CN117551163A - 一种安麻吩金类似物及其制备方法与应用 - Google Patents
一种安麻吩金类似物及其制备方法与应用 Download PDFInfo
- Publication number
- CN117551163A CN117551163A CN202311248419.4A CN202311248419A CN117551163A CN 117551163 A CN117551163 A CN 117551163A CN 202311248419 A CN202311248419 A CN 202311248419A CN 117551163 A CN117551163 A CN 117551163A
- Authority
- CN
- China
- Prior art keywords
- gold
- candida
- extracting
- ansamitocin
- culturing
- 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
- 238000002360 preparation method Methods 0.000 title claims description 8
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 26
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000000855 fermentation Methods 0.000 claims abstract description 16
- 230000004151 fermentation Effects 0.000 claims abstract description 16
- 241000233866 Fungi Species 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 13
- 238000012258 culturing Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 238000004440 column chromatography Methods 0.000 claims description 9
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 8
- 239000002609 medium Substances 0.000 claims description 8
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims description 8
- 238000004007 reversed phase HPLC Methods 0.000 claims description 8
- 239000000287 crude extract Substances 0.000 claims description 6
- 241000222122 Candida albicans Species 0.000 claims description 5
- 241000222178 Candida tropicalis Species 0.000 claims description 5
- 201000007336 Cryptococcosis Diseases 0.000 claims description 5
- 241000221204 Cryptococcus neoformans Species 0.000 claims description 5
- 241000222126 [Candida] glabrata Species 0.000 claims description 5
- 229940095731 candida albicans Drugs 0.000 claims description 5
- 208000032343 candida glabrata infection Diseases 0.000 claims description 5
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000011218 seed culture Methods 0.000 claims description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 4
- 241000222173 Candida parapsilosis Species 0.000 claims description 4
- 241000800290 Hormonema carpetanum Species 0.000 claims description 4
- 239000003429 antifungal agent Substances 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 3
- 235000007164 Oryza sativa Nutrition 0.000 claims description 3
- 239000001888 Peptone Substances 0.000 claims description 3
- 108010080698 Peptones Proteins 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- 235000019319 peptone Nutrition 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 235000009566 rice Nutrition 0.000 claims description 3
- 238000004809 thin layer chromatography Methods 0.000 claims description 3
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims description 3
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims description 3
- 235000012141 vanillin Nutrition 0.000 claims description 3
- 229940055022 candida parapsilosis Drugs 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000001963 growth medium Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 235000016594 Potentilla anserina Nutrition 0.000 claims 2
- 244000308495 Potentilla anserina Species 0.000 claims 2
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 claims 1
