JP6182720B2 - カンプトセシンの新規な20(s)−スルホニルアミジン誘導体および当該誘導体の強力な抗癌剤としての使用方法 - Google Patents
カンプトセシンの新規な20(s)−スルホニルアミジン誘導体および当該誘導体の強力な抗癌剤としての使用方法 Download PDFInfo
- Publication number
- JP6182720B2 JP6182720B2 JP2016518190A JP2016518190A JP6182720B2 JP 6182720 B2 JP6182720 B2 JP 6182720B2 JP 2016518190 A JP2016518190 A JP 2016518190A JP 2016518190 A JP2016518190 A JP 2016518190A JP 6182720 B2 JP6182720 B2 JP 6182720B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- compound
- cancer
- derivatives
- phenyl
- 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.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title description 10
- 229940127093 camptothecin Drugs 0.000 title description 8
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 title description 6
- 239000002246 antineoplastic agent Substances 0.000 title description 6
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 title description 6
- 230000003389 potentiating effect Effects 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 37
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- -1 C1-C3 alkoxylphenyl Chemical group 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 6
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- 125000004799 bromophenyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 29
- 230000000694 effects Effects 0.000 description 22
- 241000699670 Mus sp. Species 0.000 description 16
- 231100000135 cytotoxicity Toxicity 0.000 description 13
- 230000003013 cytotoxicity Effects 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 10
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- 231100000419 toxicity Toxicity 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 230000006907 apoptotic process Effects 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 230000037361 pathway Effects 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 6
- 102000002804 Ataxia Telangiectasia Mutated Proteins Human genes 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 6
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 6
- DFEXVBOMMIJOAW-UHFFFAOYSA-N carbamimidoylsulfonylmethanimidamide Chemical group NC(=N)S(=O)(=O)C(N)=N DFEXVBOMMIJOAW-UHFFFAOYSA-N 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 150000002596 lactones Chemical group 0.000 description 6
- 230000003902 lesion Effects 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 230000022131 cell cycle Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 230000028617 response to DNA damage stimulus Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 5
- 102100021573 Bcl-2-binding component 3, isoforms 3/4 Human genes 0.000 description 4
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 4
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 4
- 101000971203 Homo sapiens Bcl-2-binding component 3, isoforms 1/2 Proteins 0.000 description 4
- 101000971209 Homo sapiens Bcl-2-binding component 3, isoforms 3/4 Proteins 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 230000005778 DNA damage Effects 0.000 description 3
- 231100000277 DNA damage Toxicity 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 102100026693 FAS-associated death domain protein Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102100034533 Histone H2AX Human genes 0.000 description 3
- 101000911074 Homo sapiens FAS-associated death domain protein Proteins 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- 230000018199 S phase Effects 0.000 description 3
- 238000000692 Student's t-test Methods 0.000 description 3
