title: Generation of novel epothilone analogs with cytotoxic activity by biotransformation.
abstract: The epothilones represent a new class of bacterial natural products with broad spectrum of antiproliferative activity against various types of human tumors and tumor cell lines. The attractive preclinical profile of epothilones has made them promising lead compounds for novel anticancer agents and has spurred a strong interest in obtaining different derivatives to fully evaluate their therapeutic potentials. We have generated a number of novel epothilone D and 10,11-dehydroepothilone D (Epo490) analogs via biotransformation using Amycolata autotrophica to alter the oxidation state of the parental compounds. The bioconverted compounds displayed different degrees of potency in cytotoxicity assays against a panel of human tumor cell lines, with 11-hydroxyepothilone D, 14-hydroxyepothilone D, and 21-hydroxyepothilone D showing comparable activity to that of epothilone D, and 21-hydroxy Epo490 being comparable to Epo490. The addition of hydroxyl group(s) seems to cause a decrease in cytotoxic activity against multiple drug resistant cell lines (with overexpressed P-glycoprotein). The compounds generated by biotransformation exert differential effects on tubulin polymerization, which correlate with their biological activities.
authors.affiliation: Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA. tang@kosan.com
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.forename: Rong-Guo
authors.initials: RG
authors.lastname: Qiu
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Leonard
authors.initials: L
authors.lastname: Katz
mesh_terms: D000192:Actinomycetales / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D034261:Epothilones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D018942:Macrolides; D013844:Thiazoles; C466502:epothilone 490; C114026:desoxyepothilone B; C093788:epothilone B