- 240000007594 Oryza sativa Species 0.000 claims 1
- PVNFMCBFDPTNQI-UIBOPQHZSA-N [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] acetate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 3-methylbutanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] propanoate Chemical class CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(C)=O)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CCC(=O)O[C@H]1CC(=O)N(C)c2cc(C\C(C)=C\C=C\[C@@H](OC)[C@@]3(O)C[C@H](OC(=O)N3)[C@@H](C)C3O[C@@]13C)cc(OC)c2Cl.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)CC(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 PVNFMCBFDPTNQI-UIBOPQHZSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 15
- BODYFEUFKHPRCK-ZCZMVWJSSA-N ibrexafungerp Chemical compound N1([C@@H]2C[C@@]34COC[C@]([C@H]2OC[C@](C)(N)C(C)(C)C)(C)[C@@H]3CC[C@@H]2[C@@]3(C)CC[C@]([C@H]([C@]3(C)CC=C24)C(O)=O)(C)[C@H](C)C(C)C)N=CN=C1C1=CC=NC=C1 BODYFEUFKHPRCK-ZCZMVWJSSA-N 0.000 description 14
- 238000011282 treatment Methods 0.000 description 10
- 150000003648 triterpenes Chemical class 0.000 description 10
- -1 ambroxol gold analogue Chemical class 0.000 description 9
- 229940121286 ibrexafungerp Drugs 0.000 description 8
- 108010049047 Echinocandins Proteins 0.000 description 7
- 206010017533 Fungal infection Diseases 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 208000031888 Mycoses Diseases 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000002538 fungal effect Effects 0.000 description 6
- 208000035473 Communicable disease Diseases 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- IAOFPTKYKOAKGZ-CRWQHXLTSA-N enfumafungin Chemical class O([C@H]1[C@H](OC(C)=O)C[C@@]23C(O)OC[C@]1(C)[C@@H]2CC[C@@H]1[C@@]2(C)CC[C@]([C@H]([C@]2(C)CC=C13)C(O)=O)(C)[C@H](C)C(C)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O IAOFPTKYKOAKGZ-CRWQHXLTSA-N 0.000 description 5
- ZRLNBWWGLOPJIC-PYQRSULMSA-N A'-neogammacerane Chemical compound C([C@]1(C)[C@H]2CC[C@H]34)CCC(C)(C)[C@@H]1CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@@H]1C(C)C ZRLNBWWGLOPJIC-PYQRSULMSA-N 0.000 description 4
- 241000645784 [Candida] auris Species 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- BSLYZLYLUUIFGZ-JRUDBKCSSA-N 4,4,14-trimethyl-9,19-cyclo-5alpha,9beta-cholestane Chemical compound C1CCC(C)(C)[C@H]2[C@@]31C[C@@]13CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@]3(C)[C@@H]1CC2 BSLYZLYLUUIFGZ-JRUDBKCSSA-N 0.000 description 2
- 229920002498 Beta-glucan Polymers 0.000 description 2
- 241000675278 Candida albicans SC5314 Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RRTBTJPVUGMUNR-UHFFFAOYSA-N Cycloartanol Natural products C12CCC(C(C(O)CC3)(C)C)C3C2(CC)CCC2(C)C1(C)CCC2C(C)CCCC(C)C RRTBTJPVUGMUNR-UHFFFAOYSA-N 0.000 description 2
- KVSNMTUIMXZPLU-UHFFFAOYSA-N D:A-friedo-oleanane Natural products CC12CCC3(C)C4CC(C)(C)CCC4(C)CCC3(C)C2CCC2(C)C1CCCC2C KVSNMTUIMXZPLU-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 241000235645 Pichia kudriavzevii Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000011483 antifungal activity assay Methods 0.000 description 2
