷基也可以指具有至多20个碳原子的烷基,例如但不限于庚基,辛基,壬基,癸基等。
术语“烯基”本身或作为另一取代基的一部分,是指具有一个或多个碳-碳双键的本文定义的烷基。烯基的实例包括但不限于乙烯基(即,乙烯基),巴豆基(即,丁-2-烯-1-基),戊-1,3-二烯-1-基等。烯基部分可以进一步被例如芳基取代基(如4-羟基苯乙烯基情况下的苯基或羟基苯基)取代。
术语“卤素”和“卤代”本身或作为另一取代基的一部分,是指氟,氯,溴或碘原子。
术语“卤代烷基”本身或作为另一个取代基的一部分,是指其中一些或全部氢原子被卤素原子取代的烷基。对于烷基,卤代烷基可具有任何合适数目的碳原子,例如C1-6。例如,卤代烷基包括三氟甲基,氟甲基等。在一些情况下,术语“全氟”可用于定义其中所有氢均被氟取代的化合物或基团。例如,全氟甲基是指1,1,1-三氟甲基。
术语“羟基烷基”本身或作为另一取代基的一部分,是指其中一些或全部氢原子被羟基(即,-OH基团)取代的烷基。对于烷基和卤代烷基,羟基烷基可具有任何合适数目的碳原子,例如C1-6。
术语“氘代”是指具有一个或多个氘原子(即2H原子)替代一个或多个氢原子的取代基(例如烷基)。
术语“氚代”是指具有一个或多个氚原子(即3H原子)替代一个或多个氢原子的取代基(例如烷基)。
术语“异戊二烯基部分(prenyl moiety)”是指含有至少一个甲基丁烯基的取代基(例如3-甲基丁-2-烯-1-基)。在许多情况下,异戊二烯基部分是由异戊烯基焦磷酸和/或异戊烯基二磷酸通过生物化学方法合成的,从而产生了萜烯天然产物和其他化合物。异戊二烯基部分的实例包括但不限于异戊二烯基(即3-甲基丁-2-烯-1-基),异平基(即3-甲基丁-3-烯-1-基),香叶基,月桂烯基,罗勒烯基(ocimenyl),法呢基和香叶基香叶基。
术语“香叶醇”是指(2E)-3,7-二甲基-2,6-辛二烯-1-醇(CAS登记号106-24-1)。术语“香叶酰化”是指3,7-二甲基-2,6-辛二烯-1-基基团与诸如2-烷基-4,6-羟基苯甲酸的分子共价键合。如本文所述,可以化学或酶促进行香叶酰化。术语“柠檬醛”是指3,7-二甲基辛基-2,6-二烯醛。
“有机溶剂”是指在环境温度和压力下为液体且基本上不含水的含碳物质。有机溶剂的实例包括但不限于甲苯,二氯甲烷,乙酸乙酯,乙腈,四氢呋喃,苯,氯仿,乙醚,二甲基甲酰胺,二甲基亚砜和石油醚。
术语“酸”是指能够给予质子(即氢阳离子)以形成酸的共轭碱的物质。酸的实例包括但不限于无机酸(例如,盐酸,硫酸等),羧酸(例如,乙酸,甲酸等)和磺酸(例如,甲磺酸,对甲苯磺酸等)。
如本文所用,术语“治疗”是指成功治疗或减轻伤害,病理,病症或症状(例如疼痛)的任何指标,包括任何客观或主观参数,例如消减;缓解;减轻症状或使患者更能耐受症状,伤害,病理或病状;或减少症状或病症的频率或持续时间。症状的治疗或改善可以基于任何客观或主观参数,包括例如身体检查的结果。
如本文所用,术语“施用”是指对受试者口服,局部,肠胃外,静脉内,腹膜内,肌肉内,病灶内,鼻内,皮下,肺或鞘内施用,以及作为栓剂或将缓释装置(例如微型渗透泵)植入给受试者中的施用。
如本文所用,术语“有效量”是指所施用的产生治疗效果的剂量。确切的剂量将取决于治疗的目的,并且将由本领域技术人员使用已知技术确定(参见,例如,Lieberman,Pharmaceutical Dosage Forms(Vols.1-3,1992);Lloyd,The Art,Science andTechnology of Pharmaceutical Compounding(1999);Pickar,Dosage Calculations(1999);以及Remington:The Science and Practice of Pharmacy,第20版,2003年,Gennaro,Ed.,Lippincott,Williams&Wilkins。
在整个说明书和权利要求书中,词语“包括”或诸如“包含”或“含有”的变型将被理解为暗示包括陈述的整体或整体组,但不排除任何其他整体或整体组。
在两个或更多个多肽序列的情况中,术语“相同”或百分“同一性”是指,当比较和比对齐以在比较窗口或者指定区域上达到最大对应性时,在指定区域内相同或具有指定百分比的相同氨基酸残基(例如,至少70%,至少75%,至少80%,85%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或更高同一性)的两个或更多个序列或亚序列。用于确定氨基酸序列同一性百分比目的的比对可以以多种方法进行,包括使用诸如BLAST,BLAST-2,ALIGN,Megalign(DNASTAR)或Geneious软件的公共可用计算机软件的比对方法。适用于确定序列同一性和序列相似性百分比的算法示例包括BLAST2.0算法,其在Altschulet al.,Nuc.Acids Res.25:3389-3402(1977)和Altschul et al.,J.Mol.Biol.215:403-410(1990)中描述。因此,BLAST2.0可以与描述的默认参数一起使用以确定序列同一性百分比。
如本文所用,“保守”置换是指使得维持侧链的电荷,疏水性和/或大小的氨基酸置换。可以互相置换的示例性氨基酸组包括:(i)带正电荷的氨基酸Lys,Arg和His;(ii)带负电荷的氨基酸Glu和Asp;(iii)芳香族氨基酸Phe,Tyr和Trp;(iv)氮环氨基酸His和Trp;(v)大型脂肪族非极性氨基酸Val,Leu和Ile;(vi)弱极性氨基酸Met和Cys;(vii)小侧链氨基酸Ser,Thr,Asp,Asn,Gly,Ala,Glu,Gln和Pro;(viii)脂肪族氨基酸Val,Leu,Ile,Met和Cys;和(ix)小羟基氨基酸Ser和Thr。在本段中,提及氨基酸的电荷是指在生理pH下的电荷。
在特定情况下,使用缩写词。例如,术语“CBGA”是指大麻萜酚酸。类似地:“OA”是指二羟基戊基苯甲酸;“CBG”是指大麻萜酚;“CBDA”是指大麻二酚酸;“CBD”是指大麻二酚;“THC”是指Δ9-四氢大麻酚(Δ9-THC);“Δ8-THC”是指Δ8-四氢大麻酚;“THCA”是指Δ9-四氢大麻酚酸(Δ9-THCA);“Δ8-THCA”是指Δ8-四氢大麻酚酸;“CBCA”是指大麻环萜酚酸;“CBC”是指大麻环萜酚;“CBN”是指大麻酚;“CBND”是指脱氢大麻二酚;“CBNA”是指大麻酚酸;“CBV”是指次大麻酚;“CBVA”是指次大麻酚酸;“THCV”是指Δ9-四氢次大麻酚(Δ9-THCV);“Δ8-THCV”是指“Δ8-四氢次大麻酚”;“THCVA”是指Δ9-四氢次大麻酚酸(Δ9-THCV);“Δ8-THCVA”是指Δ8-四氢次大麻酚酸;“CBGV”是指次大麻萜酚;“CBGVA”是指次大麻萜酚酸;“CBCV”是指次大麻环萜酚;“CBCVA”是指次大麻环萜酚酸;“CBDV”是指次大麻二酚;“CBDVA”是指次大麻二酚酸;“MPF”是指多前体进料;“PKS”是指聚酮合成酶;“GOT”是指香叶基焦磷酸:二羟基戊基苯甲酸香叶基转移酶;“YAC”是指酵母人工染色体;“IRES”或“内部核糖体进入位点”是指直接促进核糖体结合和mRNA翻译的专门序列,而与帽结构无关;并且“HPLC”是指高效液相色谱法。
如本文和所附权利要求书中所使用的,单数形式的“一个”,“一”和“该”包括复数指示物,除非上下文另外明确指出。
如本文所用,术语“约”和“大约”表示当用于修饰特定值时在该数值附近的接近范围。如果“X”为该值,例如,“约X”或“大约X”将指示0.9X到1.1X的值,例如0.95X到1.05X的值或0.98X到1.02的值X,或从0.99X到1.01X的值。凡提及“约X”或“大约X”具体地表示至少值X,0.9X,0.91X,0.92X,0.93X,0.94X,0.95X,0.96X,0.97X,0.98X,0.99X,1.01X,1.02X,1.03X,1.04X,1.05X,1.06X,1.07X,1.08X,1.09X和1.1X,以及此范围内的值。
本文描述或参考的分子生物学技术和程序通常是本领域技术人员很好地理解的并通常使用常规方法利用的,例如,Sambrook等,Molecular Cloning:A LaboratoryManual,第2版(1989),Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y中描述的广泛使用的分子克隆方法。除非另有说明,适当时,通常根据制造商定义的方案和/或参数进行涉及使用市售试剂盒和试剂的程序。在描述本发明的方法,表达系统及其用途之前,应当理解,本发明不限于所描述的特定的方法,方案,细胞系,动物物种或属,构建体和试剂,而是当然可以不同。还应理解,本文所使用的术语仅出于描述特定实施方案的目的,而无意限制本发明的范围,本发明的范围仅由所附权利要求书限定。
Ⅱ.大麻素类似物
本文提供根据式I的化合物及其盐和大麻素衍生物:
其中:
R1选自由C1-C20卤代烷基,C1-C20羟基烷基,氘代C1-C10烷基,氘代C1-C20烷基和C2-C20烯基组成的组,
R2选自由COOR2a和H组成的组,
R2a选自由C1-C6烷基和H组成的组
R3选自由H和异戊二烯基部分组成的组。
在一些实施方案中,R1是C1-C20卤代烷基(例如,C1-C15卤代烷基或C1-C10卤代烷基)。R1可以是例如卤代乙基(含有1-5个卤原子),卤代丙基(含有1-7个卤原子),卤代丁基(含有1-9个卤原子),卤代戊基(含有1-11个卤原子)),卤代己基(含有1至13个卤原子),卤代庚基(含有1至15个卤原子),卤代辛基(含有1至17个卤原子)和卤代壬基(含有1至19个卤原子)。卤代烷基的实例包括但不限于氯甲基,二氯甲基,三氯甲基,氟甲基,二氟甲基,三氟甲基,2,2,2-三氯乙基,2,2,2-三氟乙基,五氯乙基,五氟乙基,1,1,1,3,3,3-六氯丙基,1,1,1,3,3,3-六氟丙基等。在一些实施方案中,R1选自C1-C10氟代烷基,C1-C10氯代烷基,C1-C10溴代烷基和C1-C10碘代烷基。在一些实施方案中,R1选自C1-C10氟烷基,C1-C10氯烷基和C1-C10溴烷基。在一些实施方案中,R1是C1-C10氟烷基。
在一些实施方案中,R1选自氟乙基(含有1至5个氟原子),氟丙基(含有1至7个氟原子),氟丁基(含有1至9个氟原子),氟戊基(含有1至11个氟原子),氟己基(含1至13个氟原子),氟庚基(含1至15个氟原子),氟辛基(含1至17个氟原子)和氟壬基(含1至19个氟原子)。
在一些实施方案中,R1选自3-氟丙基;3,3,3-三氟丙基;1,1-二氟丙基;全氟丙基;4-氟丁基;1,1-二氟丁基;全氟丁基;5-氟戊基;1,1-二氟戊基;和全氟戊基。
在一些实施方案中,R1选自3-氟丙基,4-氟丁基和5-氟戊基。
在一些实施方案中,R1选自3-氯丙基,3-溴丙基,3-羟基丙基,4-氯丁基,4-溴丁基,4-羟丁基,5-氯戊基,5-溴戊基,5-羟基戊基,6-氯己基,6-溴己基和6-羟基己基。在一些实施方案中,R1是全氘代戊基(即-C5D11)。
在一些实施方案中,R2为COOH。其中R2为COOH并且R3为H的式I化合物包括二羟基戊基苯甲酸类似物,其中R1为卤代戊基,羟基戊基,氘代戊基或氚代戊基。
在一些实施方案中,R2为H。其中R2为H且R3为H的式I化合物包括二羟基戊基苯甲酸类似物,其中R1为卤代戊基,羟基戊基,氘代戊基或氚代戊基。
在一些实施方案中,R2为COOR2a且R2a为C1-C6烷基。R2a可以是例如甲基,乙基,丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,正戊基,异戊基,正己基或支链己基。
在一些实施方案中,提供2,4-二羟基-6-全氘代戊基苯甲酸;2,4-二羟基-6-(5-氟戊基)-苯甲酸;2,4-二羟基-6-(4-氟丁基)-苯甲酸;6-(4-氯丁基)-2,4-二羟基苯甲酸;和/或2,4-二羟基-6-(3-氟丙基)-苯甲酸。在一些实施方案中,提供了5-全氘代戊基苯-1,3-二醇;5-(5-氟戊基)-苯-1,3-二醇;5-(4-氟丁基)-苯-1,3-二醇;5-(4-氯丁基)-苯-1,3-二醇;和/或5-(3-氟丙基)-苯-1,3-二醇。
在一些实施方案中,R3是异戊二烯基部分。R3可以是,例如,异戊二烯基(即2-甲基丁-2-烯-1-基),香叶基(即3,7-二甲基辛-2,6-二烯-1-基),法呢基(即,3,7,11-三甲基十二烷-2,6,10-三烯-1-基)或香叶基香叶基(即3,7,11,15-四甲基十六烷-2,6,10,14-四烯-1-醇)。在一些实施方案中,异戊二烯基部分是香叶基。异戊二烯基部分的碳-碳双键可以呈顺式(Z)构型或反式(E)构型,如下文所列的非限制性实例所示,其中波浪线表示异戊二烯基部分与式I化合物的连接点。在一些实施方案中,R3为反式-香叶基(即,(E)-3,7-二甲基辛-2,6-二烯-1-基)。
在一些实施方案中,该化合物具有根据式Ia的结构:
其中R2为COOH的式Ia化合物包括大麻萜酚酸类似物,其中R1为卤代戊基,羟基戊基,氘代戊基或氚代戊基。式Ia的化合物(其中R2为H)包括大麻萜酚类似物,其中R1为卤代戊基,羟基戊基,氘代戊基或氚代戊基。
在一些实施方案中,提供了6-(4-氯丁基)-3-(3,7-二甲基-辛-2,6-二烯基)-2,4-二羟基苯甲酸;3-(3,7-二甲基-辛-2,6-二烯基)-6-(5-氟戊基)-2,4-二羟基苯甲酸;2-甲基-2-(4-甲基-戊-3-烯基)-7-全氘代戊基-2H-色烯-5-醇;5-羟基-2-甲基-2-(4-甲基-戊-3-烯基)-7-全氘代戊基-2H-色烯-6-羧酸;7-(5-氟戊基)-2-甲基-2-(4-甲基-戊-3-烯基)-2H-色烯-5-醇;和/或7-(5-氯戊基)-2-甲基-2-(4-甲基-戊-3-烯基)-2H-色烯-5-醇。
在一些实施方案中,提供了根据式I和式Ia的化合物的大麻素衍生物。在一些实施方案中,大麻素衍生物选自卤代大麻二酚酸,卤代大麻二酚,卤代Δ9-四氢大麻酚酸,卤代Δ8-四氢大麻酚酸,卤代大麻环萜酚酸,卤代大麻环萜酚,卤代大麻酚,卤代脱氢大麻二酚,卤代大麻酚酸,次大麻酚,卤代次大麻酚酸,卤代Δ9-四氢次大麻酚,卤代Δ8-四氢次大麻酚,卤代Δ9-四氢次大麻酚酸,卤代Δ8-四氢次大麻酚酸,卤代次大麻萜酚,卤代次大麻萜酚酸,卤代次大麻环萜酚,卤代次大麻环萜酚酸,卤代次大麻二酚,卤代次大麻二酚酸,卤代二羟基大麻酚,和卤代大麻环酚。
在一些实施方案中,大麻素衍生物选自氘代大麻二酚酸,氘代大麻二酚,氘代Δ9-四氢大麻酚酸,氘代Δ8-四氢大麻酚酸,氘代大麻环萜酚酸,氘代大麻环萜酚,氘代大麻酚,氘代脱氢大麻二酚,氘代大麻酚酸,次大麻酚,氘代次大麻酚酸,氘代Δ9-四氢次大麻酚,氘代Δ8-四氢次大麻酚,氘代Δ9-四氢次大麻酚酸,氘代Δ8-四氢次大麻酚酸,氘代次大麻萜酚,氘代次大麻萜酚酸,氘代次大麻环萜酚,氘代次大麻环萜酚酸,氘代次大麻二酚,氘代次大麻二酚酸,氘代二羟基大麻酚,和氘代大麻环酚。
在一些实施方案中,大麻素衍生物选自氚代大麻二酚酸,氚代大麻二酚,氚代Δ9-四氢大麻酚酸,氚代Δ8-四氢大麻酚酸,氚代大麻环萜酚酸,氚代大麻环萜酚,氚代大麻酚,氚代脱氢大麻二酚,氚代大麻酚酸,次大麻酚,氚代次大麻酚酸,氚代Δ9-四氢次大麻酚,氚代Δ8-四氢次大麻酚,氚代Δ9-四氢次大麻酚酸,氚代Δ8-四氢次大麻酚酸,氚代次大麻萜酚,氚代次大麻萜酚酸,氚代次大麻环萜酚,氚代次大麻环萜酚酸,氚代次大麻二酚,氚代次大麻二酚酸,氚代二羟基大麻酚,和氚代大麻环酚。
在一些实施方案中,大麻素衍生物选自羟基-大麻二酚酸,羟基-大麻二酚,羟基-Δ9-四氢大麻酚酸,羟基-Δ8-四氢大麻酚酸,羟基-大麻环萜酚酸,羟基-大麻环萜酚,羟基-大麻酚,羟基-脱氢大麻二酚,羟基-大麻酚酸,次大麻酚,羟基-次大麻酚酸,羟基-Δ9-四氢次大麻酚,羟基-Δ8-四氢次大麻酚,羟基-Δ9-四氢次大麻酚酸,羟基-Δ8-四氢次大麻酚酸,羟基-次大麻萜酚,羟基-次大麻萜酚酸,羟基-次大麻环萜酚,羟基-次大麻环萜酚酸,羟基-次大麻二酚,羟基-次大麻二酚酸,羟基-二羟基大麻酚,和羟基-大麻环酚。
式I和式Ia的化合物的大麻素衍生物包括但不限于表1中列出的大麻素衍生物。可以将式I和式Ia的化合物酶促(例如,使用大麻素合酶)或化学转化为大麻素衍生物,如下所述。
表1.根据式I和式Ia的化合物的大麻素衍生物
