Restoration of Microtubule Interaction and Cytotoxicity in D-seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-allyloxy Groups

Abstract

To probe the exact role of the oxetane D ring in both tubulin binding and cytotoxicity of taxanes, novel D-seco taxanes bearing a C4 ether substituent have been prepared from paclitaxel 1a. Among them, 20-hydroxymethyl-4-allyloxy D-seco taxane 5e is the most active in both tubulin and cytotoxicity assays. It is only slightly less potent than 1a on tubulin polymerization promotion in vitro and the most cytotoxic among all D-seco taxanes known to date. The reason for the loss and restoration of bioactivity for these D-seco taxanes is also discussed with the assistance of NMR and molecular modeling studies. From these results, we draw a conclusion that the intact D ring of taxanes is not strictly necessary for their binding to tubulin and cytotoxic effects.

Diterpenoids of terrestrial origin

“…177 The modication of the structure of ring D-seco-taxanes in the context of microtubule interactions has been examined. 178 Further synthetic studies directed at paclitaxel continue to be reported. 179 A large number of esters of jatrophanes, lathyranes, myrsinanes, daphnanes, tiglianes and ingenanes have been isolated, particularly from members of the Euphorbiaceae and Thymelaeaceae.…”

Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry

“…Computational studies concluded that the oxetane acted as a conformational lock, rigidifying the structure, or alternatively as a hydrogen-bond acceptor . Although lower activity was observed when the oxetane was replaced with related alternative ring structures, ,, very recent studies have shown that the oxetane is not in fact essential for biological activity . In the purported biosynthesis of taxol, cyclization occurs via an enzyme-mediated epoxy ester/oxetane ester rearrangement mechanism.…”

“…45 Although lower activity was observed when the oxetane was replaced with related alternative ring structures, 45,47,48 very recent studies have shown that the oxetane is not in fact essential for biological activity. 49 In the purported biosynthesis of taxol, cyclization occurs via an enzyme-mediated epoxy ester/oxetane ester rearrangement mechanism. Three separate mechanisms for this transformation have been proposed: a neutral-concerted pathway (Figure 3a), 50 an acid-catalyzed route (Figure 3b), 51 and a dissociative pathway (Figure 3c).…”

Synthesis and Cytotoxicity of 7,9-O-Linked Macrocyclic C-Seco Taxoids

“…18b was immersed in a cubic box containing TIP3P water molecules and simulated under periodic boundary conditions for 50 ns at 300 K. Subsequent gradual cooling, from 300 to 273 K over 1 ns, of snapshots taken regularly every 2.5 ns, followed by energy minimization until the root-mean-square of the Cartesian elements of the gradient was less than 0.1 kcal·mol −1 ·Å −1 , provided representative structures of this molecule; those displaying the shortest distance between the free hydroxyl groups were chosen to build 22b by means of a C=O linkage. The simulated macromolecular ensemble representing a short piece of a microtubule with bound 22b was constructed as previously reported for D-seco taxol derivatives [20].…”