- 238000002815 broth microdilution Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- YNBJLDSWFGUFRT-UHFFFAOYSA-N cycloartenol Natural products CC(CCC=C(C)C)C1CCC2(C)C1(C)CCC34CC35CCC(O)C(C)(C)C5CCC24C YNBJLDSWFGUFRT-UHFFFAOYSA-N 0.000 description 2
- OORMXZNMRWBSTK-LGFJJATJSA-N dammarane Chemical compound C1CCC(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@H]([C@H](C)CCCC(C)C)[C@H]4CC[C@@H]3[C@]21C OORMXZNMRWBSTK-LGFJJATJSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 2
- KVSNMTUIMXZPLU-XOZXFAFYSA-N friedelane Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)C(C)(C)CC[C@]1(C)CC[C@]2(C)[C@H]4CC[C@@]1(C)[C@H]3CCC[C@@H]1C KVSNMTUIMXZPLU-XOZXFAFYSA-N 0.000 description 2
- 108010052221 glucan synthase Proteins 0.000 description 2
- 150000002338 glycosides Chemical group 0.000 description 2
- 150000002343 gold Chemical class 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 2
- ZQIOPEXWVBIZAV-ZKYCIREVSA-N lanostane Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C)[C@@H]1[C@@H]2[C@]2(C)CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 ZQIOPEXWVBIZAV-ZKYCIREVSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- NKMDIWKRKQFYPH-VIUFNMEASA-N lupane Chemical compound C1CCC(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C)CC[C@@H](C(C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C NKMDIWKRKQFYPH-VIUFNMEASA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- IDUYJRXRDSPPRC-NRFANRHFSA-N oteseconazole Chemical compound C([C@](O)(C=1C(=CC(F)=CC=1)F)C(F)(F)C=1N=CC(=CC=1)C=1C=CC(OCC(F)(F)F)=CC=1)N1C=NN=N1 IDUYJRXRDSPPRC-NRFANRHFSA-N 0.000 description 2
- 229950011629 oteseconazole Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229930000044 secondary metabolite Natural products 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- OOTXFYSZXCPMPG-BMYLZFHVSA-N ursane Chemical compound C1CCC(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C)CC[C@@H](C)[C@H](C)[C@H]5[C@H]4CC[C@@H]3[C@]21C OOTXFYSZXCPMPG-BMYLZFHVSA-N 0.000 description 2
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 description 1
- XBZYWSMVVKYHQN-MYPRUECHSA-N (4as,6as,6br,8ar,9r,10s,12ar,12br,14bs)-10-hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(sulfooxy)methyl]-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid Chemical compound C1C[C@H](O)[C@@](C)(COS(O)(=O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C XBZYWSMVVKYHQN-MYPRUECHSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- 108010070892 1,3-beta-glucan synthase Proteins 0.000 description 1
- VCNKUCWWHVTTBY-UHFFFAOYSA-N 18alpha-Oleanane Natural products C1CCC(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C)(C)CC5C4CCC3C21C VCNKUCWWHVTTBY-UHFFFAOYSA-N 0.000 description 1
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 description 1
- 241001480043 Arthrodermataceae Species 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 241000235646 Cyberlindnera jadinii Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 208000037026 Invasive Fungal Infections Diseases 0.000 description 1