- 101710183280 Topoisomerase Proteins 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 239000011543 agarose gel Substances 0.000 description 3
- 150000001345 alkine derivatives Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004671 cell-free system Anatomy 0.000 description 3
- POADTFBBIXOWFJ-VWLOTQADSA-N cositecan Chemical compound C1=CC=C2C(CC[Si](C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 POADTFBBIXOWFJ-VWLOTQADSA-N 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- 229960004768 irinotecan Drugs 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000005556 structure-activity relationship Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 108090000672 Annexin A5 Proteins 0.000 description 2
- 102000004121 Annexin A5 Human genes 0.000 description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 2
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 description 2
- 101100220616 Caenorhabditis elegans chk-2 gene Proteins 0.000 description 2
- 102000013392 Carboxylesterase Human genes 0.000 description 2
- 108010051152 Carboxylesterase Proteins 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- 102100029855 Caspase-3 Human genes 0.000 description 2
- 102100026548 Caspase-8 Human genes 0.000 description 2
- 108090000538 Caspase-8 Proteins 0.000 description 2
- 102000004039 Caspase-9 Human genes 0.000 description 2
- 108090000566 Caspase-9 Proteins 0.000 description 2
- 108090000323 DNA Topoisomerases Proteins 0.000 description 2
- 102000003915 DNA Topoisomerases Human genes 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 101710195517 Histone H2AX Proteins 0.000 description 2
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010043189 Telangiectasia Diseases 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 238000002841 anti-cancer assay Methods 0.000 description 2
- 229940125648 antineoplastic drug candidate Drugs 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 230000005775 apoptotic pathway Effects 0.000 description 2
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 2
- 229950011276 belotecan Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 101150113535 chek1 gene Proteins 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000012137 double-staining Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 229960005542 ethidium bromide Drugs 0.000 description 2
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- UIVFUQKYVFCEKJ-OPTOVBNMSA-N gimatecan Chemical compound C1=CC=C2C(\C=N\OC(C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UIVFUQKYVFCEKJ-OPTOVBNMSA-N 0.000 description 2
- 229950009073 gimatecan Drugs 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
- 239000001257 hydrogen Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000005917 in vivo anti-tumor Effects 0.000 description 2
- 230000006882 induction of apoptosis Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 230000004660 morphological change Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 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
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 208000009056 telangiectasis Diseases 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- NDLIRBZKZSDGSO-UHFFFAOYSA-N tosyl azide Chemical compound CC1=CC=C(S(=O)(=O)[N-][N+]#N)C=C1 NDLIRBZKZSDGSO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AXQACEQYCPKDMV-RZAWKFBISA-N (4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,7,9-trihydroxy-n-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3C(O)=C(C[C@]2(O)[C@]34CC1)C(=O)NC(C)(C)C=1ON=C(N=1)C=1C=CC=CC=1)CC1CC1 AXQACEQYCPKDMV-RZAWKFBISA-N 0.000 description 1