式I和式Ia的化合物的大麻素衍生物包括但不限于CBG,CBDA,CBD,THC,Δ8-THC,THCA,Δ8-THCA,CBCA,CBC,CBN,CBND,CBNA,CBV,CBVA,THCV,THCVA,Δ8-THCA,CBGV,CBGVA,CBCV,CBCVA,CBDV和CBDVA的素衍生物。进一步的实例包括但不限于大麻二氢色原酮类,大麻香豆酮,大麻二吡喃环烷,10-氧代-Δ6a(10a)-四氢大麻酚(OTHC),大麻环醚萜酚和Δ7-异四氢大麻酚。Ⅲ.酶和化学酶法制备大麻素类似物的方法
本文还提供了在工程化宿主细胞中经由代谢途径合成大麻素类似物及其中间体的方法。术语“代谢途径”是指一系列的两个或更多个酶促反应,其中一个酶促反应的产物成为下一个酶促反应的底物。在代谢途径的每个步骤中,形成中间体化合物并将其用作后续步骤的底物。在一些实施方案中,代谢途径的每个步骤发生在本文所述的修饰的重组细胞中。在一些实施方案中,代谢途径的至少一个步骤发生在本文所述的修饰的重组细胞中,并且代谢途径的至少一个步骤发生在修饰的重组细胞之外,酵母培养基中或另外的共培养的修饰的重组细胞内。
因此,本公开的一些实施方案提供了制备根据式IV的化合物及其盐的方法:
其中R1选自由C1-C20卤代烷基,C1-C20羟基烷基,氘代C1-C20烷基,氚代的C1-C10烷基和C2-C20烯基组成的组。
该方法包括在包含式II的硫酯的培养基中培养修饰的重组宿主细胞:
其中R4选自由辅酶A(CoA)部分,泛酰巯基乙胺部分和半胱胺部分组成的组,
其中修饰的重组宿主细胞包含:
i.编码将式II的硫酯和丙二酰CoA转化为式III的四酮化合物的合成酶的第一多核苷酸:
ii.编码将式III的四酮化合物转化为式IV的化合物的2-烷基-4,6-二羟基苯甲酸环化酶的第二多核苷酸,
并且其中修饰的重组宿主细胞在表达第一和第二多核苷酸编码的产物并产生式IV的化合物的条件下培养。
二羟基戊基苯甲酸合酶
在一些实施方案中,合成酶是二羟基戊基苯甲酸合酶。在一些这样的实施方案中,宿主细胞被遗传修饰以表达编码二羟基戊基苯甲酸合酶或其变体(例如天然同源物或直系同源物,或具有聚酮合成酶活性的非天然存在的变体)的外源多核苷酸。二羟基戊基苯甲酸合酶(Taura等人,FEBS Letters 583:2061-2066,2009),也称为3,5,7-三氧代十二烷酰基-CoA合酶,UniProtKB-B1Q2B6,是一种III型PKS,其催化酰基辅酶A与三分子丙二酰-辅酶A的缩合以形成3,5,7-三氧代链烷酰基-辅酶A四酮,如下所示:
其中“CoA”是辅酶A,“R”是烷基。当使用己酸作为天然存在的系统中生产大麻素的原料时,己酰基-CoA与三分子丙二酰基-CoA缩合以形成3,5,7-三氧代十二烷酰基-CoA(即“R”为n-戊基)。III型PKS是直接作用于酰基辅酶A底物的同型二聚酶(与在I型PKS和II型PKS情况下酰基载体蛋白结合的底物相反)。例如,Yu等人(IUBMB Life,64(4):285-295,2012)对III型PKS进行了很好的表征。。
在一些实施方案中,二羟基戊基苯甲酸合酶多核苷酸编码的多肽包含与SEQ IDNO:4所示序列具有约60%或更高同一性的氨基酸序列(例如,约60%,61%,62%,63%,64%,65%,66%,67%,68%,69%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%的同一性)。在一些实施方案中,二羟基戊基苯甲酸合酶多核苷酸编码III型PKS,其包含与SEQ ID NO:4所示的序列具有约70%,75%,80%,85%,90%,95%或更高的同一性的氨基酸序列。
在天然存在的系统中观察到的底物特异性可以扩展到多种具有本文所述的R1基团的原料,例如,C1-C20卤代烷基,C1-C20羟基烷基,氘代的C1-C20烷基,氚代的C1-C20烷基和/或C2-C20烯基。类似地,在本发明的方法中使用的硫酯不限于在天然存在的系统中使用的辅酶A(CoA)酯。R4可以是如下所示的CoA部分,其中波浪线表示CoA部分与式II硫酯中的硫原子的连接点:
可选地,R4可以是泛酰巯基乙胺部分:
或半胱胺部分:
其中,波浪线表示R4与式II的硫酯中的硫原子的连接点,并且其中R4a为H或乙酰基(-C(O)CH3)。式II的硫酯可以如下所述酶促形成或化学制备。
2-烷基-4,6-二羟基苯甲酸环化酶
用于产生式IV的化合物的宿主细胞可以被修饰以表达编码2-烷基-4,6-二羟基苯甲酸环化酶的外源多核苷酸。在一些实施方案中,2-烷基-4,6-二羟基苯甲酸环化酶是类似于来自链霉菌属的DABB型聚酮环化酶的二聚α+β桶状(DABB)蛋白结构域。二羟基戊基苯甲酸环化酶由例如Gagne等人(Proc.Nat.Acad.Sci.USA 109(31):12811-12816;2012)描述。术语“2-烷基-4,6-二羟基苯甲酸环化酶”包括具有环化酶活性的变体,例如截短的或修饰的多肽;以及天然存在的同源物或直系同源物。在一些实施方案中,2-烷基-4,6-二羟基苯甲酸环化酶是来自大麻的二羟基戊基苯甲酸环化酶(EC编号4.4.1.26)。在一些实施方案中,2-烷基-4,6-二羟基苯甲酸环化酶产生divarinic酸(参见,例如,Yang等人,FEBSJ.283:1088-1106,2016)。在一些实施方案中,2-烷基-4,6-二羟基苯甲酸环化酶是来自以下的二羟基戊基苯甲酸环化酶同源物:拟南芥AtHS1(Uniprot Q9LUV2),欧洲山杨SP1(P0A881),拟南芥At5g22580(Q9FK81),S.glaucescens TcmI环化酶(P39890),天蓝色链霉菌(S.coelicolor)ActVA-Orf6(Q53908),雷氏假单胞菌(P.reinekei)MLMI(C5MR76),S.nogalater SnoaB(O54259),结核分枝杆菌Rv0793(O86332)或铜绿假单胞菌PA3566(Q9HY51)。在一些实施方案中,2-烷基-4,6-二羟基苯甲酸环化酶包含来自链霉菌属(例如,链霉菌A2991200)的benastatin基因簇的benH基因产物(B1GSN4)的环化酶结构域,如SEQID NO:9所示。在一些实施方案中,2-烷基-4,6-二羟基苯甲酸的2-烷基含有1-18个碳原子。在一些实施方案中,2-烷基-4,6-二羟基苯甲酸的2-烷基含有1-12个碳原子。在一些实施方案中,2-烷基-4,6-二羟基苯甲酸的2-烷基基团包含1-9个碳原子。
在一些实施方案中,编码2-烷基-4,6-二羟基苯甲酸环化酶的多核苷酸编码与SEQID NO:5、6、7或9中所示的序列具有约60%或更高同一性的多肽(例如,约60%,61%,62%,63%,64%,65%,66%,67%,68%,69%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%的同一性)。在一些实施方案中,该多肽与SEQ ID NO:5、6、7或9所示的序列具有约70%,75%,80%,85%,90%,95%或更高的同一性。
酰基辅酶A合成酶
式II的硫酯可以由宿主细胞酶促形成或在细胞培养之前化学形成。在一些实施方案中,宿主细胞进一步包含编码酰基辅酶A合成酶的第三多核苷酸,该酰基辅酶A合成酶将式IIa的起始材料
转化为式II的硫酯,
且步骤a)包括在第三多核苷酸编码的产物被表达,并产生式II的硫酯的条件下培养宿主细胞。
如本文所用,术语“酰基-CoA合成酶”,其也可以被称为“酰基-CoA合酶”,“酰基活化酶”或“酰基-CoA连接酶”,是一种通过两步的过程将羧酸(例如,式Ila的酸原料)转化为酰基-CoA硫酯的酶,其中伴随着焦磷酸盐(PPi)的释放,羧酸和ATP被转化为酶结合的羧基-AMP中间体(称为腺苷酸)。腺苷酸的活化羰基碳与CoA的硫醇偶联,然后酶释放硫酯和AMP。
可以使用多种酰基-CoA合成酶来形成根据式II的硫酯。酰基辅酶A合成酶包括但不限于短链酰基辅酶A合成酶(EC6.2.1.1),中链酰基辅酶A合成酶(EC6.2.1.2),长链酰基辅酶A合成酶(EC6.2.1.3)和香豆酸-CoA连接酶(EC6.2.1.12)。酰基辅酶A合成酶通常包含称为AMP结合基序的12-氨基酸残基结构域(PROSITE PS00455):[LIVMFY]-{E}-{VES}-[STG]-[STAG]-G-[ST]-[STEI]-[SG]-x-[PA SLIVM]-[KR]。在PROSITE序列中,序列中的每个位置均由“-”分隔,符号“x”表示在序列中的给定位置处接受任何残基。给定位置的可接受氨基酸置于方括号中(例如,[ST]表示在序列中的给定位置处丝氨酸或苏氨酸是可接受的),而在给定位置处不能接受的氨基酸置于大括号中(例如,{VES}表示除缬氨酸,谷氨酸和丝氨酸外的任何残基在序列中的该给定位置可接受)。AMP结合基序已用于将多肽分类为酰基活化酶(AAE),并有助于鉴定拟南芥(Shockey等,2003,Plant Physiology 132:1065-1076),莱茵衣藻(Chlamydomon as reinhardtii),毛果杨(Populus trichocharpa)和小立碗藓(Shockey和Browse,2011,The Plant Journal 66:143-160)中存在的大AAE基因超家族。酰基-CoA合成酶也描述于,例如,WO2018/209143;Black等(Biochim BiophysActa.1771(3):286-98,2007);Miyazawa等人(J.Biol.Chem 290(45):26994-27011,2015);以及Stout等人(PlantJ.71(3):353-365,2012)中。
在一些实施方案中,酰基-CoA合成酶来自生物合成白藜芦醇的生物体。在一些实施方案中,酰基-CoA合成酶是来自桑属或葡萄属的香豆酸-CoA连接酶。在一些实施方案中,酰基辅酶A合成酶来自青枯雷尔氏菌。在一些实施方案中,来自青枯雷尔氏菌的酰基-CoA合成酶在N-末端缺失,参见例如SEQ ID NO:8。在一些实施方案中,跨膜结构域可以从酰基-CoA合成酶中删除。
在一些实施方案中,宿主细胞被遗传修饰以表达编码来自链霉菌属的revS多肽(参见,例如,Miyazawa等人,J.Biol.Chem.290:26994-27001,2015),或其变体的外源多核苷酸,例如具有酰基-CoA合成酶活性的天然同源物,直系同源物或非天然存在的变体。在一些实施方案中,多核苷酸编码与SEQ ID NO:1所示序列具有约60%或更高同一性的多肽(例如,约60%,61%,62%,63%,64%,65%,66%,67%,68%,69%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%同一性)。在一些实施方案中,多核苷酸编码RevS多肽,其与SEQ ID NO:1所示的序列具有约70%,75%,80%,85%,90%,95%或更高的同一性。在一些实施方案中,与SEQ ID NO:1相比,例如在AMP结合基序或催化位点之外的区域中,非天然存在的变体包含一个或多个修饰,例如置换,例如保守置换。
在一些实施方案中,对宿主细胞进行遗传修饰以表达编码来自大麻的酰基活化酶(CsAAE3)或其变体的外源多核苷酸,例如具有酰基-CoA合成酶活性的天然同源物,直系同源物或非天然存在的变体。在一些实施方案中,由多核苷酸编码的CsAAE3多肽包含的氨基酸序列与SEQ ID NO:2所示的序列具有至少约60%或更高同一性(例如,约60%,61%,62%,63%,64%,65%,66%,67%,68%,69%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%,或100%同一性)。在一些实施方案中,酰基辅酶A合成酶多核苷酸编码CsAAE3,或其同源物或非天然存在的变体,其包含与SEQ ID NO:2所示的序列具有约70%,75%,80%,85%,90%,95%或更高的同一性的氨基酸序列。在一些实施方案中,与SEQ ID NO:2相比,例如在AMP结合基序或催化位点之外的区域中,非天然存在的变体包含一个或多个修饰,例如置换,例如保守置换。
在一些实施方案中,宿主细胞被遗传修饰以表达编码来自大麻的酰基活化酶(CsAAE1)或其变体的外源多核苷酸,例如具有酰基-CoA合成酶活性的天然同源物,直系同源物或非天然存在的变体。在一些实施方案中,由多核苷酸编码的CsAAEl多肽包含的氨基酸序列与SEQ ID NO:3所示的序列具有至少约60%或更高同一性(例如,约60%,61%,62%,63%,64%,65%,66%,67%,68%,69%,70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%,或100%的同一性)。在一些实施方案中,酰基-CoA合成酶多核苷酸编码CsAAE1或其同源物,其包含与SEQ ID NO:3所示的序列具有约70%,75%,80%,85%,90%,95%或更高同一性的氨基酸序列。在一些实施方案中,CsAAE1多核苷酸编码从中删除跨膜结构域的多肽。在一些实施方案中,与SEQ ID NO:3相比,例如在AMP结合基序或催化位点之外的区域中,非天然存在的变体包含一个或多个修饰,例如置换,例如保守置换。
在一些实施方案中,R1选自4-氟丁酸;4,4,4-三氟丁酸;2,2-二氟丁酸;全氟丁酸;5-氟戊酸;2,2-二氟戊酸;全氟戊酸;6-氟己酸;2,2-二氟己酸;和全氟己酸。
在一些实施方案中,式IIa的起始材料中的R1选自4-氟丁酸,5-氟戊酸和6-氟己酸。
在一些实施方案中,R1选自4-氯丁酸,4-溴丁酸,4-羟基丁酸,5-氯戊酸,5-溴戊酸,5-羟基戊酸,6-氯己酸,6-溴己酸,6-羟基己酸,7-氯庚酸,7-溴庚酸和7-羟基庚酸。在一些实施方案中,R1是全氘代己酸(即,D11C5COOH)。
化学硫酯合成
式II的硫酯可以含有CoA R4部分,泛酰巯基乙胺R4部分或半胱胺R4部分。可以使用如上所述由宿主细胞表达的酰基-CoA合成酶酶促地制备式II的硫酯,或者可以通过用式Ila所示羧酸或其活化衍生物化学酰化CoA,泛酰巯基乙胺(即2,4-二羟基-3,3-二甲基-N-[2-(2-硫烷基乙基氨基甲酰基)乙基]丁酰胺)或半胱胺(即2-氨基乙硫醇)来合成硫酯。
许多合适的羧酸是可商购的,或者可以根据已知方法制备,包括Fiesers’Reagents for Organic Synthesis 1-28卷(John Wiley&Sons,2016),March(AdvancedOrganic Chemistry 6th Ed.John Wiley&Sons,2007)和Larock(Comprehensive OrganicTransformations 3rd Ed.John Wiley&Sons,2018)中描述的那些。作为非限制性实例,可以在Hell-Volhard-Zelinsky反应中使用卤素(例如,Br2)和催化性磷来制备α-卤代羧酸。作为另一个非限制性实例,可以使用-SELECTFLETOR(氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷双(四氟硼酸酯))和含有铜(I)双亚胺复合物的催化剂体系(如Bloom等人(Angew.Chem.Int.Ed.2012,51,1-5)所述来制备氟代羧酸。可以根据Kao和Sen(J.Chem.Soc.,Chem.Commun.,1991,1242-1243)的方法,使用铂催化剂进行羧酸的羟基化。根据Yamada等人的方法(RSC Adv.,2015,5,13727-13732),可以使用铂碳和铑碳进行羧酸的氘代。
可以将式IIa的羧酸与偶联剂结合使用,以将要酰化的硫醇(例如,CoA,泛酰巯基乙胺或半胱胺)酰化。偶联剂包括例如碳二亚胺类(例如,N,N′-二环己基碳二亚胺(DCC),N,N-二环戊基碳二亚胺,N,N′-二异丙基碳二亚胺(DIC),1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)等),鏻盐(HOBt,PyBOP,HOAt等),铵/脲盐(例如,嘧啶脲盐如HATU,四甲基铵盐,双吡咯烷铵盐,双哌啶铵盐,咪唑鎓脲盐,衍生自N,N,N-三甲基-N’-苯基脲的脲盐,基于吗啉的铵/脲偶联剂,锑酸脲盐等),有机磷试剂(例如次膦酸和磷酸衍生物),有机硫试剂(例如磺酸衍生物),三嗪偶联剂(例如2-氯-4,6-二甲氧基-1,3,5-三嗪,4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4甲基吗啉氯化物,4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉四氟硼酸盐等),吡啶偶联剂(例如Mukaiyama试剂,四氟硼酸吡啶偶联剂等),聚合物支持的试剂(例如,聚合物结合的碳二亚胺,聚合物结合的TBTU,聚合物结合的2,4,6-三氯-1,3,5-三嗪,聚合物-结合的HOBt,聚合物结合的HOSu,聚合物结合的IIDQ,聚合物结合的EEDQ等),等等。