- IABBAGAOMDWOCW-UHFFFAOYSA-N Nicametate citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCN(CC)CCOC(=O)C1=CC=CN=C1 IABBAGAOMDWOCW-UHFFFAOYSA-N 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 238000010162 Tukey test Methods 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960005174 ambroxol Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 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 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- ZYZJWAJOTPNVPI-ZVBSCDOUSA-N cucurbitane Chemical compound C([C@H]1[C@]2(C)CC[C@@H]([C@]2(CC[C@]11C)C)[C@H](C)CCCC(C)C)CC2[C@H]1CCCC2(C)C ZYZJWAJOTPNVPI-ZVBSCDOUSA-N 0.000 description 1
- 230000037304 dermatophytes Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 125000001976 hemiacetal group Chemical group 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- SIOMFBXUIJKTMF-UHFFFAOYSA-N hypoglauterpenic acid Natural products C1CC(O)C(C)(C)C2=CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C SIOMFBXUIJKTMF-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000002013 molluscicidal effect Effects 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- SBOJXQVPLKSXOG-UHFFFAOYSA-N o-amino-hydroxylamine Chemical compound NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 description 1
- BPAWXSVOAOLSRP-UHFFFAOYSA-N oleanane Natural products CCCCCCCCCCCCCCCC(=O)OC1CCC2(C)C(CCC3(C)C2CC=C4C5CC(C)(C)CCC5(C)C(O)CC34C)C1(C)C BPAWXSVOAOLSRP-UHFFFAOYSA-N 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- JVNIAJRGELYGEG-UHFFFAOYSA-N pyridine;2h-triazole Chemical group C1=CNN=N1.C1=CC=NC=C1 JVNIAJRGELYGEG-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229930182493 triterpene saponin Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
- C12P33/00—Preparation of steroids
- C12P33/20—Preparation of steroids containing heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/645—Fungi ; Processes using fungi
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Microbiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种安麻吩金类似物，结构选自以下结构的一种：
Description
技术领域
本发明属于医药技术领域，具体地说，涉及一种安麻吩金类似物及其制备方法与应用。
背景技术
三萜是萜类化合物的一大亚类，由30个碳原子构成的基本碳架，大多数可看作是由6个异戊二烯单体串联而成，以游离状态或苷的形式存在，其苷类多数可溶于水，也称为三萜皂苷。按分子中基本碳骨架类型，三萜类可分为无环三萜、单环三萜、双环和三环三萜、四环和五环三萜。三萜类化合物广泛分布于自然界，具有重要的生物活性，如溶血、抗癌、抗炎、抗菌、杀软体动物、抗生育等活性。大多数三萜类为四环三萜和五环三萜。四环三萜分为：羊毛甾烷型(lanostane)、达玛烷型(dammarane)、甘遂烷型(triucallane)、环阿屯烷型(cycloartane)、葫芦烷型(cucurbitane)；五环三萜类分为：齐墩果烷型(oleanane)、羽扇豆烷型(lupane)、熊果烷型(ursane)、木栓烷型(friedelane)、羊齿烷型(Amniodane)和异羊齿烷型(Isoamniodane)、何帕烷型(hopane)、异何帕烷型(Isoparane)。
真菌感染正在成为对个人的一种危害，在全球影响了将近1亿人[8.A.M.Rauseo,A.Coler-Reilly,L.Larson,A.Spec,Hope on the Horizon:Novel Fungal Treatments inDevelopment,Open Forum Infectious Diseases 2020,7.]。真菌感染具体可以分为两类，浅表性真菌感染和侵袭性真菌感染[9.D.W.DenningM.J.Bromley,How to bolster theantifungal pipeline,2015,347,1414-1416.]。常规的抗真菌药物主要有4类，即：多烯类、氮唑类、棘白菌素类和氟胞嘧啶[10.T.J.Gintjee,M.A.Donnelley,G.R.Thompson,Aspiring Antifungals:Review of Current Antifungal Pipeline Developments,2020,6,28.]。对于真菌感染的治疗的过程中，常规的抗真菌药物治疗虽然有效，但有些治疗周期较长且易复发，如甲癣[11.J.Mohr,M.Johnson,T.Cooper,J.S.Lewis,L.Ostrosky-Zeichner,Current Options in Antifungal Pharmacotherapy,2008,28,614-645.]。这些药物在治疗疾病的同时，也暴露出一些缺点，比如耐药性、药代动力学变化、毒性、生物利用度降低和药物间相互作用[12.T.F.Patterson,G.R.Thompson,III,D.W.Denning,J.A.Fishman,S.Hadley,R.Herbrecht,D.P.Kontoyiannis,K.A.Marr,V.A.Morrison,M.H.Nguyen,B.H.Segal,W.J.Steinbach,D.A.Stevens,T.J.Walsh,J.R.Wingard,J.-A.H.Young,J.E.Bennett,Practice Guidelines for the Diagnosis and ManagementofAspergillosis:2016 Update by the Infectious Diseases Society of America,Clinical Infectious Diseases 2016,63,e1-e60.]