Epoxidation at C22-C23 significantly increases the potency of microtubule stabilizing taccalonolides

J Peng; J Li; AL Risinger; SL Mooberry

doi:10.1055/s-0032-1321110

Planta Medica, Table of Contents

Epoxidation at C22-C23 significantly increases the potency of microtubule stabilizing taccalonolides

J Peng ¹^,², J Li ¹, AL Risinger ¹^,², SL Mooberry ¹^,²

¹Department of Pharmacology
²Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

Abstract

Microtubules remain an important target for anticancer drug discovery. Paclitaxel, a plant-derived microtubule stabilizer, is one of the most successful anticancer drugs currently used. A second class of microtubule stabilizers, the taccalonolides, were isolated from the tropical plant Tacca chantrieri. Recently, we isolated a number of known and new taccalonolides from Tacca sp. and obtained preliminary structure and activity relationship information. A wide range of antiproliferative potencies was obtained with the natural taccalonolides with IC₅₀ values ranging from 23 nM to >50µM in HeLa cells. Taccalonolide AF with an epoxy group at C22–23 showed the most potent activity. A simple and efficient method was developed to convert the taccalonolides A and B to taccalonolides AF and AJ, respectively.² AJ has an IC₅₀ value of 4.2 nM, 734-fold more potent than the parent molecule, B. Based on this result, each natural taccalonolide was subject to the epoxidation reaction. All the new compounds possessing 22,23-epoxy group exhibited significant increased potency as compared to their natural precursor, with the most potent having an IC₅₀ value of 0.73 nM. The new compounds also retained microtubule stabilizing activities. These results demonstrate that the C22–23 epoxy group facilitates optimal potency for these microtubule stabilizers.