可选地,可以使用活化的羧酸衍生物,例如酸酐,混合酸酐,酰氯或活化的酯(例如,五氟苯基酯或N-羟基琥珀酰亚胺酯)进行酰化。通常,相对于硫醇,将使用1-10摩尔当量的羧酸或活化的衍生物。例如,可以使用1-5摩尔当量的酸/酸衍生物或1-2摩尔当量的酸/酸衍生物。在一些实施方案中,相对于硫醇,约1.0、1.1、1.2、1.3、1.4或1.5摩尔当量的酸/酸衍生物用于形成式II的硫酯。
碱可用于促进羧酸或活化的羧酸衍生物对硫醇的酰化。合适的碱的实例包括碳酸钾,碳酸钠,乙酸钠,Huenig氏碱(即,N,N-二异丙基乙胺),包括2,6-卢剔啶(即,2,6-二甲基吡啶)的卢剔啶类,三乙胺,三丁胺,吡啶,2,6-二-叔-丁基吡啶,1,8-二氮杂双环十一烷-7-烯(DBU),奎宁环和可力丁类。可以使用两种或更多种碱基的组合。通常,相对于硫醇,少于一摩尔当量的碱将用于形成硫酯。例如,可以使用0.05-0.9摩尔当量或0.1-0.5摩尔当量的碱。在一些实施方案中,相对于硫醇,约0.05、0.1、0.15或0.2摩尔当量的碱与酸/酸衍生物结合使用以形成式II的硫酯。
任何合适的溶剂可用于形成硫酯。合适的溶剂包括但不限于甲苯,二氯甲烷,乙酸乙酯,乙腈,四氢呋喃,苯,氯仿,乙醚,二甲基甲酰胺,二甲基亚砜,石油醚及其混合物。酰化反应通常在约25℃至约100℃的温度下进行足以形成式II的硫酯的一段时间。反应可以进行几分钟到几小时或更长的时间,这取决于反应中使用的特定硫醇和酸/酸衍生物。例如,该反应可以在约40℃,或约50℃,或约60℃,或约70℃,或约80℃下进行约10分钟,或约30分钟,或约1小时,或约2小时,或约4小时,或约8小时,或约12小时。
可以保护诸如半胱胺的伯胺或泛酰巯基乙胺和CoA的羟基的官能团,以防止在酰化步骤中发生不希望的副反应。胺保护基的实例包括但不限于苄氧基羰基;9-芴基甲氧羰基(Fmoc);叔丁氧羰基(Boc);烯丙氧羰基(Alloc);对甲苯磺酰基(Tos);2,2,5,7,8-五甲基色满-6-磺酰基(Pmc);2,2,4,6,7-五甲基-2,3-二氢苯并呋喃-5-磺酰基(Pbf);均三甲苯基-2-磺酰基(Mts);4-甲氧基-2,3,6-三甲基苯基磺酰基(Mtr);乙酰氨基;邻苯二甲酰亚胺基;等等。羟基保护基的实例包括但不限于苄基;叔丁基;三苯甲基;叔丁基二甲基甲硅烷基(TBDMS;TBS);4,5-二甲氧基-2-硝基苄氧基羰基(Dmnb);炔丙氧基羰基(Poc);等等。其他醇保护基和胺保护基是本领域技术人员已知的,包括例如Green和Wuts(Protective Groupsin Organic Synthesis,4th Ed.2007,Wiley-Interscience,NewYork)所述的那些。可以使用标准条件除去保护基,以便在酰化步骤之后恢复原始的官能团。
异戊二烯基转移酶
在一些实施方案中,重组宿主细胞被进一步修饰以表达编码编码异戊二烯基转移酶的外源多核苷酸,该异戊二烯基转移酶催化活化的异戊二烯基物质(例如,香叶基焦磷酸)与式IV的化合物或式IVa的化合物的偶联,从而形成式IV和式Va的化合物。异戊二烯基转移酶的实例包括但不限于,如Fellermeier&Zenk(FEBS Letters 427:283-285;1998)所述的香叶基焦磷酸:二羟基戊基苯甲酸香叶基转移酶(GOT;EC2.5.1.102),以及WO2018/200888和WO2019/071000中所述的大麻异戊二烯基转移酶。如Kumano等人(Bioorg MedChem.
16(17):8117-8126;2008)所述的链霉菌异戊二烯基转移酶(包括NphB)也可以根据本发明使用。在一些实施方案中,异戊二烯基转移酶是来自肉桂地链霉菌的fnq26:flaviolin linalyltransferase。在一些实施方案中,经遗传修饰以表达异戊二烯基转移酶的宿主细胞可以是如下所述的修饰的宿主细胞。
因此,本公开的一些实施方案提供了包括将如上所述的式IV的化合物转化为式V的化合物或其盐的方法:
其中R3是异戊二烯基部分。R3可以是例如含有顺式(Z)构型和/或反式(E)构型的碳-碳双键的香叶基,法呢基或香叶基香叶基。一些实施方案提供了包括转化式IVa的脱羧化合物为式Va的化合物的方法:
其中R3是异戊二烯基部分。
在一些实施方案中,用于香叶基焦磷酸:二羟基戊基苯甲酸香叶基转移酶的DNA构建体编码野生型或具有酵母优选密码子的突变酶。在一些实施方案中,使用编码具有松弛底物特异性的细菌异戊二烯基转移酶(例如,链霉菌异戊二烯基转移酶)的DNA构建体(Kumano等,2008)。
外源异戊二烯基物质,例如香叶醇,可以在培养和异戊二烯基化的化合物的产生过程中提供给宿主细胞。可选地,可以在含有高水平异戊二烯前体的培养基中培养宿主细胞,所述异戊二烯前体例如异戊烯醇,异戊二烯醇,香叶醇等。在包括多前体进料(MPF)的程序中,可以将5-碳的异戊烯醇和异戊二烯醇酶促转化为单磷酸水平(即转化为二甲基烯丙基单磷酸和异戊烯基单磷酸),然后再转化为二磷酸水平(即转化为二甲基烯丙基焦磷酸和异戊烯基焦磷酸),然后偶联以形成10-碳香叶基焦磷酸。
在一些实施方案中,初始磷酸化事件是由羟乙基噻唑激酶催化的。已经在得到编码基因的几种生物体中描述了这种酶,包括大肠杆菌,枯草芽孢杆菌,豆科根瘤菌,霍氏热球菌,酿酒酵母和玉米物种。可以通过使用美国专利No.6235514中所述的异戊二烯基二磷酸合酶或异戊烯基磷酸激酶进一步磷酸化为二磷酸水平。在一些实施方案中,通过使用嗜酸热原体,热自养甲烷热杆菌,Methano-caldococcus jannaschii,胡椒薄荷(Mentha xpiperita)或芒果(Mangifera indica)氨基酸序列或具有激酶活性的其他同源序列,得到编码该酶或更高活性的突变体的化学合成基因。可以通过转移酶,例如香叶基焦磷酸合酶(GPP合酶)来催化与香叶基焦磷酸的偶联。
10-碳香叶基焦磷酸也可以由将香叶醇磷酸化为单磷酸水平的激酶来产生,随后是产生香叶基焦磷酸的第二激酶。在一些实施方案中,第一激酶事件由法呢醇激酶(FOLK)(Fitzpatrick,Bhandari和Crowell,2011;Plant J.2011Jun;66(6):1078-88)或其变体进行。这种激酶存在于许多具有磷酸化5-碳异戊烯醇的能力的生物体中,包括植物(拟南芥,亚麻荠,荠菜(Capsella rubella),Noccaea caerulescens等)和真菌(白色念珠菌,踝节菌等)。通过使用异戊烯基单磷酸激酶(IPK)或其变体,可以将香叶磷酸进一步磷酸化至香叶基焦磷酸水平。在许多细菌和古细菌物种中发现了该激酶,包括但不限于Methanocaldococcus jannaschii和嗜酸热原体。据报道,IPK中的某些突变(Val73,Val130,Ile140)引起增强的香叶基磷酸激酶活性(Mabanglo等人,2012,ACS Chem.Biol.,7,7,1241-1246)。
在一些实施方案中,宿主细胞包含一种或多种选自以下三个外源多核苷酸的另外的外源多核苷酸:编码异戊烯醇和异戊二烯醇激酶的外源多核苷酸;以及编码激酶的外源性多核苷酸,所述激酶在外源性异戊烯醇和异戊二烯醇存在下生长时产生二甲基烯丙基焦磷酸和异戊烯基焦磷酸;以及编码香叶基焦磷酸合酶的外源多核苷酸。
化学异戊烯化
在一些实施方案中,转化步骤在体外进行。例如,转化步骤可包括在足以产生式V或式Va化合物的条件下形成反应混合物,该反应混合物包含1)式IV或式IVa的化合物,2)香叶醇,活化的香叶醇(例如,香叶基溴,香叶基氯,香叶基甲苯磺酸,香叶基甲磺酸,等),或柠檬醛;和2)有机溶剂。
任何合适的有机溶剂可用于本文提供的化学异戊烯化步骤中。合适的溶剂包括但不限于甲苯,二氯甲烷,二氯乙烷,乙酸乙酯,乙腈,四氢呋喃,苯,乙苯,二甲苯类(即间二甲苯,邻二甲苯,对二甲苯或其任何组合),氯仿,乙醚,二甲基甲酰胺,二甲基亚砜,石油醚及其混合物。在一些实施方案中,有机溶剂是甲苯,苯,乙苯,二甲苯或其混合物。在一些实施方案中,有机溶剂是甲苯。在一些实施方案中,有机溶剂是二氯乙烷。也可以使用水性有机溶剂混合物(即水和与水混溶的有机溶剂如四氢呋喃或二甲基甲酰胺的混合物)。通常,溶剂与式IV或式IVa的化合物的比例按重量计将在约1:1至约1000:1的范围内。溶剂与式IV或式IVa的化合物的比例按重量计可以为例如约100:1,或按重量计约10:1,或按重量计约5:1。在某些实施方案中,式IV或式IVa的化合物存在于酵母混合物(例如干燥的酵母细胞或从培养物收集的湿酵母细胞沉淀)中。在一些这样的实施方案中,反应混合物包含宿主细胞(例如,干燥的酵母细胞)。溶剂与酵母混合物(例如,干燥的酵母细胞)的比例按重量计可以在约1:1至约1000:1的范围内。溶剂与酵母混合物的比例可以是例如按重量计约100:1,或按重量计约10:1,或按重量计约5:1,或按重量计约2:1。
在转化步骤中可以使用任何合适量的香叶醇,活化的香叶醇或柠檬醛。通常,相对于式IV或式IVa的化合物,反应混合物包含至少一个摩尔当量的香叶醇,活化的香叶醇或柠檬醛。相对于式IV或式IVa的化合物,反应混合物可包含例如约1摩尔当量至约10摩尔当量的香叶醇,活化的香叶醇或柠檬醛(例如约1.1摩尔当量或约1.2摩尔当量,或约2摩尔当量)。
在一些实施方案中,包括使用香叶醇或活化的香叶醇的实施方案,反应混合物还包含酸。在转化步骤中可以使用任何合适的酸。合适的酸的实例包括但不限于盐酸,硫酸,硝酸,甲酸,乙酸,三氟乙酸,对甲苯磺酸,甲磺酸和三氟甲磺酸。在一些实施方案中,该酸是磺酸。在一些实施方案中,酸是对甲苯磺酸。在转化步骤中可以使用任何合适量的酸。通常,相对于式IV或式IVa的化合物,反应混合物包含约0.01摩尔当量的酸(例如对甲苯磺酸)至约10摩尔当量的酸(例如,约0.01摩尔当量,或约0.1摩尔当量,或约1摩尔当量)。
在一些实施方式中,包括使用柠檬醛的实施方式,反应混合物还包含胺,例如二胺(例如1,2-二胺)。在转化步骤中可以使用任何合适的二胺或其他胺。合适的二胺的实例包括但不限于乙二胺,N,N-二甲基乙二胺,N,N-二乙基乙二胺,N,N’-二甲基乙二胺,N,N'-二苯基乙二胺,N,N'-二苄基乙二胺和N,N′-双(2-羟乙基)乙二胺。在一些实施方案中,异戊烯化反应混合物包括柠檬醛和N,N-二甲基乙二胺。在转化步骤中可以使用任何合适量的胺。通常,相对于式IV或式IVa的化合物,反应混合物包含约0.01摩尔当量的胺(例如,N,N-二甲基乙二胺)至约10摩尔当量的胺(例如,约0.01摩尔当量,或约0.25摩尔当量,或约0.1摩尔当量,或约1摩尔当量)。
在一些实施方案中,手性二胺(例如,(1S,2S)-1,2-二-1-萘基-乙二胺,(S)-1-[(1-甲基-2-吡咯烷基)甲基]哌啶等)可有助于在异戊烯化大麻素产物中形成一个或多个立体中心。例如,在手性二胺存在下,二羟基戊基苯甲酸类似物(例如,全氘代戊基-二羟基戊基苯甲酸)与柠檬醛的反应可得到相应的立体选择性的大麻环萜酚类似物。可以选择手性二胺以产生特定的大麻环萜酚类似物对映体(例如,(S)-2-甲基-2-(4-甲基戊-3-烯-1-基)-7-全氘代戊基-2H-色烯-5-醇或(R)-2-甲基-2-(4-甲基戊-3-烯-1-基)-7-全氘代戊基-2H-色烯-5-醇)。手性二胺也可用于本文所述的R1位具有未取代烷基的大麻素的立体选择性合成中。在一些实施方案中,例如,R1可以是C1-C10烷基,并且形成异戊烯化大麻素产物可以包括在手性二胺的存在下,使5-烷基-间苯二酚(例如橄榄酚或divarinol,即5-丙基间苯二酚)或2-烷基-4,6-二羟基苯甲酸(例如二羟基戊基苯甲酸或divarinic酸)与柠檬醛反应以手性选择性的方式形成异戊烯化产物(例如,大麻环萜酚,大麻环萜酚酸或其类似物)。可选地,可以制备对映异构体的混合物(例如外消旋混合物),并且可以通过手性色谱法或选择性结晶分离所需的对映异构体。
可以在任何合适的温度下进行化学异戊烯化转化步骤。通常,转化步骤在约20℃至约200℃,例如约20℃至约100℃,或约20℃至约80℃,或约20℃至约70℃的温度下进行。转化步骤进行足以将未异戊烯化的化合物转化为异戊烯化产物的时间。取决于诸如所使用的特定异戊二烯基化合物,所使用的特定溶剂以及未异戊烯化的化合物的状态(例如,存在于酵母混合物中)的因素,转化时间将在几分钟至几小时的范围内。在一些实施方案中,将反应混合物维持在约20℃至约100℃(例如,约60℃)的温度下约5分钟至约360分钟的时间。在一些实施方案中,将反应混合物在60℃或约60℃下保持60分钟或更短(例如,约55分钟或约30分钟或约15分钟或约10分钟)。在一些实施方案中,将反应混合物在20℃至25℃之间(例如,约23℃)保持1小时或更长时间(例如约60分钟,或约2小时,或约4小时,或约12小时,或约18小时,或约24小时)。
宿主细胞
在一些实施方案中,如上所述的,修饰宿主细胞以表达编码酰基-CoA合成酶例如revS多肽,CsAAE3或CsAAE1多肽的外源多核苷酸;编码二羟基戊基苯甲酸合酶的外源多核苷酸;和/或编码2-烷基-4,6-二羟基苯甲酸环化酶(例如,二羟基戊基苯甲酸环化酶,包括在氨基末端,羧基末端或两个末端被截短的二羟基戊基苯甲酸环化酶的实施方案)的外源多核苷酸。
可以使用任何方法将多核苷酸引入宿主细胞。在一些实施方案中,编码如本文所述的两种或更多种酶,例如酰基-CoA合成酶,二羟基戊基苯甲酸合酶如revS或CsAAE3,和2-烷基-4,6-二羟基苯甲酸环化酶(例如,二羟基戊基苯甲酸环化酶或其工程化突变体)中的两种的外源多核苷酸存在于相同的表达构建体中,例如自主复制表达载体,并表达为多顺反子RNA,其中表达由相同启动子驱动。因此,例如,在一些实施方案中,编码二羟基戊基苯甲酸合酶的外源多核苷酸和编码2-烷基-4,6-二羟基苯甲酸环化酶(例如,二羟基戊基苯甲酸环化酶)的外源多核苷酸包含在相同表达构建体中,例如,自主复制的表达载体,并且被内部核糖体进入位点(IRES)隔开,这种表达由相同的启动子驱动以产生比顺反子mRNA。在一些实施方案中,启动子是醇脱氢酶-2启动子。在一些实施方案中,外源多核苷酸存在于相同的表达构建体中,例如,自主复制的表达载体,并且可操作地连接至单独的启动子。在一些实施方案中,外源多核苷酸存在于两个或更多个表达构建体中,例如,自主复制的表达载体。在一些实施方案中,自主复制表达载体是酵母人工染色体。在一些实施方案中,一种或多种外源多核苷酸整合到宿主基因组中。在某些实施例中,通过逆转录转座子整合将多个外源多核苷酸引入宿主细胞。
在一些实施方案中,使用在宿主细胞内表达的式IV或式IVa的化合物产生大麻素化合物,并且进一步修饰宿主细胞以表达异戊二烯基转移酶;异戊烯醇和异戊二烯醇激酶;当在外源异戊烯醇和异戊二烯醇存在下生长时产生二甲基烯丙基焦磷酸和异戊烯基焦磷酸的激酶;或编码如本文所述的香叶基焦磷酸合酶的多核苷酸。此类多核苷酸可如前段所述包含在相同或单独的表达载体中。
在一些实施方案中,修饰的重组宿主细胞还包含编码大麻素合酶的外源多核苷酸,该酶催化在宿主细胞中产生的第一大麻素化合物中间体的转化以形成第二大麻素化合物。
在一些实施方案中,宿主细胞是酵母或丝状真菌宿主细胞,例如曲霉属宿主细胞。可以用作宿主细胞的酵母属包括但不限于酿酒酵母,裂殖酵母,念珠菌,汉逊酵母,毕赤酵母,克鲁维酵母,耶氏酵母属和法夫酵母属的细胞。合适的酵母物种包括但不限于酿酒酵母,粟酒裂殖酵母,白色念珠菌,多形汉逊酵母,巴斯德毕赤酵母,加拿大毕赤酵母,马克斯克鲁维酵母,乳酸克鲁维酵母,红法夫酵母和解脂耶氏酵母。可用作宿主细胞的丝状真菌属包括但不限于:支顶孢属,曲霉属,短梗霉属,黑管菌属,拟蜡菌属,金孢属,鬼伞属,革盖菌属,棒囊壳属,毛壳菌属,隐球菌属,线黑粉酵母属(Filobasidium),镰刀菌属,赤霉属,腐质霉属,梨孢菌属,毛霉属,毁丝霉属,毛霉菌,新考玛脂霉属,脉孢霉属,拟青霉属,青霉属,原毛平革菌,白腐菌属,梨囊鞭菌属,侧耳属,柱顶孢属,裂褶菌属,孢子丝菌属,篮状菌属,嗜热子囊菌属,梭孢壳菌属,弯颈霉属,栓菌属和木霉属。丝状真菌种类的示例性物种包括泡盛曲霉,烟曲霉,臭曲霉,日本曲霉,构巢曲霉,黑曲霉,米曲霉,Chrysosporiumlucknowense,杆孢状镰孢(Fusarium bactridioides),禾谷镰孢,Fusariumcrookwellense,黄色镰刀菌,禾谷镰刀菌,禾赤镰孢菌(Fusarium graminum),异孢镰孢菌,合欢木镰孢,尖孢镰刀菌,多枝镰孢,粉红色镰刀菌,接骨木镰刀,肤色镰孢,拟枝孢镰孢菌,硫色镰刀菌,圆镰孢(Fusarium torulosum),拟丝孢镰刀,镶片镰孢(Fusariumvenenatum),烟管菌,干拟蜡菌,干拟蜡菌,虫拟蜡菌,Ceriporiopsis gilvescens,Ceriporiopsis pannocinta,Ceriporiopsis rivulosa,微红拟蜡菌,虫拟蜡菌(Ceriporiopsis subvermispora),灰盖鬼伞菌,毛云芝菌,特异腐质霉,柔毛腐质霉,米赫毛霉,嗜热毁丝霉,粗糙链孢霉,间型脉孢菌,产紫青霉菌,变灰青霉菌,Penicilliumsolitum,绳状青霉菌,黄孢原毛平革菌,Phlebia radiate,杏鲍菇,黄蓝状菌,太瑞斯梭孢壳霉,长绒毛栓菌,变色栓菌(Trametes versicolor),哈茨木霉,康宁木霉,长梗木霉,里氏木霉,和绿色木霉菌。
在一些实施方案中,宿主细胞选自由以下组成的组:酿酒酵母,乳酸克鲁维酵母,马克斯克鲁维酵母,巴斯德毕赤酵母,解脂耶氏酵母,多形汉逊酵母和曲霉。
在以上实施方案中,基因可以由化学合成的基因编码,并具有酵母密码子优化,其编码来自大麻,拟南芥或假单胞菌属的野生型或突变体酶。
用于驱动啤酒酵母和其他酵母中的基因转录的启动子在本领域中是众所周知的,并且包括受生长培养基中葡萄糖浓度调节的DNA元件,例如醇脱氢酶2(ADH2)启动子。当需要条件表达时,使用其他调节型启动子或诱导型启动子,例如那些驱动GAL1,MET25和CUP1基因表达的启动子。GAL1和CUP1分别由半乳糖和铜诱导,而MET25由不存在蛋氨酸诱导。
在一些实施方案中,一个或多个外源多核苷酸可操作地连接至葡萄糖调节的启动子。在一些实施方案中,一种或多种外源多核苷酸的表达由醇脱氢酶-2启动子驱动。
其他启动子以组成型方式强烈驱动转录。此类启动子包括但不限于高表达酵母糖酵解酶类的控制元件,例如甘油醛-3-磷酸脱氢酶(GPD),磷酸甘油酸激酶(PGK),丙酮酸激酶(PYK),磷酸丙糖异构酶(TPI),烯醇酶(EN02)和醇脱氢酶-1(ADH1)。可以使用的其他强组成型启动子是来自酿酒酵母转录延伸因子EF-1α基因(TEF1和TEF2)(Partow et al.,Yeast.2010,(11):955-64;Peng et al.,Microb Cell Fact.2015,(14):91-102),以及在酿酒酵母diauxic shift后低糖条件下表现良好的高亲和力葡萄糖转运蛋白(HXT7)和伴侣蛋白(SSA1)启动子(Peng et al.,Microb Cell Fact.2015,(14):91-102)的那些。
在其他实施方案中,宿主细胞可以通过增加前体池等来增加大麻素的产生。用于如具有丙二酸进料的丙二酰-CoA合成酶(Mutka et al.,FEMS Yeast Res.2006),以及乙酰辅酶A羧化酶1和2的异源的天然或化学合成的基因上调对PKS生物合成重要的丙二酰-CoA。类似地,乙酰辅酶A合成酶-1和-2以及甲羟戊酸途径中的其他基因产物,例如乙酰乙酰辅酶A硫解酶或来自链霉菌属的NphT7基因产物(Okamura et al.,Proc Natl Acad SciUSA.2010),HMG-CoA合酶,来自酵母菌或其他真核生物种的甲羟戊酸激酶,磷酸甲羟戊酸激酶,甲羟戊酸二磷酸脱羧酶,异戊烯基二磷酸:二甲基烯丙基二磷酸异构酶,HMG-CoA还原酶,突变法呢基-焦磷酸合酶(ERG20;Zhao et al.,2016)也可以使用本领域技术人员熟知的方法引入高水平表达质粒载体或通过基因组整合引入。此类方法可涉及CRISPR Cas-9技术,酵母人工染色体(YAC)或逆转录转座子的使用。或者,如果是宿主生物天然的,则可以通过本领域技术人员已知的遗传元件整合方法来上调此类基因。
在再其他方面,可以采用类似的工程化来减少天然产物的产生,例如利用碳源的乙醇,这导致用于大麻素产生的碳源利用减少。这样的基因可以通过缺失而完全“敲除”出基因组,或者可以通过降低启动子强度等来降低活性。这样的基因包括酶ADH1和/或ADH6的那些。其他基因“敲除”包括涉及麦角固醇途径的基因,例如ERG9,和酵母的两个最突出的芳香族脱羧酶基因,PAD1和FDC1。
进一步的实施方案包括旨在辅助终产物大麻素产生的辅助酶的基因。一种这样的酶,过氧化氢酶,能够中和由参与CBGA和类似物氧化环化的酶产生的过氧化氢,诸如大麻二酚酸合成酶(Taura et al.,2007,FEBS Lett 581:2929–2934),Δ9-四氢大麻酚酸合酶(Sirikantaramas et al.,2004,J.Biol.Chem.,279:39767-39774)和大麻环萜酚酸合酶(Morimoto et al.,1998,Phytochemistry 49:1525-1529)。
在进一步的实施方案中,工程化的宿主细胞包含上调或下调的内源或异源基因,以优化例如用于大麻素生物合成的前体池。另外,可以表达其他异源基因产物以在细胞内提供“辅助”功能。例如,可以表达过表达的过氧化氢酶以将在氧化环化步骤中形成的过氧化氢中和为重要的酸性大麻素,例如CBDA,Δ9-THCA和CBCA。“辅助”基因及其表达的产物可以通过本领域众所周知的技术整合到酵母基因组中来提供,或者可以从质粒(也称为酵母表达载体),酵母人工染色体(YACs)或酵母转座子表达。
在一些实施方案中,将用含有上述每个基因的质粒或载体转化或基因组整合的宿主细胞,例如酵母菌株,与另一个表达系统一起转化,以将CBGA或CBGA类似物转化为第二酸性大麻素,如下所述。在一些这样的实施方案中,表达系统在相同载体上或在分开的载体上,或整合到宿主细胞基因组中。
可以通过基因组整合或使用游离质粒(也称为表达载体或简称载体)而用编码参与工程化代谢途径的酶的至少一种核苷酸序列转化宿主细胞来制备本发明的产生大麻素的工程化细胞。如本文所用,术语“核苷酸序列”,“核酸序列”和“遗传构建体”可互换使用,是指单链或双链RNA或DNA的聚合物,任选地包含合成的,非天然的或改变的核苷酸碱基。核苷酸序列可包含cDNA,基因组DNA,合成DNA或RNA的一个或多个区段。在一些实施方案中,对核苷酸序列进行密码子优化以反映宿主细胞的典型密码子使用,而不改变由核苷酸序列编码的多肽。在某些实施方案中,术语“密码子优化”或“密码子优化的”是指改变核酸序列的密码子内容而不改变该核酸编码的多肽的序列以增强在特定宿主细胞中的表达。在某些实施方案中,该术语旨在涵盖改变核酸序列的密码子内容作为控制多肽表达水平的手段(例如,增加或降低表达水平)。因此,描述了编码参与工程化代谢途径的酶的核酸序列。在一些实施方案中,代谢工程化的细胞可以表达一种或多种具有执行下述步骤所必需的酶活性的多肽。在一些实施方案中,根据美国专利号7,561,972中描述的方法,合成核苷酸序列并对其进行密码子优化以在酵母中表达。
例如,特定细胞可以包含1、2、3、4、5或超过5种核酸序列,每一个编码产生本文所述的大麻素化合物或大麻素化合物中间体所必需的多肽。或者,单个核酸分子可编码一种或多于一种的多肽。例如,单个核酸分子可包含编码两个,三个,四个或甚至五个不同多肽的核酸序列。可用于本文所述的本发明的核酸序列可从多种来源获得,例如cDNA序列的扩增,DNA文库,从头合成,基因组片段的切除。然后可以使用标准分子生物学和/或重组DNA技术修饰从此类来源获得的序列,以产生具有所需修饰的核酸序列。修饰核酸序列的示例性方法包括例如位点定向诱变,PCR诱变,缺失,插入,置换,使用限制酶交换序列的部分,任选地与连接,同源重组,定点重组或其各种组合结合。在其他实施方案中,核酸序列可以是合成的核酸序列。合成的多核苷酸序列可以使用美国专利号7,323,320,以及美国专利申请公开号2006/0160138和2007/0269870中描述的多种方法产生。酵母细胞的转化方法是本领域众所周知的。
发酵条件
根据本文提供的方法的大麻素生产通常包括培养已被工程化以包含上述表达系统的宿主细胞(例如酵母或丝状真菌)。在一些实施方案中,用于酵母生长的碳源是糖,例如葡萄糖,右旋糖,木糖,或其他可持续的原料糖,例如衍生自纤维素来源的那些。在其他实施方案中,使用的碳源可以是甲醇,甘油,乙醇或乙酸盐。在一些实施方案中,通过实验优化原料组成以提供最佳的酵母生长和最终的大麻素生产水平,如使用分析技术如HPLC所测量的。在这样的实施方案中,方法包括利用葡萄糖/乙醇或葡萄糖/乙酸盐混合物,其中葡萄糖与2-碳源(乙醇或乙酸盐)的摩尔比在50/50、60/40、80/20或90/10的范围内。优化进料以诱导葡萄糖调节的启动子,并使生产菌株中乙酰辅酶A和丙二酰辅酶A前体的产生最大化。在一些实施方案中,可以将长链烃组分(例如癸烷,十二烷,油酸,油酸甲酯或肉豆蔻酸异丙酯)(例如,以约1%(w/v)至约20%(w/v)的量,例如1-10%(w/v))加入培养物中。
在一些实施方案中,可以通过进料丙二酸盐(钠盐)并表达丙二酰-CoA合酶(例如,来自三叶草根瘤菌(Rhizobium trifolii)的MatB/C,或来自相关生物体例如链霉菌属的同源物,参见Biochem.J.(1999)344:159-166)来增加丙二酰-CoA水平。在一些实施方案中,可以通过过表达乙酰基-CoA羧化酶及生物素生物合成和生物素连接的相关途径,以及过表达产生丙二酰-CoA,乙酰-CoA的前体,增加丙二酰-CoA水平。
在本发明的其他方面,二羟基戊基苯甲酸或其类似物可以通过化学合成获得,或者可以在重组生产系统中生物合成。在一些实施方案中,在含有用于产生大麻素的代谢途径的同一酵母细胞株中以高水平产生二羟基戊基苯甲酸及其类似物。酵母中用于单环聚酮芳烃的高水平生产系统是本领域已知的。参见例如美国专利No.9,637,763。在其他实施方案中,可以浓缩来自产生高水平二羟基戊基苯甲酸或其类似物的酵母菌株的培养基,并在用于制造大麻素的MPF程序中用作高度相容的原料。
由于它们的碳利用途径或表达控制模式的差异,发酵方法可以适应于特定的酵母菌株。例如,酵母属酵母发酵可能需要单一葡萄糖进料,复杂的氮源(例如酪蛋白水解物)和多种维生素补充。这与甲基营养酵母巴斯德毕赤酵母相反,后者可能需要甘油,甲醇和微量矿物质进料,但仅需简单的铵(氮)盐用于实现最佳生长和表达。参见例如,Elliott etal.J.Protein Chem.(1990)9:95104,美国专利No.5,324,639以及Fieschko etal.Biotechnol.Bioeng.(1987)29:1113-1121。培养基可以包含诸如酵母提取物,蛋白胨等的组分。可以以常规发酵模式培养微生物,所述常规发酵模式包括但不限于分批,补料分批和连续流。
在一些实施方案中,控制向发酵罐添加葡萄糖的速率,使得添加葡萄糖的速率约等于酵母消耗葡萄糖的速率,在这种条件下,葡萄糖或乙醇的量不会明显积累。在这种情况下,葡萄糖的添加速率可以取决于多种因素,包括但不限于特定的酵母菌株,发酵温度和发酵装置的物理尺寸。
对于MPF程序,在分批模式下,前体二羟基戊基苯甲酸(或二羟基戊基苯甲酸类似物,例如另一种2-烷基-4,6-二羟基苯甲酸),异戊烯醇,异戊二烯醇或香叶醇的浓度可以在0.1和50克/升之间(例如1到10克/升之间)。在分批补料模式中,可以在2到20个小时将前体缓慢加入发酵中,使得发生每种必需的前体的1到100克/升的最终添加(例如1到10克/升之间,或10到100克/升之间)。
类似地,羧酸起始材料(包括取代的羧酸,例如卤代羧酸,氘代羧酸,氚代的羧酸和羟基化羧酸),例如取代的己酸,取代的丁酸,取代的戊酸等可以0.1至50克/升(例如1至10克/升)的浓度存在。在分批补料模式下,可以在2至72小时(例如15至60小时)内将羧酸缓慢进料到发酵中,以使得发生1至100克/升(例如,1至10克/升之间,或10至100克/升之间)的羧酸最终添加。
可以控制培养条件,例如表达时间,温度和pH值,以便以高收率提供目标大麻素中间体(例如,二羟基戊基苯甲酸类似物)和/或目标大麻素产物(例如,CBGA类似物,CBG类似物)。宿主细胞通常在起始物质例如己酸,异戊烯醇,异戊烯二醇等的存在下,在约20℃至约40℃的温度范围内,培养数小时至一天或更长时间(例如24小时,30小时,36小时,或48小时)的时间,取决于所用特定宿主细胞。例如,酿酒酵母可以在25-32℃下培养24-40小时(例如,在30℃下培养30小时)。可以通过添加酸,碱和/或缓冲剂将培养基的pH维持在特定水平。在某些实施方案中,在6或更高的pH值下培养酵母可以减少不需要的副产物如橄榄醇的产生。在一些实施方案中,酵母培养物的pH范围为约6至约8。在一些实施方案中,酵母培养物的pH为约6.5。在一些实施方案中,酵母培养物的pH为约7。在一些实施方案中,酵母培养物的pH为约8。
在一些实施方案中,对重组酵母细胞进行了遗传修饰,使得当在如上所述的含合适前体的培养基中进行体内培养时,其产生至少为约0.1g/L,至少约0.25g/L,至少约0.5g/L,至少约0.75g/L,至少约1g/L,至少约1.5g/L,至少约2g/LL,至少约2.5g/L,至少约3g/L,至少约3.5g/L,至少约4g/L,至少约4.5g/L,至少约5g/L,至少约5.5g/L,至少约6g/L,至少约7g/L,至少约8g/L,至少约9g/L或至少10g/L水平的目的大麻素产物或中间体。在一些实施方案中,对重组酵母细胞进行了遗传修饰,使得当在合适的培养基中体内培养时,它产生至少约20g/L,至少约30g/L,至少约50g/L,或至少约80g/L水平的目标大麻素产物或中间体。
大麻素的产生可以在允许细胞生长和/或孵育的任何容器中进行。例如,反应混合物可以是生物反应器,细胞培养瓶或板,多孔板(例如96、384、1056孔微量滴定板等),培养瓶,发酵罐或其他用于细胞生长或孵育的容器。可以使用本领域已知的方法从发酵培养基或细胞提取物中分离生物产生的目的产物。例如,可以通过离心或过滤除去固体或细胞碎片。目的产物可以例如通过蒸馏,液-液萃取,膜蒸发,吸附或其他方法分离。
2-烷基-4,6-二羟基苯甲酸转化为大麻素产物
本文还提供了生产大麻素产物的方法。在一些实施方案中,所述方法包括在酵母细胞中表达大麻素原料(其中所述酵母细胞被遗传修饰以表达大麻素原料),分离酵母细胞,并将大麻素原料转化为分离的酵母细胞中的大麻素产物。大麻素原料可以是酸性大麻素,中性大麻素或大麻素前体,例如二羟基戊基苯甲酸或另一种2-烷基-4,6-二羟基苯甲酸。可以使用本文所述的方法(例如化学或酶促香叶酰化,热或酶促脱羧等)进行大麻素原料的转化,或可以根据特定的大麻素原料或特定的大麻素产物的特性进行修饰。大麻素原料可以例如使用上述任何表达系统表达。分离酵母细胞可以任选地包括:通过离心,过滤或其他方式从培养基中收集酵母细胞;洗涤酵母细胞以去除培养基或其他成分;从细胞中去除至少一部分液体(例如培养基);和/或干燥细胞(例如,通过冻干或其他方式)。分离的酵母细胞可以直接经受反应条件以形成大麻素产物。例如,如下所述,酵母细胞可以直接与溶剂和其他试剂结合。
在一些实施方案中,酸性物质,例如根据式V的化合物或其大麻素衍生物,是大麻素产物。在一些实施方案中,该方法进一步包括将酸性物质转化成脱羧的大麻素产物,例如式Va的化合物或其大麻素衍生物。因此,最终的大麻素产物可以是中性大麻素或酸性大麻素。在一些实施方案中,中间体化合物例如卤代CBGA到另一大麻素的转化是通过物理或化学过程如加热,自氧化或UV光处理进行的。例如,该方法可以包括大麻素的脱羧作用,或是在工程酵母细胞内或在完全或部分纯化之后,通过热的作用或通过在体内或体外接触大麻素酸的野生型或突变型脱羧酶的作用。酸性大麻素的脱羧提供相应的中性大麻素。作为非限制性实例,其中R1为卤代烷基的卤代CBGA的脱羧提供了相应的卤代CBG。
可以对所形成的大麻素进行另外的化学转化,以制备完全非天然的类似物,例如酯,醚和卤代衍生物,以用作前药或更高活性或生物利用度的药物物质。在一些实施方案中,可以在携带生物合成大麻素底物的全酵母细胞上进行该化学反应,以避免在形成所需最终产物之前进行不必要的纯化步骤。
在一些实施方案中,在相同工程化宿主细胞内或与两种或更多种重组宿主细胞株(例如酵母菌株)共同培养,通过野生型或突变的大麻素合酶或野生型或突变的大麻酸合酶的作用,将第一大麻素产物(其为式V或式Va的化合物)转化为第二大麻素产物。例如,表达系统可编码大麻THCA合酶,大麻CBDA合酶和/或大麻CBCA合酶。在一些实施方案中,合成酶是来自蛇麻草的同源物,例如来自蛇麻草的CBDA合酶同源物。可以分别用CBDA合酶,THCA合酶和CBCA合酶将CBGA类似物酶促转化为相应的CBDA,THCA和CBCA类似物;酶促转化可以在体内或离体进行。
