Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues.

Laura M Woods,Richard E Taylor,Joseph W Arico,Dan L Sackett,Jeffrey D Frein

doi:10.3390/ijms18030648

Abstract

The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand–target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides.

Highlights

Modulation of microtubule dynamics by natural products through either inhibiting polymerization or by stabilizing the polymeric form (e.g., paclitaxel (Taxol®), docetaxel (Taxotere®), and the epothilones (Ixempra®)) leads to mitotic arrest and apoptosis and is the basis of many clinically relevant therapeutic agents [1,2,3,4,5]
While the microtubule-depolymerizing vinca alkaloids have been used clinically for more than fifty years, the more recent advent of tubulin-stabilizing agents has led to notable success in developing new generations of anticancer agents for solid tumors
Epothilones have been demonstrated by Bollag et al [9] to interact with β-tubulin at the paclitaxel binding site, inducing tubulin assembly and stabilization of the polymeric form [10,11]

Summary

Introduction

Modulation of microtubule dynamics by natural products through either inhibiting polymerization (e.g., vincristine, vinblastine, colchicine) or by stabilizing the polymeric form (e.g., paclitaxel (Taxol®), docetaxel (Taxotere®), and the epothilones (Ixempra®)) leads to mitotic arrest and apoptosis and is the basis of many clinically relevant therapeutic agents [1,2,3,4,5]. Compared to Taxol®, epothilones show reduced peripheral neuropathy, resistance to P-glycoprotein efflux pumps, and increased water solubility in vitro [9]. RReessuullttss aanndd DDiissccuussssiioonn AAss sshhoowwnn iinn SScchheemmee 11,, tthheessyynntthheessiiss ooff77--ddeeooxxyy--eeppootthhiilloonnee DD ccoommmmeenncceedd wwiitthh kknnoowwnn aallddeehhyyddee. The 1H NMR spectra of the two products nearly overlapped, suggesting that the two products were diastereomers or closely related. Comparable couplings were observed for H6 in 7-deoxy-(S)-14-methoxy-epothilone D.

Materials and Methods

General Information

3.13. Cell Growth Inhibition by Compounds

Findings

74. Epothilons A and B