。而且在对于真菌感染的治疗过程中，还引起一些不良事件[13.A.Khurana,K.Sardana,A.Chowdhary,Antifungal resistancein dermatophytes:Recent trends and therapeutic implications,Fungal Geneticsand Biology 2019,132,103255.]。近年来，抗真菌耐药性在临床上日益受到关注[14.J.A.Hendrickson,C.Hu,S.L.Aitken,N.Beyda,Antifungal Resistance:aConcerning Trend for the Present and Future,Current Infectious DiseaseReports 2019,21,47.]，欧洲主要地区还出现了对棘白菌素类药物[15.B.D.Alexander,M.D.Johnson,C.D.Pfeiffer,C.Jiménez-Ortigosa,J.Catania,R.Booker,M.Castanheira,S.A.Messer,D.S.Perlin,M.A.Pfaller,Increasing Echinocandin Resistance inCandida glabrata:Clinical Failure Correlates With Presence of FKS Mutationsand Elevated Minimum Inhibitory Concentrations,Clinical Infectious Diseases2013,56,1724-1732.]以及唑类耐药菌株的获得性耐药性[16.J.F.Meis,A.Chowdhary,J.L.Rhodes,M.C.Fisher,P.E.Verweij,Clinical implications of globally emergingazole resistance in Aspergillus fumigatus,2016,371,20150460.]。抗真菌耐药性不仅给研究人员和制药公司开发更新带来了更大的挑战，还使医生对于患者的治疗变得更加复杂。新型抗真菌药物的研发和新治疗策略迫在眉睫。但是近些年来，对于新型抗真菌药物的开发进展甚微[17.L.Scorzoni,E.S.A.C.de Paula,C.M.Marcos,P.A.Assato,W.C.deMelo,H.C.de Oliveira,C.B.Costa-Orlandi,M.J.Mendes-Giannini,A.M.Fusco-Almeida,Antifungal Therapy:New Advances in the Understanding and Treatment ofMycosis,Frontiers in microbiology 2017,8,36.]，美国食品和药物管理局(FDA)只批准了两种新药，Oteseconazole(2022年4月)[18.S.M.Hoy,Oteseconazole:First Approval,Drugs 2022,82,1017-1023.]和Ibrexafungerp(2021年6月)[19.K.N.Barnes,A.M.Yancey,A.B.Forinash,Ibrexafungerp in the Treatment of Vulvovaginal Candidiasis,2023,57,99-106.]。
Ibrexafungerp是天然三萜糖苷类化合物安麻吩金(enfumafungin)的半合成衍生物之一。Enfumafungin具有非常好的抗真菌的活性，后续为了提高enfumafungin的口服功效和药代动力学性质，Merck和Scynexis制备了一系列半合成的enfumafungin衍生物[20.R.F.HectorD.E.Bierer,Newβ-glucan inhibitors as antifungal drugs,ExpertOpinion on Therapeutic Patents 2011,21,1597-1610.]。与enfumafungin相比，ibrexafungerp(以前称为SCY-078或MK-3118)最终成功地通过用吡啶三氮唑基团取代C-2的乙酰氧基团，用氨基醚取代C-3的糖苷基团，以及用醚取代C-25的半缩醛基团，完成了开发[21.M.A.Pfaller,S.A.Messer,M.R.Motyl,R.N.Jones,M.Castanheira,Activity ofMK-3118,a new oral glucan synthase inhibitor,tested against Candida spp.bytwo international methods(CLSI and EUCAST),The Journal of AntimicrobialChemotherapy 2013,68,858-863.22.S.Wring,K.Borroto-Esoda,E.Solon,D.Angulo,SCY-078,a Novel Fungicidal Agent,Demonstrates Distribution to Tissues Associatedwith Fungal Infections during Mass Balance Studies with Intravenous and Oral[(14)C]SCY-078 in Albino and Pigmented Rats,Antimicrob Agents Chemother 2019,63.]。Ibrexafungerp(29)已于2021年6月获得FDA批准，作为治疗外阴阴道念珠菌病的唯一非唑类药物，约75％的女性一生中至少感染一次，主要由白色念珠菌感染引起[23.M.C.Masone,Ibrexafungerp to treat acute vulvovaginal candidiasis,NatureReviews Urology 2021,18,638-638.]。Ibrexafungerp是一种口服活性的β-(1,3)-葡聚糖合成抑制剂，是过去20年来批准的第一类新型抗真菌药物。Ibrexafungerp虽然在结构上与echinocandins不同，但ibrexafungerp的作用机制与echinocandins类似，通过非竞争性抑制β-(1,3)-D-葡聚糖合成酶(GS)，从而破坏真菌细胞壁的形成[24.S.JallowN.Govender,Ibrexafungerp:A First-in-Class Oral Triterpenoid Glucan Synthase Inhibitor,Journal of Fungi 2021,7,163.]。然而，ibrexafungerp和echinocandins在酶上的结合部位并不相同，而是部分重叠，导致耐药株之间的交叉耐药性非常有限[25.C.Jiménez-Ortigosa,W.B.Perez,D.Angulo,K.Borroto-Esoda,D.S.Perlin,De Novo Acquisition ofResistance to SCY-078 in Candida glabrata Involves FKS Mutations That bothOverlap and Are Distinct from Those Conferring Echinocandin Resistance,2017,61,10.1128/aac.00833-00817.]。