在一些实施方案中,可以使用脱羧酶,例如构巢曲霉orsB脱羧酶,将酸性大麻素例如卤代CBGA或卤代CBDA脱羧以形成中性大麻素化合物,例如卤代CBG或卤代CBD。可选地,可以通过将酸性大麻素在升高的温度(例如约40℃,50℃或100℃)下保持几分钟到几小时的时间来使酸性大麻素脱羧。
IV.药物组合物
本文还提供了包含一种或多种如上所述的大麻素衍生物或其一种或多种药学上可接受的盐以及一种或多种药学上可接受的赋形剂的药物组合物。
可以通过药学和药物递送领域中众所周知的任何方法来制备药物组合物。通常,制备组合物的方法包括使活性成分与含有一种或多种辅助成分的载体结合的步骤。药物组合物通常是通过将活性成分与液体载体或细分的固体载体或两者均匀且紧密地结合在一起,然后,如果需要,将产品成型为所需制剂来制备的。组合物可以方便地制备和/或包装成单位剂型。
药物组合物可以是无菌可注射水性或油质溶液和悬浮液的形式。可以使用无毒的肠胃外可接受的媒介物(包括水,林格氏溶液和等渗盐水溶液)以及可接受的溶剂(例如1,3-丁二醇)来配制无菌注射制剂。另外,无菌的不挥发油通常用作溶剂或悬浮介质。为此,可以使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。另外,发现脂肪酸如油酸可用于注射剂的制备中。
水性悬浮液包含活性材料与适于制造水性悬浮液的赋形剂混合。这类赋形剂包括但不限于:悬浮剂,例如羧甲基纤维素钠,甲基纤维素,oleagino-丙基甲基纤维素,藻酸钠,聚乙烯基吡咯烷酮,黄原胶和阿拉伯胶;分散剂或润湿剂,例如卵磷脂,聚氧乙烯硬脂酸酯和聚乙烯脱水山梨糖醇单油酸酯;以及防腐剂,例如乙基、正丙基和羟基苯甲酸酯。
油性悬浮液可以通过将活性成分悬浮在植物油(例如花生油,橄榄油,芝麻油或椰子油)或矿物油(例如液体石蜡)中来配制。油性悬浮液可包含增稠剂,例如蜂蜡,硬石蜡或鲸蜡醇。这些组合物可以通过添加抗氧化剂例如抗坏血酸来防腐。
可分散的粉末和颗粒(适于通过添加水来制备水性悬浮液)可以包含与分散剂,湿润剂,助悬剂或其组合混合的活性成分。也可以存在其他赋形剂。
药物组合物也可以是水包油乳剂的形式。油相可以是植物油,例如橄榄油或花生油,或矿物油,例如液体石蜡或这些的混合物。合适的乳化剂可以是天然存在的树胶,例如阿拉伯树胶或黄芪胶;天然存在的磷脂,例如大豆卵磷脂;衍生自脂肪酸和己糖醇酐的酯或偏酯,如脱水山梨醇单油酸酯;及所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨醇单油酸酯。
含有化合物的药物组合物也可以是适合口服使用的形式。口服施用的合适组合物包括但不限于片剂,糖锭,锭剂,水性或油性悬浮液,可分散的粉末或颗粒,乳剂,硬或软胶囊,糖浆,酏剂,溶液,颊贴剂,口服凝胶,口香糖,咀嚼片,泡腾粉和泡腾片。可以根据本领域技术人员已知的任何方法配制用于口服的组合物。此类组合物可包含一种或多种选自甜味剂,调味剂,着色剂,抗氧化剂和防腐剂的试剂,以提供药学上典雅且可口的制剂。
片剂通常包含活性成分与无毒的药学上可接受的赋形剂混合,所述赋形剂包括:惰性稀释剂,例如纤维素,二氧化硅,氧化铝,碳酸钙,碳酸钠,葡萄糖,甘露醇,山梨糖醇,乳糖,磷酸钙和磷酸钠;制粒和崩解剂,例如玉米淀粉和海藻酸;粘合剂,例如聚乙烯吡咯烷酮(PVP),纤维素,聚乙二醇(PEG),淀粉,明胶和阿拉伯胶;及润滑剂,例如硬脂酸镁,硬脂酸和滑石粉。片剂可以未包衣或通过已知技术通过肠溶或其他方式进行包衣以延迟在胃肠道中的崩解和吸收,且由此在更长的时间内提供持续的作用。例如,可以使用延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。片剂还可以根据已知技术用半透膜和任选的聚合物渗透剂包衣,以形成用于控制释放的渗透泵组合物。
口服组合物可以配制成硬明胶胶囊,其中活性成分与惰性固体稀释剂(例如碳酸钙,磷酸钙或高岭土)混合,或配制成软明胶胶囊,其中活性成分与水或油介质(例如花生油,液体石蜡或橄榄油)混合。
用于肺部给药的组合物还包括但不限于含有如本文所述的大麻素衍生物的干粉组合物。可以从本领域技术人员已知的任何合适的干粉吸入器装置吸入用于肺部给药的组合物。在某些情况下,可使用合适的推进剂,例如二氯二氟甲烷,三氯氟甲烷,二氯四氟乙烷,二氧化碳或其他合适的气体,以气溶胶喷雾形式方便地从加压包装或喷雾器中递送组合物。在使用加压气雾剂的情况下,可以通过提供阀门来确定剂量单位,从而递送计量的量。可以配制用于吸入器或吹入器的胶囊和药筒例如明胶,其包含化合物和合适的粉末基质例如乳糖或淀粉的粉末混合物。
本文提供的大麻素衍生物也可以以溶液,软膏,乳膏,凝胶,混悬剂,滴眼剂等形式局部施用。更进一步,大麻素衍生物的透皮递送可以借助于离子电渗疗法贴剂等来实现。大麻素衍生物也可以栓剂的形式施用而用于直肠给药。这些组合物可以通过将药物与合适的非刺激性赋形剂混合而制备,该赋形剂在常温下为固体,但在直肠温度下为液体,因此会在直肠中融化以释放药物。这样的材料包括可可脂和聚乙二醇。
V.治疗大麻素受体介导的疾病的方法
本文还提供了用于治疗疾病,状况和/或病症的方法,包括由大麻素受体活性介导的那些。该方法包括向有此需要的受试者施用有效量的如上所述的大麻素衍生物。所述方法可用于治疗许多病症,包括但不限于疼痛;和/或皮肤状况;肌肉疾病,包括但不限于肌肉营养不良;代谢综合征,例如2型糖尿病,血脂异常和肥胖;饮食失调;胃肠道疾病;过敏;哮喘;慢性阻塞性肺疾病;青光眼;心血管疾病或病症,例如高血压,充血性心力衰竭,心脏肥大,外周动脉疾病,动脉粥样硬化,中风,心肌梗塞以及与化疗有关的心脏毒性;脂肪肝疾病(脂肪性肝炎)和非酒精性脂肪肝疾病;肾脏疾病;以成瘾成分为特征的疾病或失调,例如吸烟成瘾或戒烟,酒精成瘾或戒酒以及药物成瘾或药物戒断;骨骼疾病或病症,例如骨质疏松症,佩吉特氏骨病和骨癌;癌症,包括但不限于乳腺癌;炎症性疾病或自身免疫性疾病,例如类风湿性关节炎,炎症性肠病和牛皮癣;图雷特氏综合症;精神疾病或病症,例如抑郁症,焦虑症,躁狂症,精神分裂症;睡眠障碍(例如失眠);疲劳;与记忆障碍和/或认知功能丧失相关的疾病或病症,例如帕金森氏病,阿尔茨海默氏病和痴呆;多发性硬化症;癫痫;脊柱损伤;以及感染如细菌,真菌和病毒感染。
所述化合物可以在所述方法中以任何合适的剂量施用。通常,以每千克受试者体重约0.1毫克至约1000毫克的剂量(即约0.1-1000mg/kg)施用化合物。化合物的剂量可以是例如约0.1-1000mg/kg,或约1-500mg/kg,或约25-250mg/kg,或约50-100mg/kg。剂量可以是约1、2、3、4、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、150、200、250、300、350、400、450、500,550、600、650、700、750、800、850、900、950或1000mg/kg。
剂量可以根据患者的需求,所治疗疾病的严重程度以及所施用的特定制剂而变化。给予患者的剂量应足以在患者中产生有益的治疗反应。剂量的大小也将由在特定患者中给予药物所伴随的任何不良副作用的存在,性质和程度来确定。确定对于特定情况的适当剂量在一般从业者的能力范围内。可以将总剂量分开,并在适合于治疗该疾病或病症一段时间内分批施用。
施用可以进行一段时间,该时间将取决于特定疾病的性质,其严重性和患者的整体状况。施用可以例如每小时,每2小时,3小时,4小时,6小时,8小时,或每天两次,包括每12小时,或其任何间隔进行。给药可以每天进行一次,或者每36小时或48小时一次,或者每月一次或几个月一次。治疗后,可以监测患者病情的变化以及疾病症状的缓解。如果患者对特定剂量水平没有明显反应,则可以增加剂量,或者如果观察到疾病症状缓解,或疾病已消除,或特定剂量产生了不可接受的副作用,则可以降低剂量。
治疗有效量的大麻素衍生物可以包含两个剂量之间的至少1小时或6小时或12小时或24小时或36小时或48小时的间隔的治疗方案给予受试者。给药间隔可以至少为72、96、120、168、192、216或240小时,或等量的天数。剂量方案可以由两个或更多个不同的间隔组组成。例如,剂量方案的第一部分可以每天多次,每天,每隔一天或每三天给予受试者。给药方案可开始于每隔一天,每三天,每周,每两周或每月给受试者给药。给药方案的第一部分可以施用例如长达30天,例如7、14、21或30天。后续第二部分给药方案可以采取不同的给药间隔,每周,每14天,或每月给药,持续4周直至两年或更长时间,例如4、6、8、12、16、26,32、40、52、63、68、78或104周。或者,如果病症缓解或总体上得到改善,则可以维持或保持低于最大量的剂量。如果病情或病症复发,则可以恢复第一剂量方案直到看到改善,并且可以再次实施第二剂量方案。该循环可以根据需要重复多次。
可以将其他活性剂或疗法与大麻素衍生物共同给药或以其他方式组合。适用于该方法的其他活性剂和疗法包括但不限于用于治疗2型糖尿病和肥胖症的化合物,例如胰岛素和胰岛素类似物,二肽基肽酶-4(DPP-4)抑制剂,胰高血糖素样肽-1类似物,降糖药,例如α-葡萄糖苷酶抑制剂,双胍类,磺酰脲,噻唑烷二酮,减肥疗法,例如食欲抑制剂,5-羟色胺再摄取抑制剂,去甲肾上腺素再摄取抑制剂,β3-肾上腺素受体激动剂和脂肪酶抑制剂。用于治疗心血管疾病和功能障碍的化合物也可用于这些方法中,包括但不限于利尿药,血管紧张素转换酶(ACE)抑制剂,血管紧张素II拮抗剂,β受体阻滞剂,钙离子拮抗剂,例如硝苯地平,HMG-CoA-还原酶抑制剂,例如他汀类,地高辛,醛固酮拮抗剂和有机硝酸盐。所述方法中可以使用其他脂质调节剂,包括但不限于贝特类和胆汁酸结合树脂。大麻素衍生物可与用于辅助戒烟的化合物一起使用,包括但不限于去甲肾上腺素-多巴胺再摄取抑制剂,例如安非拉酮。
用于治疗骨疾病和病症的化合物可以与大麻素衍生物组合用于本方法中。这类化合物包括但不限于抗再吸收剂,例如双膦酸盐;合成代谢剂,例如甲状旁腺激素;RANKL抑制剂,例如狄诺塞麦布;雌激素替代物和选择性雌激素受体调节剂,如雷洛昔芬。用于治疗癌症的药物也可以与大麻素衍生物结合使用。抗癌剂的实例包括但不限于化学治疗剂(例如,卡铂,紫杉醇,培美曲塞等),酪氨酸激酶抑制剂(例如,埃洛替尼,克唑替尼,奥西替尼等)和免疫治疗剂(例如,帕博利珠单抗,纳武单抗,德瓦鲁单抗,阿替利珠单抗等)。
用于治疗具有炎症或自身免疫成分的疾病或病症的化合物可以与大麻素衍生物组合使用。这些化合物包括非甾体抗炎药(NSAIDs);改善疾病的抗风湿药,例如免疫抑制剂;抗TNF药物,例如英夫利昔单抗,依那西普和阿达木单抗;和抗B细胞治疗剂,如利妥昔单抗。
用于治疗精神疾病和病症的化合物可以与大麻素衍生物组合用于本方法中。此类化合物包括作为GABAA调节剂的物质,例如苯并二氮杂;5HT1A受体激动剂,例如丁螺环酮;β受体阻滞剂;抗精神病药,例如多巴胺受体阻滞剂和其他调节单胺受体,转运蛋白或代谢的药物,例如三环抗抑郁药,选择性5-羟色胺再摄取抑制剂和单胺氧化酶抑制剂;锂;和抗癫痫药,例如阻断钠通道的药物,阻断T型钙通道的药物或阻断GABA转氨酶或再摄取的药物,包括苯妥英钠,卡马西平,丙戊酸盐和维加巴特林。用于治疗以记忆力减退和/或认知功能丧失为特征的疾病或病症的化合物也可用于该方法中,包括但不限于此类多巴胺激动剂和抗胆碱酯酶。
可与大麻素衍生物一起用于治疗细菌感染的抗生素的实例包括但不限于:喹诺酮类(例如莫西沙星,吉非沙星,环丙沙星,氧氟沙星,曲伐沙星,西他沙星等),β-内酰胺类(例如青霉素,如阿莫西林,阿莫西林-克拉维酸盐,哌拉西林-他唑巴坦,青霉素G等;以及头孢菌素,如头孢曲松等),大环内酯类(例如红霉素,阿奇霉素,克拉霉素等),氨基糖苷类(例如阿米卡星,庆大霉素,卡那霉素,新霉素,奈替米星,妥布霉素等),单酰胺环类(例如氨曲南等),碳青霉烯类(例如多瑞培南,亚胺培南,美洛平,厄他培南等),噻唑内酯类(例如噻唑烷,硝唑烷,RM4807,RM4809等),四环素类(例如四环素,米诺环素,多西环素,色拉环素等),林可酰胺类(例如,林可霉素,克林霉素等),磺酰胺类(例如,甲氧苄啶,磺胺甲恶唑等)和硝基咪唑类(例如,甲硝唑,沙曲硝唑等)。可与大麻素衍生物一起用于治疗病毒感染的抗病毒剂的实例包括但不限于:病毒脱壳抑制剂(例如金刚烷胺,金刚乙胺等),神经氨酸酶抑制剂(例如奥司他韦,扎那米韦,拉尼米韦和帕拉米韦),逆转录酶抑制剂(例如替诺福韦,司他夫定,齐多夫定,扎西他滨,恩曲他滨,拉米夫定等)和蛋白酶抑制剂(例如利托那韦,茚地那韦,波西普韦等)和多核苷酸合成抑制剂(例如,索非布韦,达沙布韦等)
VI.实施例
实施例1.在酿酒酵母中产生2,4-二羟基-6-全氘代戊基苯甲酸和5-全氘代戊基苯-1,3-二醇
化学合成酿酒酵母ADH2启动子,并将其与用于突变的大麻酰基激活酶-1(CsAAE1ΔTM)的合成基因融合,其中跨膜结构域编码序列(氨基酸245至267)已删除。还将酿酒酵母ADH2终止子序列紧接在合成的终止密码子之后与基因序列融合。将表达盒克隆到含有URA3选择标记的酵母表达载体中。类似地,将酰基激活酶CsAAE3(来自大麻)和revS(来自链霉菌SN-593的中链脂肪酰基-CoA连接酶)的合成基因克隆到单独的URA3载体中。每个基于URA3的载体均被转化到感受态酿酒酵母InvScl(MATa/alpha his3D1 leu2 trpl-289ura3-52)细胞(Invitrogen)中,其之前已用包含大麻二羟基戊基苯甲酸合酶/四酮合酶(OAS/TKS)基因的基于选择标记LEU2的载体进行了转化,该二羟基戊基苯甲酸合酶/四酮合酶(OAS/TKS)基因通过酿酒酵母p150内部核糖体进入位点(IRES)和人泛素蛋白基因与多个单独突变的大麻二羟基戊基苯甲酸环化酶基因以及与编码拟南芥环化酶AtHS1的合成基因融合。
将转化的细胞接种在含有用于基于尿嘧啶和亮氨酸原养型的选择的氨基酸的最小琼脂平板(6.7g/L不含氨基酸或硫酸铵的酵母氮碱基(DIFCO),20g/L葡萄糖,20g/L琼脂)上。挑取转化子,并在尿嘧啶和亮氨酸缺乏的基本培养基中生长24小时。从转化体中分离质粒DNA,并通过限制性消化分析进行分析以确认身份。
每个菌株的成功转化子被用于接种2mL缺乏尿嘧啶和亮氨酸的基本培养基,其在30℃下在轨道振荡器中生长过夜。使用该培养物的500μL等分试样接种50mL相同的培养基,并将该培养物在30℃的振荡器中生长24小时。类似地,将培养物接种到300mL相同的培养基中,过夜生长后,转移到包含1.2L 2X YEP的培养基(Wobbe,Current Protocols inMolecular Biology,Supplement 34:13.0.1-13.13.9(Wiley,1996))(20g/L酵母提取物,40g/L蛋白胨)的氧-、进料-和搅拌-控制的7升发酵罐(Eppendorf)中。
接种后约16小时后,消耗掉所有残留的葡萄糖后,将0.2克的全氘代己酸(D11-HA)直接添加到发酵罐中,并向培养物中加入2XYEPD,其中含有14.3%的葡萄糖,3.5%的乙酸钠和0.8克的D11-HA,直至经过72小时的发酵时间。
生长24、48和72小时后,离心500μL培养物等分试样来收集细胞,并通过在50μL 2XSDS凝胶上样缓冲液中煮沸约2分钟来裂解细胞。通过将细胞裂解物加载到4-20%SDS-PAGE凝胶上进行分析。观察到与编码酶的预期大小相对应的条带。
为了进一步定量和类似物验证,通过离心将细胞与培养基分离,用冰醋酸酸化培养基,并使用乙酸乙酯萃取氘代产物。通过柱色谱法或使用具有乙腈/甲酸洗脱的Sep-PakC18柱进一步纯化产物,并进行NMR和质谱分析。
2,4-二羟基-6-全氘代戊基苯甲酸(1)。
LC-MS/ESI:计算值[C12H8D11O4]235.17;测定值[M+H]236.23,[M-H]234.05,[M-H-CO2]190.15.1H-NMR(MeOH-D4,300MHz):δ6.13(1H,d,J=2.4Hz),6.18(1H,d,J=2.4Hz).
5-全氘代戊基苯-1,3-二醇(2)。
LC-MS/ESI:计算值[C11H5D11O2]191.18;测定值[M+H]192.35.
发现使用各种酰基活化酶生物合成高水平的类似物:revS(>40mg/L);CsAAE3(~20-30mg/L);CsAAE1ΔTM(3-4mg/L)。二羟基戊基苯甲酸到橄榄醇类似物的产物分布随所使用的突变环化酶的实际长度而变化,其中AtHS1环化酶产生基本上所有的橄榄醇类似物(5-全氘代戊基苯-1,3-二醇)。