- 108091064702 1 family Proteins 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XRKYMMUGXMWDAO-UHFFFAOYSA-N 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone Chemical compound O1C(C=2C=3SC4=CC=CC=C4SC=3C=CC=2)=CC(=O)C=C1N1CCOCC1 XRKYMMUGXMWDAO-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 108050008874 Annexin Proteins 0.000 description 1
- 102000000412 Annexin Human genes 0.000 description 1
- 102100027308 Apoptosis regulator BAX Human genes 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000004308 Carboxylic Ester Hydrolases Human genes 0.000 description 1
- 108090000863 Carboxylic Ester Hydrolases Proteins 0.000 description 1
- 240000002199 Carissa bispinosa Species 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 230000007018 DNA scission Effects 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 102000009058 Death Domain Receptors Human genes 0.000 description 1
- 108010049207 Death Domain Receptors Proteins 0.000 description 1
- 102000010170 Death domains Human genes 0.000 description 1
- 108050001718 Death domains Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010040476 FITC-annexin A5 Proteins 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101000830681 Homo sapiens DNA topoisomerase 1 Proteins 0.000 description 1
- 101001067891 Homo sapiens Histone H2AX Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- QTUVCTXXMOZFHS-UHFFFAOYSA-N N-(8-aminooctyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetamide Chemical compound NCCCCCCCCNC(=O)COC1=CC=CC2=C1C(=O)N(C1CCC(=O)NC1=O)C2=O QTUVCTXXMOZFHS-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 1
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108020005088 Superhelical DNA Proteins 0.000 description 1
- 239000008049 TAE buffer Substances 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- QPMSXSBEVQLBIL-CZRHPSIPSA-N ac1mix0p Chemical compound C1=CC=C2N(C[C@H](C)CN(C)C)C3=CC(OC)=CC=C3SC2=C1.O([C@H]1[C@]2(OC)C=CC34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O QPMSXSBEVQLBIL-CZRHPSIPSA-N 0.000 description 1
- HGEVZDLYZYVYHD-UHFFFAOYSA-N acetic acid;2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid Chemical compound CC(O)=O.OCC(N)(CO)CO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O HGEVZDLYZYVYHD-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 229940019748 antifibrinolytic proteinase inhibitors Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000018486 cell cycle phase Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000034725 extrinsic apoptotic signaling pathway Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000056859 human TOP1 Human genes 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000006676 mitochondrial damage Effects 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000012335 pathological evaluation Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000001686 pro-survival effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000026938 proteasomal ubiquitin-dependent protein catabolic process Effects 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000003007 single stranded DNA break Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 231100000338 sulforhodamine B assay Toxicity 0.000 description 1
- 238000003210 sulforhodamine B staining Methods 0.000 description 1
- HSVFKFNNMLUVEY-UHFFFAOYSA-N sulfuryl diazide Chemical compound [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-] HSVFKFNNMLUVEY-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本本発明は、カンプトセシン(1)の新規な20−スルホニルアミジン誘導体、当該誘導体の合成方法、および当該誘導体の抗癌剤としての使用方法に関する。