安麻吩金是一种天然的三萜糖苷类化合物，最早是从Hormonema carpetanumATCC 74360分离得到的。为了寻找新的enfumafungin类似物，探讨enfumafungin的生物合成，对H.carpetanum ACTT 74360进行了重新研究，以期发现新的类似物。
发明内容
本发明的第一个目的是提供一种安麻吩金类似物。
本发明的第二个目的是提供一种所述安麻吩金类似物的制备方法。
本发明的第三个目的是提供一种所述安麻吩金类似物在制备抗真菌的药物中的应用。
为了实现上述目的，本发明采用的技术方案如下：
本发明的第一方面，提供了一种安麻吩金类似物，结构选自以下结构的一种：
所述安麻吩金类似物是从真菌H.carpetanum ATCC 74360的发酵物中提取分离获得。
本发明的第二方面，提供了一种所述安麻吩金类似物的提取方法，包括以下步骤：
将Hormonema carpetanum菌株接种在瓶中，每个瓶中含有种子培养基，培养3-4天；种子培养物转移到发酵培养基中，继续培养获得发酵液；
将上述发酵液用等体积的乙酸乙酯提取，直至提取液基本无色，在减压下浓缩得到粗浸膏；
将上述粗浸膏用等体积的甲醇溶解，MCI填料拌样，MCI柱层析，以甲醇-水梯度洗脱，得到18个组分Fr.1-Fr.18；
Fr.13经Sephadex LH-20凝胶柱层析，通过RP-HPLC纯化，得到enfumafungin B(13.1毫克，tR 14.9分钟)；
Fr.14经Sephadex LH-20凝胶柱层析，通过RP-HPLC纯化，得到enfumafungin C(6毫克，tR 13.3分钟)。
所述培养3-4天的条件：在25℃和220rpm的条件下培养3-4天。
所述继续培养的条件：在25℃培养28天获得发酵液。
所述种子培养基每100毫升含有40克/升麦芽糖，10克/升麦芽提取物，2.1克/升蛋白胨。
所述发酵培养基每60升含有50克/升大米，1克/升麦芽提取物，0.5克/升磷酸二氢钾。
所述MCI柱是指柱内径3.8cm，柱高46cm。
所述甲醇-水梯度洗脱的条件：MeOH/H2O 30％-100％，25.0mL/min。
所述得到18个组分Fr.1-Fr.18是根据HSGF254薄层色谱板检测，10％的硫酸香草醛显色。
所述Sephadex LH-20凝胶柱层析的条件：CH2Cl2/MeOH，2:1。
所述RP-HPLC的条件：70％MeCN，2.0毫升/分钟。
本发明的第三方面，提供了一种所述安麻吩金类似物在制备抗真菌的药物中的应用。
所述真菌选自白色念珠菌Candida albicans SC5314、热带念珠菌Candidatropicalis 8915、光滑念珠菌Candida glabrata 537、可柔念珠菌Candida krusei 4996、耳念珠菌(Candida auris 919、Candida auris 918)、近平念珠菌Candida parapsilosis22019、新生隐球菌Cryptoccus neoformans 32609。
由于采用上述技术方案，本发明具有以下优点和有益效果：
本发明提供的安麻吩金类似物是从微生物中发现的活性次级代谢产物，具有抗真菌的活性。对白色念珠菌、热带念珠菌、光滑念珠菌、可柔念珠菌、新生隐球菌等具有与安麻吩金相近的抗真菌活性。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
enfumafungin B和enfumafungin C的制备
将Hormonema carpetanum ATCC 74360(购买获得)菌株接种在10个容量为250毫升的三角瓶中，每个三角瓶中含有100毫升的种子培养基(40克/升麦芽糖，10克/升麦芽提取物，2.1克/升蛋白胨)。在25℃和220rpm的条件下培养3-4天。种子培养物转移到60升发酵培养基中(50克/升大米，1克/升麦芽提取物，0.5克/升磷酸二氢钾)，在25℃培养28天获得发酵液。将上述发酵液用等体积的乙酸乙酯提取，提取4-5次，直至提取液基本无色，在减压下浓缩得到粗浸膏40g。将上述粗浸膏用10mL甲醇溶解，40g MCI填料拌样，经MCI柱层析(柱内径3.8cm，柱高46cm)，以甲醇-水梯度洗脱(MeOH/H2O 30％-100％，25.0mL/min)，按极性大小收集，根据HSGF254薄层色谱板检测，10％的硫酸香草醛显色，得到18个组分(Fr.1-Fr.18)。Fr.13经Sephadex LH-20(CH2Cl2/MeOH，2:1)凝胶柱层析，并进一步通过RP-HPLC(70％MeCN，2.0毫升/分钟)纯化，得到enfumafungin B(13.1毫克，tR 14.9分钟)。Fr.14经Sephadex LH-20(CH2Cl2/MeOH，2:1)凝胶柱层析，并进一步通过RP-HPLC(70％MeCN，2.0毫升/分钟)纯化，得到enfumafungin C(6毫克，tR 13.3分钟)。
enfumafungin B和enfumafungin C的结构鉴定:
本发明从H.carpetanum ATCC 74360次级代谢产物中分离得到的2种新化合物，命名为enfumafungin B和enfumafungin C，2种化合物的理化数据和1H和13C NMR数据(表1-2)如下：
enfumafungin B:无定型粉末；Rf0.3和0.4(EtOAc/MeOH/H2O 90:10:1)；旋光度[α]24.1 D-33(c 0.4,CH2Cl2)；红外吸收数据IR(film)νmax 33379,2960,2872,1701,1385,1160,1073,1029cm-1；1H and 13C NMR数据见表1；高分辨质谱HRESIMS m/z:665.3907[M-H]-(calcd for C36H57O11,665.3901),711.3958[M+COOH]-(calcd for C37H59O13,711.3956),1331.7850[2M-H]-(calcd for C72H115O22,1331.7880).
enfumafungin C:无定型粉末；Rf0.4和0.5(EtOAc/MeOH/H2O 90:10:1)；旋光度[α]24.1 D-21(c 0.2,CH2Cl2)；红外吸收数据IR(film)νmax 3381,2929,1732,1452,1373,1262,1069,1029cm-1；1H and 13C NMR数据见表2；高分辨质谱HRESIMS m/z:708.4333[M+NH4]+(calcd for C38H62NO11,708.4323),1398.8376[2M+NH4]+(calcd for C76H120NO22,1398.8302),511.3415[M-glucose+H]+(calcd for C32H47O5,511.3423).
表1.化合物enfumafungin B的1H和13C NMR数据a
aIn CD3OD,600MHz for 1H and 150MHz for 13C NMR.
表2.化合物enfumafungin C的1H和13C NMR数据a
aIn CD3OD,600MHz for 1H and 150MHz for 13C NMR.