实施例2.在酿酒酵母中产生2,4-二羟基-6-(5-氟戊基)-苯甲酸、2,4-二羟基-6-(4-氟丁基)-苯甲酸、5-(5-氟戊基)-苯-1,3-二醇和5-(4-氟丁基)-苯-1,3-二醇
如实施例1中所述,将表达酰基活化酶revS和CsAAE3的菌株在4mL选择培养基中于30℃生长24h,然后接种到1×YPD中,总共得到40mL细胞培养量。在30℃下生长30小时后,将6-氟己酸或5-氟戊酸添加到培养物中,使总浓度为2mM,然后在30℃下再培养48h。通过HPLC监测类似物的产生,并如上所述完成纯化。2,4-二羟基-6-(4-氟丁基)-苯甲酸的产率为约5毫克/升,而2,4-二羟基-6-(5-氟戊基)-苯甲酸产率为约60mg/L。
2,4-二羟基-6-(4-氟丁基)-苯甲酸。
LC-MS/ESI:计算值[C11H13FO4]228.08;测定值[M-H]226.95,[M-H-CO2]183.05.
2,4-二羟基-6-(5-氟戊基)-苯甲酸。
LC-MS/ESI:计算值[C12H15FO4]242.10;测定值[M-H]240.95,[M-H-CO2]197.05,[2M-H]482.80.
实施例3.在酿酒酵母中产生2,4-二羟基-6-(5-氟戊基)-苯甲酸和5-(5-氟戊基)-苯-1,3-二醇
如实施例1所述,将表达酰基活化酶revS和CsAAE3的菌株在4mL选择培养基中于30℃生长24h,然后接种到1X YPD中,总共得到40mL细胞培养量。在30℃下生长30小时后,将6-氟己酸添加到培养物中,使其总浓度为2mM,然后在30℃下再培养48小时。通过HPLC监测类似物的产生,并如上所述纯化。
实施例4.在酿酒酵母中产生2,4-二羟基-6-(3-氟丙基)-苯甲酸和5-(3-氟丙基)苯-1,3-二醇
如实施例1中所述,将表达revS和CsAAE3的菌株在4mL选择培养基中于30℃生长24h,然后接种到1X YPD中,总共得到40mL细胞培养物。在30℃下生长30小时后,将4-氟丁酸添加到培养物中,使其总浓度为2mM,然后将培养物在30℃下再培养48小时。通过HPLC监测类似物的产生,并如上所述完成纯化。不同于全氘代类似物的产生,仅在表达revS的菌株中观察到3-氟丙基divarinic酸类似物。表达CsAAE3的菌株未产生高于HPLC检测极限水平的类似物。如上所述,使用截短的(95-氨基酸)大麻环化酶或AtHS1环化酶,观察到酸类似物与脱羧的氟-divarinol类似物的比率的总偏移。
实施例5.酿酒酵母中产生6-(4-氯丁基)-2,4-二羟基苯甲酸和5-(4-氯丁基)-苯-1,3-二醇
如实施例1中所述,将表达revS的菌株直接在50mL选择培养基中于选择性培养板中在30℃生长24小时,然后接种到2X YEPD中,总共得到500mL细胞培养物量。在30℃下生长30小时后,将5-氯戊酸添加到培养物中,使其总浓度为2mM,然后将培养物在30℃下再培养48小时。通过在预测区域中出现反相HPLC峰来监控类似物的产生,并如上所述纯化。培养物中6-(4-氯丁基)-2,4-二羟基苯甲酸的产率为~30mg/L。
6-(4-氯丁基)-2,4-二羟基苯甲酸
LC-MS/ESI:计算值[C11H13ClO4]244.05;观察值[M-H]242.95.
在所有上述实施例中,在需要的情况下,可以通过离心去除酵母细胞并在100℃下加热剩余的含类似物的培养基1小时,将含有不同量的酸类似物和橄榄醇/divarinol类似物的培养基定量地转化为脱羧类似物。
实施例6.使用有机相覆盖层以降低起始原料和产物的毒性
将全氘代己酸,6-氟己酸,4-氟丁酸,5-氯戊酸,己酸和丁酸单进料到上述实施例1-3中所述的酵母菌株。如实施例3中所述进行细胞的培养,除了在30小时时,将10体积%的油醇与脂族酸或脂族酸类似物一起添加到培养物中。该过程导致所需产物的水平增加。
实施例7.直接在酿酒酵母中产生CBGA类似物
将上述氘-,氟-和氯代脂肪族酸类似物,连同己酸和丁酸,单独进料至如实施例1-3中所述生长的酵母菌株,不同之处在于,这些菌株事先通过基因的整合转化进行修饰,所述基因涉及到酵母甲羟戊酸途径的上调,从而产生高水平的香叶基二磷酸。该菌株还带有整合的基因,这些基因分别表达各种异戊二烯基转移酶用于将二羟基戊基苯甲酸类似物转化为CBGA类似物。通过使用甲醇,乙醇或乙酸乙酯的溶剂提取从离心的酵母细胞中分离得到的CBGA类似物,并通过质谱和NMR分析对其进行表征。使用该方法制备6-(4-氯丁基)-3-(3,7-二甲基-辛-2,6-二烯基)-2,4-二羟基苯甲酸。LC-MS/ESI:计算值[C21H29ClO4]380.18;测定值[M+H]380.95(Cl),[M-H]378.85(Cl)。
还使用该方法制备了3-(3,7-二甲基-辛-2,6-二烯基)-6-(5-氟戊基)-2,4-二羟基-苯甲酸(5-氟-大麻萜酚酸)。LC-MS/ESI:计算值[C22H31FO4]278.22;测定值[M+H]379.05,[M-H]376.90。
实施例8.橄榄醇/二羟基戊基苯甲酸类似物化学转化为CBC/CBCA类似物
CBCA和CBC类似物的制备如下:向35mg(0.2mmol)的全氘代戊基-二羟基戊基苯甲酸或全氘代戊基-橄榄醇的0.5mL二氯乙烷溶液中加入0.085mL(约2.5当量)的E/Z-柠檬醛,然后在23℃下加入0.005mL(25mol%)的N,N-二甲基乙二胺以引发反应。通过定量RP-HPLC监测反应,并且在18小时后,没有底物残留。使用水/甲醇/0.1%甲酸(2.5mL/min)的陡峭线性梯度,在Gilson制备型C18RP-HPLC自动化系统上通过单次进样直接纯化反应混合物。通过UV(在230nm)监测级分,合并适当的级分,真空浓缩,并在MeOH中再浓缩以除去残留的水,以摩尔产率在65%至73%的范围内提供产物。通过质谱和NMR分析表征CBCA和CBC类似物。
2-甲基-2-(4-甲基-戊-3-烯基)-7-全氘代戊基-2H-色原烯-5-醇(全氘代戊基-CBC)。LC-MS/ESI:计算值[C21H19D11O2]325.29;测定值:[M+H]326.25。
5-羟基-2-甲基-2-(4-甲基-戊-3-烯基)-7-全氘代戊基-2H-色烯-6-羧酸(全氘代戊基-CBCA)。LC-MS/ESI:计算值[C22H19D11O4]369.28;测定值:[M-H]367.90,[M-H-CO2]324.00。
如上文对于全氘代类似物所述的制备氟代和氯代CBC/CBCA类似物。
实施例9.N-乙酰半胱氨酸酰胺和泛酰巯基乙胺硫酯的制备和用途
向0℃的包含5mmol的琥珀酸的5.5mmol的羧酸的搅拌溶液以及溶解在4ml二氯甲烷(DCM)中的5mmol的N-乙酰半胱胺(或泛酰巯基乙胺)中,加入1mL的含有5.25mmol二环己基碳二亚胺(DCC)的DCM冷溶液。使溶液升温至23℃,并搅拌18h。冷却至0℃后,通过过滤除去所得的不溶性N,N′-二环己基脲,并用冷DCM洗涤。除去溶剂,将残余物重新溶解在DCM中,如果需要的话再过滤,然后用1N HCl萃取,然后用5%NaHCO3的饱和NaCl水溶液萃取。有机层经Na2SO4干燥,并浓缩以提供高产率的硫酯。产物通过重结晶,蒸馏或色谱法进一步纯化。特别的实例包括由己酸,丁酸,戊酸,庚酸,辛酸和氟-或氘代的取代烷基和烯基酸(例如4-氟丁酸,5-氟戊酸,6-氟己酸和全氘代己酸)制备的硫酯。
将硫酯以最高2mM的水平进料到如实施例1和2中所述的那些的培养物中,在30小时后,并在进一步生长46小时后,取出样品用于HPLC分析。每种酸产物的产率均大于40mg/L。
实施例10.将二羟基戊基苯甲酸类似物化学转化为CBGA类似物
向0.25mL甲苯中的20mg氘代,氟代或氯代二羟基戊基苯甲酸类似物的悬浮液中加入2.6mg对甲苯磺酸和18μL香叶醇。将悬浮液加热至60℃,并通过反相HPLC(Kinetex 5μm-XB,50x4.6mm,100A,在6分钟内20%50mM甲酸铵/乙腈到100%乙腈的线性梯度,2.5mL/min)进行监测。大约50分钟后,相应的CBGA类似物达到最大产率,并通过质谱和NMR进行鉴定和表征。
实施例11.产生5-氟代大麻环萜酚和5-氯代大麻环萜酚
根据实施例2制备2,4-二羟基-6-(5-氟戊基)-苯甲酸,将其脱羧并转化为5-氟大麻环萜酚。将37.5mg的2,4-二羟基-6-(5-氟戊基)-苯甲酸样品溶于1mL的95%乙醇中,并在80℃加热18小时以完全脱羧,从而得到5-(5-氟戊基)-苯-1,3-二醇LC-MS/ESI:计算值[C11H15FO2]198.11;测定值[M+H]199.25,[M-H]197.05。将所得溶液浓缩(真空)至干,并使其经历与实施例8中概述的反应条件相似的反应条件。获得11.1mg 7-(5-氟戊基)-2-甲基-2-(4-甲基-戊-3-烯基)-2H-色原烯-5-醇(5-氟大麻环萜酚)。LC-MS/ESI:计算值[C21H29FO2]332.22;测定值[M+H]333.10,[M-H]330.95,[2M-H]662.85 1H-NMR(CDCl3,300MHz):δ6.61(d,1,J=8Hz,J=1.5Hz);6.24(d,1,J=1Hz),6.11(d,1,J=1Hz),5.50(d,1,J=12Hz),5.09(dt,1,J=6Hz),4.64(bs s,1),4.51(t,1,J=6Hz),4.31(t,1,J=6Hz),2.10(m,4),1.8-1.6(m,12),1.67(s,3),1.59(s,3),1.45(m,2),1.38(s,3)。
以相似的方式,由2,4-二羟基-6-(4-氯丁基)-苯甲酸(参见实施例5)制备5-氯大麻环萜酚。LC-MS/ESI:计算值[C20H27ClO2]334.17;测定值[M+H]335.00(Cl),[M-H]332.90(Cl);1H-NMR(CDCl3,300MHz):δ6.62(d,1,J=8Hz);6.24(d,1,J=1Hz),6.12(d,1,J=1Hz),5.50(d,1,J=8Hz),5.09(dt,1,J=6Hz),3.53(t,3,J=6Hz),2.11(m,4),1.8-1.5(m,4),1.85(s,3),1.57(s,3),1.38(s,3)。
实施例12.5-氟大麻环萜酚的CB2受体激动剂活性
如Udoh等人(“Cannabichromene is a cannabinoid CB2 receptor agonist.”British Journal of Pharmacology,2019,doi:10.1111/bph.14815)所述,在稳定表达HA标记的人CB1和CB2受体的AtT20细胞中研究了5-氟大麻环萜酚(5F-CBC)的活性。在CB2处观察到的5F-CBC的EC50值为2.1μM。
VII.示例性实施方案
根据当前公开的主题提供的示例性实施方案包括但不限于权利要求和以下实施方案:
1.式I化合物:
或其盐或大麻素衍生物,其中:
R1选自由C1-C20卤代烷基,C1-C20羟烷基,氘代的C1-C20烷基,氚代的C1-C20烷基和C2-C20烯基组成的组,
R2选自由COOR2a和H组成的组,
R2a选自H和C1-C6烷基组成的组,并且
R3选自异戊二烯基部分和H组成的组。
2.实施方案1的化合物或其盐或大麻素衍生物,其中R1选自由C1-C10卤代烷基,C1-C10羟基烷基,氘代C1-C10烷基,氚代C1-C10烷基和C2-C10烯基组成的组。
3.实施方案1的化合物或其盐或大麻素衍生物,其中R1选自由C1-C10卤代烷基,C1-C10羟基烷基,氘代的C1-C10烷基和氚代的C1-C10烷基组成的组。
4.实施方案1的化合物或其盐或大麻素衍生物,其中R1为C1-C10卤代烷基。
5.实施方案4的化合物或其盐或大麻素衍生物,其中R1选自氟代戊基,氟代乙基,氟代丙基,氟代丁基,氟代己基,氟代辛基和氟代壬基。
6.实施方案4的化合物或其盐或大麻素衍生物,其中R1选自5-氟丙基,4-氟丁基和3-氟戊基。
7.实施方案4的化合物或其盐或大麻素衍生物,其中R1是C1-C10溴代烷基或C1-C10氯代烷基。
8.实施方案1的化合物或其盐或大麻素衍生物,其中R1是C1-C10羟基烷基。
9.实施方案1的化合物或其盐或大麻素衍生物,其中R1是氘代的C1-C10烷基或氚代的C1-C10烷基。
10.实施方案1-9中任一项的化合物或其盐或大麻素衍生物,其中R2选自由COOH和H组成的组。
11.实施方案1-10中任一项的化合物或其盐或大麻素衍生物,其中R2是COOH。
12.实施方案1-10中任一项的化合物或其盐或大麻素衍生物,其中R2为H。
13.实施方案1-12中任一项的化合物或其盐或大麻素衍生物,其中R3为H。
14.实施方案1-12中任一项的化合物或其盐或大麻素衍生物,其中R3是异戊二烯基部分。
15.实施方案1-12和14中任一项的化合物,或其盐或大麻素衍生物,其中异戊二烯基部分是3,7-二甲基辛-2,6-二烯-1-基。
16.实施方案1的化合物或其盐或大麻素衍生物,其中所述化合物具有式Ia的结构:
17.实施方案1-16中任一项的化合物的大麻素衍生物或其盐。
18.实施方案17的大麻素衍生物或其药学上可接受的盐,其选自:卤代大麻二酚酸,卤代大麻二酚,卤代Δ9-四氢大麻酚酸,卤代Δ8-四氢大麻酚酸,卤代大麻环萜酚酸,卤代大麻环萜酚,卤代大麻酚,卤代脱氢大麻二酚,卤代大麻酚酸,次大麻酚,卤代次大麻酚酸,卤代Δ9-四氢次大麻酚,卤代Δ8-四氢次大麻酚,卤代Δ9-四氢次大麻酚酸,卤代Δ8-四氢次大麻酚酸,卤代次大麻萜酚,卤代次大麻萜酚酸,卤代次大麻环萜酚,卤代次大麻环萜酚酸,卤代次大麻二酚,卤代次大麻二酚酸,卤代二羟基大麻酚,和卤代大麻环酚。
19.药物组合物,其包含实施方案17或实施方案18的大麻素衍生物和药学上可接受的赋形剂。
20.一种用于治疗由大麻素受体活性介导的疾病或病症的方法,该方法包括向有此需要的受试者给予有效量的实施方案17或实施方案18的大麻素衍生物或其药学上可接受的盐或有效量的实施方案19的组合物。
21.一种制备式IV的化合物或其盐的方法:
其中R1选自C1-C20卤代烷基,C1-C20羟基烷基,氘代的C1-C20烷基、氚代的C1-C20烷基和C2-C20烯基;
该方法包括在包含式II的硫酯的培养基中培养修饰的重组宿主细胞;
其中R4选自由辅酶A(CoA)部分,泛酰巯基乙胺部分和半胱胺部分组成的组,
其中修饰的重组宿主细胞包含:
i.编码将式II的硫酯和丙二酰CoA转化为式III的四酮化合物的合成酶的第一多核苷酸:
ii.编码将式III的四酮化合物转化为式IV的化合物的2-烷基-4,6-二羟基苯甲酸环化酶的第二多核苷酸,
并且其中修饰的重组宿主细胞在表达由第一和第二多核苷酸编码的产物并产生式IV的化合物的条件下培养。
22.实施方案21的方法,其中R1选自C1-C10卤代烷基,C1-C10羟基烷基,氘代C1-C10烷基、氚代的C1-C10烷基和C2-C10烯基。
23.实施方案21或实施方案22的方法,其中所述合成酶是二羟基戊基苯甲酸合酶。
24.实施方案21-23中任一项的方法,其中所述2-烷基-4,6-二羟基苯甲酸环化酶是截短的二羟基戊基苯甲酸环化酶。
25.实施方案21-24中任一项的方法,其中R4是CoA部分。
26.实施方案21-25中任一项的方法,其中所述宿主细胞进一步包含编码酰基-CoA合成酶的第三多核苷酸,所述酰基-CoA合成酶将式IIa的起始材料转化为式II的硫酯
其中步骤a)包括在表达第三多核苷酸编码的产物并产生式II的硫酯的条件下培养宿主细胞。
27.实施方案26的方法,其中所述酰基-CoA合成酶是revS或CsAAE3。
28.实施方案21-24中任一项的方法,其中式II的硫酯中的R4是泛酰巯基乙胺部分或半胱胺部分。
29.实施方案21-28中任一项的方法,进一步包括将式IV的化合物转化为式V的化合物或其盐,
其中R3是异戊二烯基部分。
30.实施方案29的方法,所述方法还包括使式V的化合物脱羧以提供式Va的化合物:
31.实施方案21-28中任一项的实施方案的方法,其进一步包括使式IV的化合物脱羧以提供式IVa的化合物:
32.实施方案31的方法,其进一步包括将化合物式IVa转化为式Va的化合物:
其中R3是异戊二烯基部分。
33.实施方案29、30和32中任一项的方法,其中所述宿主细胞进一步包含编码异戊二烯基转移酶的第四多核苷酸,所述异戊二烯基转移酶将式IV的化合物转化为式V的化合物,并且其中转化步骤b)包括在表达由第四多核苷酸编码的产物并产生式V的化合物的条件下培养宿主细胞。