カンプトセシン(CPT、1、図1)は、顕著な抗癌効果を有する天然のアルカロイドである1−3。その抗癌活性は、不可逆な薬剤−酵素−DNAの三重複合体を安定化し、トポイソメラーゼ(Topo I)によって誘導される1本鎖DNA切断の再連結を防止することによるDNA Top Iの触媒サイクルの干渉能によるものである4,5。過去数十年にわたる合成医療化学への集中的な取り組みにより、現在、卵巣癌、肺小細胞癌、及び結腸癌の治療に臨床的に使用される、トポテカン(2)及びイリノテカン(3)等の、強力な1−誘導体が得られた。また、ギマテカン(gimatecan)(4)、CKD−602(5)、及びBNP−1350(6)等の、数種の誘導体は、前臨床開発または臨床開発の様々な段階である6−8。臨床使用される1−誘導体は有望な抗癌剤ではあるものの、その治療への使用は、毒性の問題および水溶性の低さによる、デリバリーの問題、さらには血清アルブミンへの開環カルボキシレート(opened carboxylate)の優先的な結合による、活性のあるラクトン形態の不安定性によって、かなり妨げられている9,10。
本発明は、新規なカンプトセシン(1)の新規な20−スルホニルアミジン誘導体、これらの合成方法、およびこれらの抗癌剤としての使用に関する。
R2は、ヒドロキシルC1〜C6アルキル、(CH3)kH3−kSi、フェニル、C1〜C3アルキルフェニル、C1〜C3アルコキシルフェニル、フルオロフェニル、クロロフェニル、ブロモフェニル、(CH2)j−O−(CH2)i−R11であり、この際、kは0、1、2または3であり;jは、1〜5であり;iは0〜5であり;およびR11は下記であり:
R3は、H、NO2、
R4は、HまたはNO2であり;
R5は、H、C1〜C6アルキル、
R9は、H、C1〜C6アルキル、フェニル、C1〜C3アルキルフェニル、C1〜C3アルコキシルフェニル、フルオロフェニル、クロロフェニル、ブロモフェニル、ピリジル、ナフチル、フリル、チエニル、ピロリル、
nは、0〜3であり;
mは、1〜5であり;
Xは、OまたはSであり;
Yは、Oであり;
Zは、Oであり;ならびに
Wは、Oである。
我々は、本明細書において、Cu触媒によるワンポット反応(Cu-catalyzed one pot reaction)を介して1のC−20位置にスルホニルアミジン基を導入し、抗癌剤となりうるものとして9a〜9lを得たことを記載する。
化学 スキーム1に示されるように、1の20−ヒドロキシル基を、N、N’−ジイソプロピルカルボジイミド(DIPC)及び4−ジメチルアミノピリジン(DMAP)の組み合わせを用いたカルボジイミド法の単純な改変によってエステル化してN−Boc−アミノ酸誘導体(7)を適当な収率で提供した。7のN−Boc基を、CH2Cl2におけるトリフルオロ酢酸(TFA)(1:1)で除去して、カギとなる中間体TFA塩8を形成した。次に、我々は、非常に効率のよいCu触媒による3成分カップリング反応(Cu-catalyzed three-component coupling reaction)29を適用し、8をp−トルエンスルホニルアジド及び広範なアルキンと反応させて、35〜58%の収率で所望の化合物9a〜lを得た。目的分子の構造を1H−NMR、13C−NMR、IR、及びHR−MSによるデータから明らかにした。
無細胞系での9aによるTopoI活性の阻害 エステル化20−ヒドロキシ基を有する1−誘導体は、カルボキシルエステラーゼによる消化によって活性化されると予想される。そのままの9aがTopoIを阻害するかどうかを決定するために、精製組換ヒトTopoIを用いる無細胞TopoI活性アッセイを使用した。このアッセイでは、超らせんプラスミドDNAを、組換TopoIによって緩和(relax)、切断(nick)した。これにより、ベヒクルコントロールまたはTopoI活性に関して阻害効果を示さない試験化合物を用いて、緩和、切断したDNA(relaxed and nicked DNA)を見出した。細胞内でのカルボキシルエステラーゼによるのと同様この無細胞系で活性化されえないので、1のプロドラッグであることが知られている、化合物3は、同様の結果を示した。これに対して、3の生物活性のある代謝産物である、SN−38は、TopoI活性を阻害した。特に、我々は、そのままの9aが1と同様にこの無細胞アッセイにおいてTopoI活性を阻害することを発見した。我々は、TopoIに対する9aの阻害効果が用量に依存することを確認した。ゆえに、我々は、9aが新規なTopoI阻害剤であることを確認した。
一般的な化学情報 N−Boc−アミノ酸及びTFAはGL Biochem (Shanghai) Companyから購入した。DIPC及びDMAPはSigma Chemical Company (China)から購入した。他の試薬及び溶媒は市販の供給元から購入しそのまま使用した。出発物質1を、中国の薬草C. acuminataから単離し、精製した後使用した(98%超純度)。シリカゲル60 GF254(Qingdao Haiyang Chemical Co.、Ltd.)を用いたシリカゲルプレートで、分析用薄層クロマトグラフィー(TLC)及び分取薄層クロマトグラフィー(PTLC)を行った。融点は、コッフラー融点装置(Kofler melting point apparatus)でとり、修正しなかった。IRスペクトルをNIC−5DX分光光度計で得た。MS分析をZAB-HS装置およびBruker Daltonics APEXII49e装置で行った。NMRスペクトルを、TMSを参考として用い、400MHzでBruker AM-400NMRスペクトロメータで記録した(Bruker Company, USA)。すべての試験化合物の純度を、C−18結合相カラム(C-18 bounded-phase column)(Eclipse Plus C18、5μM粒径、4.6mm×250mm)を備えたHPLC(Agilent Technologies 1100 series)によって測定した。MeOH及び水を移動相として用いて勾配溶離を行い、254nmでモニターした。すべての試験化合物は95%を超える純度を有していた。
ATM、変異型毛細血管拡張性運動失調症(ataxia telangiectasia mutated);ATR、Rad3関連毛細血管拡張性運動失調症(ataxia telangiectasia and Rad3-related);Chk、チェックポイントキナーゼ(checkpoint kinase);CPT、カンプトセシン;DIPC、N,N’−ジイソプロピルカルボジイミド;DMAP、4−ジメチルアミノピリジン;FADD、Fas結合デスドメインタンパク質(Fas-associated protein with death domain);PUMA、アポトーシスp53上方調節モジュレーター(p53 upregulated modulator of apoptosis);TFA、トリフルオロ酢酸;Topo、トポイソメラーゼ。
化合物10a〜10tを合成し、実施形態Iに記載されるのと同様の方法を用いて同定し、これらを表3に示す。
より多くの誘導体を合成し、実施形態Iに記載されるのと同様の方法を用いることによって同定し、これらを表5に示す。
Claims (15)
- 下記構造:
R3は、H、NO2、下記:
R4は、HまたはNO2であり;
R5は、H、C1〜C6アルキル、下記:
R6は、H、OH、または下記:
R7は、H、C1〜C6アルキルまたはC1〜C6アルコキシルであり;ならびに
R9は、H、C1〜C6アルキル、フェニル、C1〜C3アルキルフェニル、C1〜C3アルコキシルフェニル、フルオロフェニル、クロロフェニル、ブロモフェニル、ピリジル、ナフチル、フリル、チエニル、ピロリル、下記:
nは、0〜3であり;
mは、1〜5であり;
Xは、OまたはSであり;
Yは、Oであり;
Zは、Oであり;ならびに
Wは、Oである、
を有する化合物。 - R3、R4、R5、R6およびR7はすべてHであり、nは0であり、mは1であり、ならびにXはOである、請求項1に記載の化合物。
- R9は、C1〜C6アルキル、C1〜C3アルキルフェニル、C1〜C3アルコキシルフェニル、フルオロフェニル、クロロフェニル、または下記:
- R2は、ヒドロキシルC1〜C6アルキル、フェニル、C1〜C3アルコキシルフェニル、または(CH2)j−O−(CH2)i−R11であり、この際、jは1であり;iは0または1であり;ならびにR11は下記:
- R1はH、C1〜C6アルキル、またはフェニルメチルである、請求項4に記載の化合物。
- R2はp−メトキシフェニルである、請求項5に記載の化合物。
- R2は(CH2)j−O−(CH2)i−R11であり、この際、jは1であり;iは0または1であり;ならびにR11は下記:
- R2はp−メトキシフェニルまたはp−フルオロフェニルであり、R1およびR4は双方ともHであり、R9はp−メチルフェニルであり、nは0であり、mは1であり、ならびにXはOである、請求項1に記載の化合物。
- R5はCH3CH2であり、R6はHまたはOHであり、R7はHであり、R2はp−メトキシフェニルであり、およびR3はHである、請求項8に記載の化合物。
- R5はCH3CH2であり、R6はHであり、R7はHであり、R2はp−メトキシフェニルであり、ならびにR3は下記:
- R5およびR7は双方ともHであり、R6はOHであり、R2はp−メトキシフェニルであり、ならびにR3は下記:
- R3、R5およびR6はすべてHであり、R7はメチルであり、R2はp−メトキシフェニルである、請求項8に記載の化合物。
- R3、R5、R6およびR7はすべてHであり、R2はp−フルオロフェニルである、請求項8に記載の化合物。
- 請求項1〜13のいずれか1項に記載の化合物を含む癌を治療するための薬剤。
- 前記癌が、結腸癌、鼻咽頭癌、肺癌、乳癌、前立腺癌または卵巣癌である、請求項14に記載の薬剤。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361883289P | 2013-09-27 | 2013-09-27 | |
US61/883,289 | 2013-09-27 | ||
PCT/US2014/057575 WO2015048365A1 (en) | 2013-09-27 | 2014-09-26 | Novel 20(s)-sulfonylamidine derivatives of camptothecin and the use thereof as a potent antitumor agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016531877A JP2016531877A (ja) | 2016-10-13 |
JP6182720B2 true JP6182720B2 (ja) | 2017-08-23 |
Family
ID=52744479
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016518190A Expired - Fee Related JP6182720B2 (ja) | 2013-09-27 | 2014-09-26 | カンプトセシンの新規な20(s)−スルホニルアミジン誘導体および当該誘導体の強力な抗癌剤としての使用方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US9718835B2 (ja) |
EP (1) | EP3049419B1 (ja) |
JP (1) | JP6182720B2 (ja) |
KR (1) | KR101844802B1 (ja) |
TW (1) | TWI526446B (ja) |
WO (1) | WO2015048365A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105884789A (zh) * | 2016-05-18 | 2016-08-24 | 兰州大学 | 10-氟喜树碱类衍生物及其制备方法及用途 |
CN111689978A (zh) * | 2019-03-11 | 2020-09-22 | 兰州大学 | 一种喜树碱20-位修饰的磺酰胺类化合物及其制备方法和用途 |
CN111689977A (zh) * | 2019-03-11 | 2020-09-22 | 兰州大学 | 一种喜树碱20-位修饰的磺酰脲类化合物及其制备方法和用途 |
CN111689979A (zh) * | 2019-03-12 | 2020-09-22 | 兰州大学 | 一种9-位哌嗪磺酰胺-10-羟基喜树碱类化合物及其制备方法和在抗肿瘤中的用途 |
AU2022253902A1 (en) | 2021-04-10 | 2023-11-02 | Profoundbio Us Co. | Folr1 binding agents, conjugates thereof and methods of using the same |
CA3216459A1 (en) | 2021-04-23 | 2022-10-27 | Profoundbio Us Co. | Anti-cd70 antibodies, conjugates thereof and methods of using the same |
TW202320857A (zh) | 2021-07-06 | 2023-06-01 | 美商普方生物製藥美國公司 | 連接子、藥物連接子及其結合物及其使用方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5646159A (en) * | 1994-07-20 | 1997-07-08 | Research Triangle Institute | Water-soluble esters of camptothecin compounds |
EP2370435B1 (en) | 2008-11-24 | 2015-01-07 | Cedars-Sinai Medical Center | Antioxidant camptothecin derivatives and antioxidant antineoplastic nanospheres thereof |
EP2443125B1 (en) * | 2009-06-17 | 2014-11-26 | Threshold Pharmaceuticals, Inc. | Camptothecin derivatives |
CN102086208B (zh) * | 2010-12-10 | 2013-01-02 | 兰州大学 | 4β-鬼臼毒素脒类化合物及其制备方法和用途 |
TWI480042B (zh) | 2011-11-03 | 2015-04-11 | Taiwan Liposome Co Ltd | 疏水性喜樹鹼衍生物之醫藥組合物 |
-
2014
- 2014-09-19 TW TW103132504A patent/TWI526446B/zh not_active IP Right Cessation
- 2014-09-26 WO PCT/US2014/057575 patent/WO2015048365A1/en active Application Filing
- 2014-09-26 US US15/025,296 patent/US9718835B2/en not_active Expired - Fee Related
- 2014-09-26 EP EP14848297.9A patent/EP3049419B1/en not_active Not-in-force
- 2014-09-26 KR KR1020167010185A patent/KR101844802B1/ko active IP Right Grant
- 2014-09-26 JP JP2016518190A patent/JP6182720B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
TWI526446B (zh) | 2016-03-21 |
US20160229862A1 (en) | 2016-08-11 |
TW201514183A (zh) | 2015-04-16 |
EP3049419A1 (en) | 2016-08-03 |
KR101844802B1 (ko) | 2018-04-03 |
EP3049419A4 (en) | 2017-02-22 |
US9718835B2 (en) | 2017-08-01 |
EP3049419B1 (en) | 2017-11-08 |
JP2016531877A (ja) | 2016-10-13 |
KR20160055925A (ko) | 2016-05-18 |
WO2015048365A1 (en) | 2015-04-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6182720B2 (ja) | カンプトセシンの新規な20(s)−スルホニルアミジン誘導体および当該誘導体の強力な抗癌剤としての使用方法 | |
JP6815318B2 (ja) | 二官能性分子によって標的化タンパク質分解を誘導する方法 | |
Wang et al. | Design, synthesis, mechanisms of action, and toxicity of novel 20 (s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents | |
AU2019316858B2 (en) | Smad3 inhibitors | |
CA3103282A1 (en) | Rapamycin analogs and uses thereof | |
Chia et al. | Synthesis and anti-inflammatory structure–activity relationships of thiazine–quinoline–quinones: Inhibitors of the neutrophil respiratory burst in a model of acute gouty arthritis | |
Li et al. | Discovery of novel β-carboline/acylhydrazone hybrids as potent antitumor agents and overcome drug resistance | |
CA3169315A1 (en) | Glucose triptolide conjugates and uses thereof | |
Feng et al. | Synthesis and biological evaluation of celastrol derivatives as potential anti-glioma agents by activating RIP1/RIP3/MLKL pathway to induce necroptosis | |
Li et al. | Synthesis, antitumor activity evaluation and mechanistic study of novel hederacolchiside A1 derivatives bearing an aryl triazole moiety | |
Patel et al. | Design, synthesis and antitumour evaluation of pyrrolo [1, 2-f]-phenanthridine and dibenzo [f, h] pyrrolo [1, 2-b] isoquinoline derivatives | |
Pedatella et al. | Antitumor agents 7. Synthesis, antiproliferative activity and molecular modeling of new l-lysine-conjugated pyridophenoxazinones as potent DNA-binding ligands and topoisomerase IIα inhibitors | |
US20080275088A1 (en) | Use of Collismycin and Derivatives Thereof as Oxidative Stress Inhibitors | |
Xiao et al. | Novel panaxadiol triazole derivatives induce apoptosis in HepG-2 cells through the mitochondrial pathway | |
CN107531631B (zh) | 用于治疗疾病的方法和药剂 | |
JP6545266B2 (ja) | 17β‐HSD1抑制剤のプロドラッグ | |
Zhu et al. | Design and synthesis of NAD (P) H: Quinone oxidoreductase (NQO1)-activated prodrugs of 23-hydroxybetulinic acid with enhanced antitumor properties | |
ES2309567T3 (es) | Derivados de imidazopiridinas como inhibidores de no-sintasa inducible. | |
Rhee et al. | Synthesis, cytotoxicity and topoisomerase II inhibitory activity of benzonaphthofurandiones | |
BRPI0714672A2 (pt) | derivados de camptotecina com atividade antitumor | |
CN115286689B (zh) | 靶向降解Bcl-2蛋白的化合物及其应用和药物 | |
EP4382524A1 (en) | Indole derivative, method for preparing same, and use thereof | |
CN114805375B (zh) | 一种n-苯基烷氧基二苯并吖庚因类化合物、其制备方法及医药用途 | |
EP4062942A1 (en) | Disulfide-based prodrug compounds | |
Wu et al. | Development of novel quinoline-NO donor hybrids inducing human breast cancer cells apoptosis via inhibition of topoisomerase I |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160518 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160325 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20160324 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20170118 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170124 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170404 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20170509 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20170608 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170608 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170712 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170712 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6182720 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |