title: Synthetic reactions with rare taccalonolides reveal the value of C-22,23 epoxidation for microtubule stabilizing potency.
abstract: The taccalonolides are microtubule stabilizers isolated from plants of the genus Tacca. Taccalonolide AF is 231 times more potent than the major metabolite taccalonolide A and differs only by the oxidation of the C-22,23 double bond in A to an epoxy group in AF. In the current study, 10 other rare natural taccalonolides were epoxidized and in each case epoxidation improved potency. The epoxidation products of taccalonolide T and AI were the most potent, with IC50 values of 0.43 and 0.88 nM, respectively. These potent taccalonolides retained microtubule stabilizing effects, and T-epoxide demonstrated antitumor effects in a xenograft model of breast cancer. Additional reactions demonstrated that reduction of the C-6 ketone resulted in an inactive taccalonolide and that C-22,23 epoxidation restored its activity. These studies confirm the value of C-22,23 epoxidation as an effective strategy for increasing the potency of a wide range of structurally diverse taccalonolide microtubule stabilizers.
authors: Department of Pharmacology, ‡Cancer Therapy & Research Center, and §Department of Medicine, University of Texas Health Science Center at San Antonio , San Antonio, Texas 78229, United States.
authors: Jiangnan
authors: J
authors: Peng
authors: April L
authors: AL
authors: Risinger
authors: Jing
authors: J
authors: Li
authors: Susan L
authors: SL
authors: Mooberry
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D027743:Dioscoreaceae / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008968:Molecular Conformation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D013256:Steroids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004852:Epoxy Compounds; D013256:Steroids; C475870:taccalonolide A; C570720:taccalonolide AF; C000592448:taccalonolide AI; C000592447:taccalonolide T