34.实施方案32的方法,其中所述宿主细胞进一步包含编码异戊二烯基转移酶的第四多核苷酸,所述异戊二烯基转移酶将式IVa的化合物转化为式Va的化合物,并且其中转化步骤b)包括在表达由第四多核苷酸编码的产物并产生式Va的化合物的条件下培养所述宿主细胞。
35.实施方案33或实施方案34的方法,其中异戊二烯基转移酶是香叶基焦磷酸:二羟基戊基苯甲酸香叶基转移酶。
36.实施方案29或实施方案30的方法,其中转化步骤b)包括形成反应混合物,所述反应混合物包含1)式IV的化合物,2)香叶醇,活化的香叶醇或柠檬醛,和3)有机溶剂,并将反应混合物保持在足以使式V化合物产生的条件下。
37.实施方案32的方法,其中转化步骤b)包括形成反应混合物,所述反应混合物包含1)式IVa的化合物,2)香叶醇,活化的香叶醇或柠檬醛,和3)有机溶剂,并将反应混合物保持在足以使式Va化合物产生的条件下。
38.实施方案29、30和32-37中任一项制备的化合物,其中所述化合物是大麻二酚酸类似物,大麻二酚类似物,Δ9-四氢大麻酚酸类似物,Δ8-四氢大麻酚酸类似物,大麻环萜酚酸类似物,大麻环萜酚类似物,大麻酚类似物,脱氢大麻二酚类似物,大麻酚酸类似物,次大麻酚类似物,次大麻酚酸类似物,Δ9-四氢次大麻酚类似物,Δ8-四氢次大麻酚类似物,Δ9-四氢次大麻酚酸类似物,Δ8-四氢次大麻酚酸类似物,次大麻萜酚类似物,次大麻萜酚酸类似物,次大麻环萜酚类似物,次大麻环萜酚酸类似物,次大麻二酚类似物,次大麻二酚酸类似物,二羟基大麻酚类似物,或大麻环酚类似物。
此处说明性地描述的本发明可以在不存在本文未具体公开的任何一个或多个元素,一个或多个限制的情况下适当地实践。因此,例如,在本文的每种情况下,术语“包括”,“基本上由...组成”和“由...组成”中的任何一个都可以用另外两个术语中的任一个化替。因此,例如,一些实施方案可以涵盖“包括”许多组分的宿主细胞,其他实施方案将涵盖“基本上由相同组分组成”的宿主细胞,而其他实施方案将涵盖“由相同组分组成”的宿主细胞。已使用的术语和表达用作描述性术语,而非限制性的,并且不意图在使用这样的术语和表达时排除所示出和描述的特征或其部分的任何等同形式,而是应当认识到,在所要求保护的本发明的范围内可以进行各种修改。因此,应该理解,尽管已经通过优选实施方案和可选特征具体公开了本发明,但是本领域技术人员可以对本文公开的概念进行修改和变型,这样的修改和变化被认为在所附权利要求所限定的本发明的范围内。
前述书面描述被认为足以使本领域技术人员能够实施本发明。提供以下实施例仅用于说明性目的,而无意以任何方式限制本发明的范围。实际上,除了本文中示出和描述的那些之外,根据前面的描述,本发明的各种修改对于本领域技术人员将变得显而易见,并且落入所附权利要求的范围内。
在已经参考专利说明书,其他外部文件或其他信息源的本说明书中,这通常是出于提供讨论本发明的特征的上下文的目的。除非另有特别说明,否则对此类外部文件的引用不应解释为承认此类文件或此类信息源在任何管辖范围内都是现有技术,或构成本领域公知常识的一部分。本说明书中引用的所有专利,专利申请和参考文献均通过引用全文并入本文。
示例性序列
SEQ ID NO:1说明性RevS多肽序列GenBank BAK64635.1
MELALPAELAPTLPEALRLRSEQQPDTVAYVFLRDGETPEETLTYGRLDRAARARAAALEAAGLAGGTAVLLYPSGLEFVAALLGCMYAGTAGAPVQVPTRRRGMERARRIADDAGAKTILTTTAVKREVEEHFADLLTGLTVIDTESLPDVPDDAPAVRLPGPDDVALLQYTSGSTGDPKGVEVTHANFRANVAETVELWPVRSDGTVVNWLPLFHDMGLMFGVVMPLFTGVPAYLMAPQSFIRRPARWLEAISRFRGTHAAAPSFAYELCVRSVADTGLPAGLDLSSWRVAVNGAEPVRWTAVADFTEAYAPAGFRPQAMCPGYGLAENTLKLSGSPEDRPPTLLRADAAALQDGRVVPLTGPGTDGVRLVGSGVTVPSSRVAVVDPGTGTEQPAGRVGEIWINGPCVARGYHGRPAESAESFGARIAGQEARGTWLRTGDLGFLHDGEVFVAGRLKDVVIHQGRNFYPQDIELSAEVSDRALHPNCAAAFALDDGRTERLVLLVEADGRALRNGGADALRARVHDAVWDRQRLRIDEIVLLRRGALPKTSSGKVQRRLARSRYLDGEFGPAPAREA
SEQ ID NO:2说明性大麻CSAAE3多肽序列;GenBank AFD33347.1
MEKSGYGRDGIYRSLRPPLHLPNNNNLSMVSFLFRNSSSYPQKPALIDSETNQILSFSHFKSTVIKVSHGFLNLGIKKNDVVLIYAPNSIHFPVCFLGIIASGAIATTSNPLYTVSELSKQVKDSNPKLIITVPQLLEKVKGFNLPTILIGPDSEQESSSDKVMTFNDLVNLGGSSGSEFPIVDDFKQSDTAALLYSSGTTGMSKGVVLTHKNFIASSLMVTMEQDLVGEMDNVFLCFLPMFHVFGLAIITYAQLQRGNTVISMARFDLEKMLKDVEKYKVTHLWVVPPVILALSKNSMVKKFNLSSIKYIGSGAAPLGKDLMEECSKVVPYGIVAQGYGMTETCGIVSMEDIRGGKRNSGSAGMLASGVEAQIVSVDTLKPLPPNQLGEIWVKGPNMMQGYFNNPQATKLTIDKKGWVHTGDLGYFDEDGHLYVVDRIKELIKYKGFQVAPAELEGLLVSHPEILDAVVIPFPDAEAGEVPVAYVVRSPNSSLTENDVKKFIAGQVASFKRLRKVTFINSVPKSASGKILRRELIQKVRSNM
SEQ ID NO:3说明性大麻CSAAE1多肽序列;GenBank AFD33345.1,跨膜结构域带有下划线
MGKNYKSLDSVVASDFIALGITSEVAETLHGRLAEIVCNYGAATPQTWINIANHILSPDLPFSLHQMLFYGCYKDFGPAPPAWIPDPEKVKSTNLGALLEKRGKEFLGVKYKDPISSFSHFQEFSVRNPEVYWRTVLMDEMKISFSKDPECILRRDDINNPGGSEWLPGGYLNSAKNCLNVNSNKKLNDTMIVWRDEGNDDLPLNKLTLDQLRKRVWLVGYALEEMGLEKGCAIAIDMPMHVDAVVIYLAIVLAGYVVVSIADSFSAPEISTRLRLSKAKAIFTQDHIIRGKKRIPLYSRVVEAKSPMAIVIPCSGSNIGAELRDGDISWDYFLERAKEFKNCEFTAREQPVDAYTNILFSSGTTGEPKAIPWTQATPLKAAADGWSHLDIRKGDVIVWPTNLGWMMGPWLVYASLLNGASIALYNGSPLVSGFAKFVQDAKVTMLGVVPSIVRSWKSTNCVSGYDWSTIRCFSSSGEASNVDEYLWLMGRANYKPVIEMCGGTEIGGAFSAGSFLQAQSLSSFSSQCMGCTLYILDKNGYPMPKNKPGIGELALGPVMFGASKTLLNGNHHDVYFKGMPTLNGEVLRRHGDIFELTSNGYYHAHGRADDTMNIGGIKISSIEIERVCNEVDDRVFETTAIGVPPLGGGPEQLVIFFVLKDSNDTTIDLNQLRLSFNLGLQKKLNPLFKVTRVVPLSSLPRTATNKIMRRVLRQQFSHFE
SEQ ID NO:4说明性的二羟基戊基苯甲酸合酶多肽序列;UniProtKB/Swiss-Prot:B1Q2B6.1
MNHLRAEGPASVLAIGTANPENILLQDEFPDYYFRVTKSEHMTQLKEKFRKICDKSMIRKRNCFLNEEHLKQNPRLVEHEMQTLDARQDMLVVEVPKLGKDACAKAIKEWGQPKSKITHLIFTSASTTDMPGADYHCAKLLGLSPSVKRVMMYQLGCYGGGTVLRIAKDIAENNKGARVLAVCCDIMACLFRGPSESDLELLVGQAIFGDGAAAVIVGAEPDESVGERPIFELVSTGQTILPNSEGTIGGHIREAGLIFDLHKDVPMLISNNIEKCLIEAFTPIGISDWNSIFWITHPGGKAILDKVEEKLHLKSDKFVDSRHVLSEHGNMSSSTVLFVMDELRKRSLEEGKSTTGDGFEWGVLFGFGPGLTVERVVVRSVPIKY
SEQ ID NO:5说明性的二羟基戊基苯甲酸环化酶多肽序列;UniProtKB/Swiss-Prot:I6WU39.1
MAVKHLIVLKFKDEITEAQKEEFFKTYVNLVNIIPAMKDVYWGKDVTQKNKEEGYTHIVEVTFESVETIQDYIIHPAHVGFGDVYRSFWEKLLIFDYTPRK
SEQ ID NO:6相对于SEQ ID NO:5缺少N末端甲硫氨酸和C末端赖氨酸的二羟基戊基苯甲酸环化酶多肽序列
AVKHLIVLKFKDEITEAQKEEFFKTYVNLVNIIPAMKDVYWGKDVTQKNKEEGYTHIVEVTFESVETIQDYIIHPAHVGFGDVYRSFWEKLLIFDYTPR
SEQ ID NO:7环化酶的截短形式,95aa,相对于SEQ ID NO:5,缺少N末端的蛋氨酸以及C末端的5个氨基酸序列YTPRK
AVKHLIVLKFKDEITEAQKEEFFKTYVNLVNIIPAMKDVYWGKDVTQKNKEEGYTHIVEVTFESVETIQDYIIHPAHVGFGDVYRSFWEKLLIFD
SEQ ID NO:8青枯雷尔氏菌酰基-CoA合酶的415个氨基酸的C末端结构域的氨基酸序列
MAFNERVVDWQQVAGAQPDASPERMSADDPFMIIYTSGTTGKPKGTVHTHGSFPMKIAHDSAIHFNVSPKDVFCWPADMGWVAGTLVMSCALLRGATLVCYDGAPDFPDWSRMSRLIERHRVTHFGSAPTLIRGLASNEAIATQGDVSSVKLLITAGEGIDPEHFLWFQKAFGGGHRPVINYTGGTEVSGALLSSVVIKPISPAGFNTASPGVATDVVDAEGHSVTGEVGELAIRKPFIGMTRSFWQDDERYLDSYWRTIPGIWVHGDLAMRREDGMWFMMGRSDDTIKLAGKRLGPAEIEDVLLELPEIAEAAAIGVEDPVKGQKLVVFVVASKASTASADALASVIGKHVDLRLGRPFRPSVVHVVAQLPKTRSSKIMRRVIRSVYTGKPAGDLSSLDNPLALDEIRSAAAVS
SEQ ID NO:9来自链霉菌属菌种的贝那他汀基因簇的benH基因产物的环化酶结构域的氨基酸序列
AGRTDNSVVIDAPVQLVWDMTNDVSQWAVLFEEYAESEVLAVDGDTVRFRLTTQPDEDGKQWSWVSERTRDLENRTVTARRLDNGLFEYMNIRWEYTEGPDGVRMRWIQEFSMKPSAPVDDSGAEDHLNRQTVKEMARIKKLIEEA
Claims (38)
2.权利要求1的化合物或其盐或大麻素衍生物,其中R1选自由C5-C10卤代烷基,C1-C4卤代烷基,C1-C10羟基烷基,氘代C1-C10烷基,氚代C1-C10烷基和C2-C10烯基组成的组。
3.权利要求1的化合物或其盐或大麻素衍生物,其中R1选自由C5-C10卤代烷基,C1-C4卤代烷基,C1-C10羟基烷基,氘代C1-C10烷基和氚代C1-C10烷基组成的组。
4.权利要求1的化合物或其盐或大麻素衍生物,其中R1为C5-C10卤代烷基或C1-C4卤代烷基。
5.权利要求4的化合物或其盐或大麻素衍生物,其中R1选自氟戊基,氟乙基,氟丙基,氟丁基,氟己基,氟辛基和氟壬基。
6.权利要求4的化合物或其盐或大麻素衍生物,其中R1选自5-氟丙基,4-氟丁基和3-氟戊基。
7.权利要求4的化合物或其盐或大麻素衍生物,其中R1是C1-C10溴化烷基或C1-C10氯代烷基。
8.权利要求1的化合物或其盐或大麻素衍生物,其中R1是C1-C10羟基烷基。
9.权利要求1的化合物或其盐或大麻素衍生物,其中R1是氘代的C1-C10烷基或氚代的C1-C10烷基。
10.权利要求1的化合物或其盐或大麻素衍生物,其中R2选自由COOH和H组成的组。
11.权利要求1的化合物或其盐或大麻素衍生物,其中R2是COOH。
12.权利要求1的化合物或其盐或大麻素衍生物,其中R2为H。
13.权利要求1的化合物或其盐或大麻素衍生物,其中R3为H。
14.权利要求1的化合物或其盐或大麻素衍生物,其中R3是异戊二烯基部分。
15.权利要求1的化合物或其盐或大麻素衍生物,其中所述异戊二烯基部分是3,7-二甲基辛-2,6-二烯-1-基。
17.权利要求1的化合物的大麻素衍生物或其盐。
18.权利要求17的大麻素衍生物或其药学上可接受的盐,其选自由以下组成的组:卤代大麻二酚酸,卤代大麻二酚,卤代Δ9-四氢大麻酚酸,卤代Δ8-四氢大麻酚酸,卤代大麻环萜酚酸,卤代大麻环萜酚,卤代大麻酚,卤代脱氢大麻二酚,卤代大麻酚酸,次大麻酚,卤代次大麻酚酸,卤代Δ9-四氢次大麻酚,卤代Δ8-四氢次大麻酚,卤代Δ9-四氢次大麻酚酸,卤代Δ8-四氢次大麻酚酸,卤代次大麻萜酚,卤代次大麻萜酚酸,卤代次大麻环萜酚,卤代次大麻环萜酚酸,卤代次大麻二酚,卤代次大麻二酚酸,卤代二羟基大麻酚,和卤代大麻环酚。
19.药物组合物,其包含权利要求17或权利要求18的大麻素衍生物和药学上可接受的赋形剂。
20.一种用于治疗由大麻素受体活性介导的疾病或病症的方法,该方法包括向有此需要的受试者给予有效量的权利要求17或权利要求18的大麻素衍生物或其药学上可接受的盐或者有效量的权利要求19的组合物。
21.一种制备式IV的化合物或其盐的方法:
其中R1选自C1-C20卤代烷基,C1-C20羟基烷基,氘代的C1-C20烷基、氚代的C1-C20烷基和C2-C20烯基;
该方法包括在包含式II的硫酯的培养基中培养修饰的重组宿主细胞;
其中R4选自由辅酶A(CoA)部分,泛酰巯基乙胺部分和半胱胺部分组成的组,
其中所述修饰的重组宿主细胞包含:
i.编码将式II的硫酯和丙二酰CoA转化为式III的四酮化合物的合成酶的第一多核苷酸:
ii.编码将式III的四酮化合物转化为式IV的化合物的2-烷基-4,6-二羟基苯甲酸环化酶的第二多核苷酸,
并且其中所述修饰的重组宿主细胞在表达由所述第一和第二多核苷酸编码的产物并产生式IV的化合物的条件下培养。
22.权利要求21的方法,其中R1选自C1-C10卤代烷基、C1-C10羟基烷基、氘代C1-C10烷基、氚代的C1-C10烷基和C2-C10烯基。
23.权利要求21的方法,其中所述合成酶是二羟基戊基苯甲酸合酶。
24.权利要求21的方法,其中所述2-烷基-4,6-二羟基苯甲酸环化酶是截短的二羟基戊基苯甲酸环化酶。
25.权利要求21的方法,其中R4是CoA部分。
27.权利要求26的方法,其中所述酰基-CoA合成酶是revS或CsAAE3。
28.权利要求21的方法,其中式II的硫酯中的R4是泛酰巯基乙胺部分或半胱胺部分。
33.权利要求29的方法,其中所述宿主细胞进一步包含编码异戊二烯基转移酶的第四多核苷酸,所述异戊二烯基转移酶将式IV的化合物转化为式V的化合物,并且其中转化步骤b)包括在表达由所述第四多核苷酸编码的产物并产生式V的化合物的条件下培养所述宿主细胞。
34.权利要求32的方法,其中所述宿主细胞进一步包含编码异戊二烯基转移酶的第四多核苷酸,所述异戊二烯基转移酶将式IVa的化合物转化为式Va的化合物,并且其中转化步骤b)包括在表达由所述第四多核苷酸编码的产物并产生式Va的化合物的条件下培养所述宿主细胞。
35.权利要求33的方法,其中所述异戊二烯基转移酶是香叶基焦磷酸:二羟基戊基苯甲酸香叶基转移酶。
36.权利要求29的方法,其中转化步骤b)包括形成反应混合物,所述反应混合物包含1)式IV的化合物,2)香叶醇,活化的香叶醇或柠檬醛,和3)有机溶剂,并将所述反应混合物保持在足以得到式V化合物的条件下。
37.权利要求32的方法,其中转化步骤b)包括形成反应混合物,所述反应混合物包含1)式IVa的化合物,2)香叶醇,活化的香叶醇或柠檬醛,和3)有机溶剂,并将所述反应混合物保持在足以得到式Va化合物的条件下。
38.根据权利要求29制备的化合物,其中所述化合物是大麻二酚酸类似物,大麻二酚类似物,Δ9-四氢大麻酚酸类似物,Δ8-四氢大麻酚酸类似物,大麻环萜酚酸类似物,大麻环萜酚类似物,大麻酚类似物,脱氢大麻二酚类似物,大麻酚酸类似物,次大麻酚类似物,次大麻酚酸类似物,Δ9-四氢次大麻酚类似物,Δ8-四氢次大麻酚类似物,Δ9-四氢次大麻酚酸类似物,Δ8-四氢次大麻酚酸类似物,次大麻萜酚类似物,次大麻萜酚酸类似物,次大麻环萜酚类似物,次大麻环萜酚酸类似物,次大麻二酚类似物,次大麻二酚酸类似物,二羟基大麻酚类似物,大麻环酚类似物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862753708P | 2018-10-31 | 2018-10-31 | |
US62/753,708 | 2018-10-31 | ||
US201862767447P | 2018-11-14 | 2018-11-14 | |
US62/767,447 | 2018-11-14 | ||
PCT/US2019/059237 WO2020092823A1 (en) | 2018-10-31 | 2019-10-31 | Cannabinoid analogs and methods for their preparation |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113226297A true CN113226297A (zh) | 2021-08-06 |
Family
ID=70463287
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980087003.4A Pending CN113226297A (zh) | 2018-10-31 | 2019-10-31 | 大麻素类似物及其制备方法 |
Country Status (10)
Country | Link |
---|---|
US (1) | US20210403408A1 (zh) |
EP (1) | EP3873451A4 (zh) |
JP (1) | JP2022513411A (zh) |
CN (1) | CN113226297A (zh) |
AU (1) | AU2019371379A1 (zh) |
BR (1) | BR112021008520A2 (zh) |
CA (1) | CA3117714A1 (zh) |
IL (1) | IL282822A (zh) |
MX (1) | MX2021005026A (zh) |
WO (1) | WO2020092823A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115504862A (zh) * | 2021-06-07 | 2022-12-23 | 南通新世元生物科技有限公司 | 一种大麻萜酚的制备方法 |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3130763A1 (en) | 2019-02-25 | 2020-09-03 | Ginkgo Bioworks, Inc. | Biosynthesis of cannabinoids and cannabinoid precursors |
US20220315969A1 (en) * | 2019-06-06 | 2022-10-06 | Genomatica Inc. | Olivetolic acid cyclase variants and methods for their use |
EP4149916A4 (en) * | 2020-05-12 | 2024-06-19 | Canopy Growth Corp | PROCESS FOR PRODUCING CANNABIGERGOL, CANNABIGEROL ACID AND ANALOGUES THEREOF |
MX2023004597A (es) * | 2020-10-21 | 2023-06-22 | Inmed Pharmaceuticals Inc | Composiciones y metodos para tratar trastornos neuronales con cannabinoides. |
WO2022159506A1 (en) * | 2021-01-19 | 2022-07-28 | Merit Therapeutics, Inc. | Deuterated cannabidiol compounds |
WO2022192582A1 (en) * | 2021-03-10 | 2022-09-15 | Treehouse Biosciences, Inc. | Methods of synthesizing halogenated cannabinoids and derivatives of cannabinoids |
WO2022213120A1 (en) * | 2021-04-02 | 2022-10-06 | Lygos, Inc. | Cannabinoids from substituted resorcinol carboxylic acids |
CN116648241A (zh) * | 2021-04-14 | 2023-08-25 | 成都百裕制药股份有限公司 | 氘代苯酚衍生物及其制备方法和用途 |
WO2022251714A2 (en) * | 2021-05-27 | 2022-12-01 | Cb Therapeutics, Inc. | Olivetolic acid cyclases for cannabinoid biosynthesis |
CN113846125B (zh) * | 2021-09-06 | 2024-01-30 | 云南省烟草农业科学研究院 | 枯草芽孢杆菌、红发夫酵母和根霉混合烟草发酵方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018057385A2 (en) * | 2016-09-20 | 2018-03-29 | 22Nd Century Limited, Llc | Trichome specific promoters for the manipulation of cannabinoids and other compounds in glandular trichomes |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003080043A1 (en) * | 2002-03-18 | 2003-10-02 | Immugen Pharmaceuticals, Inc. | Topical formulations of resorcinols and cannibinoids and methods of use |
US8481085B2 (en) * | 2006-06-15 | 2013-07-09 | Gw Pharma Limited | Pharmaceutical compositions comprising cannabigerol |
EP3186383A1 (en) * | 2014-08-25 | 2017-07-05 | Full Spectrum Laboratories Limited | Apparatus and methods for the simultaneous production of cannabinoid compounds |
GB2542797A (en) * | 2015-09-29 | 2017-04-05 | Gw Pharma Ltd | Use of cannabinoids in the treatment of inflammatory skin diseases |
-
2019
- 2019-10-31 CA CA3117714A patent/CA3117714A1/en active Pending
- 2019-10-31 JP JP2021548568A patent/JP2022513411A/ja active Pending
- 2019-10-31 WO PCT/US2019/059237 patent/WO2020092823A1/en unknown
- 2019-10-31 AU AU2019371379A patent/AU2019371379A1/en active Pending
- 2019-10-31 US US17/289,868 patent/US20210403408A1/en active Pending
- 2019-10-31 BR BR112021008520-3A patent/BR112021008520A2/pt not_active Application Discontinuation
- 2019-10-31 MX MX2021005026A patent/MX2021005026A/es unknown
- 2019-10-31 CN CN201980087003.4A patent/CN113226297A/zh active Pending
- 2019-10-31 EP EP19878963.8A patent/EP3873451A4/en active Pending
-
2021
- 2021-04-29 IL IL282822A patent/IL282822A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018057385A2 (en) * | 2016-09-20 | 2018-03-29 | 22Nd Century Limited, Llc | Trichome specific promoters for the manipulation of cannabinoids and other compounds in glandular trichomes |
Non-Patent Citations (7)
Title |
---|
"130414-07-2", 《STN REGISTRY》, pages 1 * |
"134914-55-9", 《STN REGISTRY》, pages 1 * |
C.G.PITT等: "THE SYNTHESIS OF DEUTERIUM, CARBON-14, AND CARRIERFREE TRITIUM LABELED CANNABINOIDS", 《JAUNAL OF LABELLED CMPATNDS》, pages 551 - 575 * |
CHIARA ZANATO等: "Synthesis, radio-synthesis and in vitro evaluation of terminally fluorinated derivatives of HU-210 and HU-211 as novel candidate PET tracers", 《ORG. BIOMOL. CHEM.》, pages 2086 - 2096 * |
DRIESSEN ROBERT ANDRE: "DEUTERIUM LABELED GANNABINOIDS", pages 1 - 143, Retrieved from the Internet <URL:https://inis.iaea.org/collection/NCLCollectionStore/_Public/11/507/11507800.pdf> * |
LONGWU QI等: "Δ9-Tetrahydrocannabinol Immunochemical Studies: Haptens, Monoclonal Antibodies, and a Convenient Synthesis of Radiolabeled Δ9-Tetrahydrocannabinol", 《J. MED. CHEM.》, pages 7389 - 7399 * |
陈璇等: "大麻植物中大麻素成分研究进展", 《植物学报》, pages 197 - 205 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115504862A (zh) * | 2021-06-07 | 2022-12-23 | 南通新世元生物科技有限公司 | 一种大麻萜酚的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
AU2019371379A1 (en) | 2021-05-27 |
WO2020092823A1 (en) | 2020-05-07 |
US20210403408A1 (en) | 2021-12-30 |
IL282822A (en) | 2021-06-30 |
EP3873451A4 (en) | 2022-08-10 |
JP2022513411A (ja) | 2022-02-07 |
EP3873451A1 (en) | 2021-09-08 |
CA3117714A1 (en) | 2020-05-07 |
MX2021005026A (es) | 2021-07-21 |
BR112021008520A2 (pt) | 2021-08-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113226297A (zh) | 大麻素类似物及其制备方法 | |
US11555211B2 (en) | Recombinant production systems for prenylated polyketides of the cannabinoid family | |
US10633681B2 (en) | Apparatus and methods for biosynthetic production of cannabinoids | |
CA2952638C (en) | Compositions and methods for making (s)-norcoclaurine and (s)-norlaudanosoline, and synthesis intermediates thereof | |
US20210403959A1 (en) | Use of type i and type ii polyketide synthases for the production of cannabinoids and cannabinoid analogs | |
US20230063396A1 (en) | Genetically modified yeast for the production of cannabigerolic acid, cannabichromenic acid and related cannabinoids | |
KR20220125300A (ko) | 오르리스타트 중간체 제조를 위한 생물학적 효소의 용도 및 제조 방법 | |
US20240117388A1 (en) | Acyl activating enzymes for preparation of cannabinoids | |
US20230279377A1 (en) | Modified terpene synthases and their use for production of pseudopterosin intermediates and/or pseudopterosins | |
US20240200107A1 (en) | Method for producing a hydroxytyrosol | |
EP3450567A1 (en) | Process for the preparation of (r)-beta-angelica lactone from alpha-angelica lactone employing ene-reductases | |
JP2005211020A (ja) | ユビキノン10の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |