10β-OH can be acylated cleanly when 7α-OH is also free, and thus a facile access to semisynthesis of 7-epi-paclitaxel was proposed. A 2's, 3's-oxazoline paclitaxel analog was serendipitously synthesized
AIM: Previous studies identify that C7-OH epimers of taxoids are the thermodynamically more stable isomers due to the strong hydrogen bonding of the C7α-OH to the C4α-acetate acyl oxygen. In order to understand the ...AIM: Previous studies identify that C7-OH epimers of taxoids are the thermodynamically more stable isomers due to the strong hydrogen bonding of the C7α-OH to the C4α-acetate acyl oxygen. In order to understand the effects of certain structure modification on taxoids’ interactions with human hepatic cytochromes P450 better, the present study attempts to clarify the identity of the CYPs involved in 7-epi-Taxol, 7-epi-10-Deacetyl-Taxol, and their corresponding C7β-OH isomers metabolism and the underlying mechanisms are also to investigate. METHODS: LC/MS/MS was used to identify the structures of various taxoids metabolites by human liver microsomes. Incubations were conducted with CYP isoform specific inhibitors and recombinant human CYP isoforms to ascribe individual reaction to a single CYP isoform. RESULTS: Two monohydroxylated metabolites (M-1 and M-2) of 7-epi-Taxol were detected by LC/MS, and C3’ (M-1), C6 (M-2) were proposed as the possible hydroxylation sites. 7-epi-10-Deacetyl-Taxol was hydroxylated at C6 by human liver microsomes thus making M-3 as the unique primary metabolite. Chemical inhibition studies and assays with recombinant human CYPs indicated that C3’ (M-1) was generated predominantly by CYP3A4 and C6 (M-2, M-3) by CYP2C8. Compared with the formation of C6-OH-majorepi-Taxol decreased significantlympounds among all chemotherapeutic drugs, Paclitaxel, the Km for C6-hydroxylation of 7-epi-Taxol decreased significantly (13 versus 3 μmol/L, 8.5 versus 1.7 μmol/L) by human liver microsomes and recombinant human CYP2C8. Moreover, the overall metabolism of 7-epi-10-Deacetyl-Taxol increased to 20% in contrast with the low biotransformation rate of 10-deacetyl-Taxol (less than 0.8%). CONCLUSION: These findings suggest the distinct 3D conformation change of taxoids caused by the intromolecular hydrogen bonding may attribute a major role in the substrate recognition by CYP2C8 and lead C-6 of taxoids more accessible to the active site.展开更多
Two new ar-bisabol sequiterpenes,(+)-(7S,10S)-10-epi-7,10-epoxy-3-hydroxy-ar-bisabol-11-ol(1)and(+)-(7R,8R,10S)-10-epi-7,10-epoxy-8-hydroxy-ar-bisabol-11-ol(2),have been isolated by a combination of various column chr...Two new ar-bisabol sequiterpenes,(+)-(7S,10S)-10-epi-7,10-epoxy-3-hydroxy-ar-bisabol-11-ol(1)and(+)-(7R,8R,10S)-10-epi-7,10-epoxy-8-hydroxy-ar-bisabol-11-ol(2),have been isolated by a combination of various column chromatographic techniques including reversed-phase semipreparative HPLC from an ethanol extract of the stem bark of Fraxinus sielboldiana.Their structures were determined by spectroscopic methods including IR,MS,and 1D and 2D NMR experiments.This is the first report of sequiterpenes in the genus Fraxinus.展开更多
文摘10β-OH can be acylated cleanly when 7α-OH is also free, and thus a facile access to semisynthesis of 7-epi-paclitaxel was proposed. A 2's, 3's-oxazoline paclitaxel analog was serendipitously synthesized
文摘AIM: Previous studies identify that C7-OH epimers of taxoids are the thermodynamically more stable isomers due to the strong hydrogen bonding of the C7α-OH to the C4α-acetate acyl oxygen. In order to understand the effects of certain structure modification on taxoids’ interactions with human hepatic cytochromes P450 better, the present study attempts to clarify the identity of the CYPs involved in 7-epi-Taxol, 7-epi-10-Deacetyl-Taxol, and their corresponding C7β-OH isomers metabolism and the underlying mechanisms are also to investigate. METHODS: LC/MS/MS was used to identify the structures of various taxoids metabolites by human liver microsomes. Incubations were conducted with CYP isoform specific inhibitors and recombinant human CYP isoforms to ascribe individual reaction to a single CYP isoform. RESULTS: Two monohydroxylated metabolites (M-1 and M-2) of 7-epi-Taxol were detected by LC/MS, and C3’ (M-1), C6 (M-2) were proposed as the possible hydroxylation sites. 7-epi-10-Deacetyl-Taxol was hydroxylated at C6 by human liver microsomes thus making M-3 as the unique primary metabolite. Chemical inhibition studies and assays with recombinant human CYPs indicated that C3’ (M-1) was generated predominantly by CYP3A4 and C6 (M-2, M-3) by CYP2C8. Compared with the formation of C6-OH-majorepi-Taxol decreased significantlympounds among all chemotherapeutic drugs, Paclitaxel, the Km for C6-hydroxylation of 7-epi-Taxol decreased significantly (13 versus 3 μmol/L, 8.5 versus 1.7 μmol/L) by human liver microsomes and recombinant human CYP2C8. Moreover, the overall metabolism of 7-epi-10-Deacetyl-Taxol increased to 20% in contrast with the low biotransformation rate of 10-deacetyl-Taxol (less than 0.8%). CONCLUSION: These findings suggest the distinct 3D conformation change of taxoids caused by the intromolecular hydrogen bonding may attribute a major role in the substrate recognition by CYP2C8 and lead C-6 of taxoids more accessible to the active site.
基金Financial support from the National Natural Sciences Foundation of China(NNSFC,Grant nos.30825044 and 20932007)the National Science and Technology Project of China(Nos.2009ZX09311-004 and 2009ZX09301-003-4-1)is acknowledged.
文摘Two new ar-bisabol sequiterpenes,(+)-(7S,10S)-10-epi-7,10-epoxy-3-hydroxy-ar-bisabol-11-ol(1)and(+)-(7R,8R,10S)-10-epi-7,10-epoxy-8-hydroxy-ar-bisabol-11-ol(2),have been isolated by a combination of various column chromatographic techniques including reversed-phase semipreparative HPLC from an ethanol extract of the stem bark of Fraxinus sielboldiana.Their structures were determined by spectroscopic methods including IR,MS,and 1D and 2D NMR experiments.This is the first report of sequiterpenes in the genus Fraxinus.