实施例2
本发明的enfumafungin B和enfumafungin C的抗真菌活性。
(一)实验方法
1.真菌菌株的选择
临床真菌来自上海长征医院(中国)和本实验室真菌收藏。针对enfumafungin B和enfumafungin C的抗真菌活性选择了以下8种临床真菌：白色念珠菌Candida albicansSC5314、热带念珠菌Candida tropicalis 8915、光滑念珠菌Candida glabrata 537、可柔念珠菌Candida krusei 4996、耳念珠菌(Candida auris 919、Candida auris 918)、近平念珠菌Candida parapsilosis 22019、新生隐球菌Cryptoccus neoformans 32609，还有两种耐fluconazole的真菌：Candida albicans 10231、Cryptoccus neoformans H99。
2.抗真菌活性检测
抗真菌活性测定采用根据CLSIM38-A2和M27-A3标准调整的肉汤微量稀释法。抗真菌活性测定使用从CLSIM38-A2和M27-A3标准品调整的肉汤微量稀释方法进行。将真菌悬浮液施用于RPMI 1640培养基中浓度为103CFU/mL的96孔板。选择fluconazole和enfumafungin为阳性对照药物，将测试的化合物，fluconazole和enfumafungin连续稀释，最终浓度范围为64至0.125μg/mL。为了评估效果，在应用于96孔板之前，将fluconazole以8μg/mL的浓度加入真菌悬浮液中，同时连续稀释化合物。将96孔板放在30℃下孵育48小时。之后用酶标仪在630nm处测量光密度，并去除背景光密度。最小抑制浓度(MIC80)是抑制80％测试菌株生长的浓度。
3.统计分析
使用GraphPad Prism 8.0进行统计分析。数据通过单向方差分析进行分析，然后进行Tukey检验，以比较空白组和对照组。P值<0.05的差异被认为具有统计学意义。
(二)实验结果
enfumafungin B、enfumafungin C、fluconazole、enfumafungin的抗真菌活性(MIC80值，μg/mL)结果如表3所示：
表3
表3中结果说明，本发明的化合物enfumafungin B对光滑念珠菌、可柔念珠菌具有抗真菌活性；enfumafungin C对白色念珠菌、热带念珠菌、光滑念珠菌、可柔念珠菌、新生隐球菌等具有与安麻吩金相近的抗真菌活性；其中enfumafungin C比enfumafungin B的活性更好。
Enfumafungin B和C是安麻吩金的结构类似物，Ibrexafungerp是在天然安麻吩金的结构基础上经过半合成获得的衍生物。为了提高该类抗真菌药物的口服功效和药代动力学性质，研究人员仍在不断致力于第二代安麻吩金类抗真菌药物的合成[S.Chu,L.Long,T.S.McCormick,K.Borroto-Esoda,S.Barat,M.A.Ghannoum,A Second-GenerationFungerp Analog,SCY-247,Shows Potent In Vivo Activity in a Murine Model ofHematogenously Disseminated Candida albicans,Antimicrob Agents Chemother2021,65,e01988-20.]，本发明提供的两种安麻吩金新类似物，将为该类抗真菌药物第二代的结构改造提供新的天然原料，经过结构改造和类似物合成，将帮助获得口服功效和药代动力学性质提高的新半合成衍生物。
以上所述仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专利的技术人员在不脱离本发明技术方案范围内，当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明方案的范围内。
Claims (10)
1.一种安麻吩金类似物，其特征在于，结构选自以下结构的一种：
2.根据权利要求1所述的安麻吩金类似物，其特征在于，所述安麻吩金类似物是从真菌H.carpetanum的发酵物中提取分离获得。
3.一种权利要求1或2所述的安麻吩金类似物的提取方法，其特征在于，包括以下步骤：
将Hormonema carpetanum菌株接种在瓶中，每个瓶中含有种子培养基，培养3-4天；种子培养物转移到发酵培养基中，继续培养获得发酵液；
将上述发酵液用等体积的乙酸乙酯提取，直至提取液基本无色，在减压下浓缩得到粗浸膏；
将上述粗浸膏用等体积的甲醇溶解，MCI填料拌样，MCI柱层析，以甲醇-水梯度洗脱，得到18个组分Fr.1-Fr.18；
Fr.13经Sephadex LH-20凝胶柱层析，通过RP-HPLC纯化，得到enfumafungin B；
Fr.14经Sephadex LH-20凝胶柱层析，通过RP-HPLC纯化，得到enfumafungin C。
4.根据权利要求3所述的安麻吩金类似物的提取方法，其特征在于，所述培养3-4天的条件：在25℃和220rpm的条件下培养3-4天；
所述继续培养的条件：在25℃培养28天获得发酵液。
5.根据权利要求3所述的安麻吩金类似物的提取方法，其特征在于，所述种子培养基每100毫升含有40克/升麦芽糖，10克/升麦芽提取物，2.1克/升蛋白胨；
所述发酵培养基每60升含有50克/升大米，1克/升麦芽提取物，0.5克/升磷酸二氢钾。
6.根据权利要求3所述的安麻吩金类似物的提取方法，其特征在于，所述MCI柱是指柱内径3.8cm，柱高46cm；
所述甲醇-水梯度洗脱的条件：MeOH/H2O 30％-100％，25.0mL/min。
7.根据权利要求3所述的安麻吩金类似物的提取方法，其特征在于，所述得到18个组分Fr.1-Fr.18是根据HSGF254薄层色谱板检测，10％的硫酸香草醛显色。
8.根据权利要求3所述的安麻吩金类似物的提取方法，其特征在于，所述Sephadex LH-20凝胶柱层析的条件：CH2Cl2/MeOH，2:1；
所述RP-HPLC的条件：70％MeCN，2.0毫升/分钟。
9.一种权利要求1或2所述的安麻吩金类似物在制备抗真菌的药物中的应用。
10.根据权利要求9所述的安麻吩金类似物在制备抗真菌的药物中的应用，其特征在于，所述真菌选自白色念珠菌、热带念珠菌、光滑念珠菌、可柔念珠菌、耳念珠菌、近平念珠菌、新生隐球菌。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311248419.4A CN117551163A (zh) | 2023-09-26 | 2023-09-26 | 一种安麻吩金类似物及其制备方法与应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311248419.4A CN117551163A (zh) | 2023-09-26 | 2023-09-26 | 一种安麻吩金类似物及其制备方法与应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117551163A true CN117551163A (zh) | 2024-02-13 |
Family
ID=89822163
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311248419.4A Pending CN117551163A (zh) | 2023-09-26 | 2023-09-26 | 一种安麻吩金类似物及其制备方法与应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117551163A (zh) |
-
2023
- 2023-09-26 CN CN202311248419.4A patent/CN117551163A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7026322B2 (en) | Phenylahistin and the phenylahistin analogs, a new class of anti-tumor compounds | |
| JPH0725692B2 (ja) | ニユーモシステイス・カリニの抑制方法 | |
| US5756472A (en) | Antifungal agent obtained from hormonema | |
| AU639698B2 (en) | Antibiotic agent | |
| CN112830949B (zh) | 海洋曲霉菌产生的抗真菌化合物及其制备方法 | |
| Basilio et al. | The discovery of moriniafungin, a novel sordarin derivative produced by Morinia pestalozzioides | |
| CN117551163A (zh) | 一种安麻吩金类似物及其制备方法与应用 | |
| JP3067869B2 (ja) | 抗生物質 | |
| EP0722940B1 (en) | Physiologically active substances PF1092A, PF1092B and PF1092C, process for the production thereof, and contraceptives and anticancer drugs containing the same as active ingredients | |
| Basha et al. | Recent progress in the chemotherapy of human fungal diseases. Emphasis on 1, 3-β-glucan synthase and chitin synthase inhibitors | |
| EP0877618B1 (en) | Antifungal agent | |
| WO2020146155A1 (en) | Turbinmicin compounds, compositions and uses thereof | |
| AU760975B2 (en) | Microbial transformation product | |
| US4910017A (en) | New compounds WF 2015 A and B | |
| Anke et al. | Non-β-lactam antibiotics | |
| CN112521439B (zh) | 桦褐孔菌醇F及其在制备α-葡萄糖苷酶抑制剂药物的应用 | |
| US5712109A (en) | Antifungal agent produced by arthrinium arundinis ATCC 74359 | |
| CN108516923B (zh) | 一系列烯萜类化合物及其制备方法和应用 | |
| JP4022360B2 (ja) | 新規生理活性物質 | |
| US5712151A (en) | Antifungal agent | |
| CA2396174C (en) | Aerothricin analogs, their preparation and use | |
| EP0443654A2 (en) | Antibiotic agent | |
| Li | Antifungal natural products: antifungal antimicrobial evaluation of Pseudolarix kaempferi and microbial metabolism of ophiobolin A | |
| KR100942368B1 (ko) | 신규한 스트렙토마이세스 속 ｙａ1766 균주 | |
| CN115197189A (zh) | 三桥环荚孢腔酮类化合物及其制备方法和用途 |
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 |