Synthesis of Novel Macrocyclic Docetaxel Analogues. Influence of Their Macrocyclic Ring Size on Tubulin Activity

Abstract

This work describes the synthesis of a series of novel macrocyclic taxoids 3 and 3(H) designed to mimic the docetaxel solid-state ("nonpolar") conformation. These compounds, bearing 18-, 20-, 21-, and 22-membered rings connecting the C-2 OH and C-3' NH moieties, were constructed by ring-closing olefin metathesis of the taxoid-omega,omega'-dienes 4. Biological evaluation of these new taxoids showed that activity is dependent on the ring size, and only the 22-membered ring taxoid 3d exhibits significant tubulin binding. Synthesis of the open-chain analogues 7 and 7(H) and comparison of their biological activities with macrocyclic taxoids show that the carbon tether between C-2 OH and C-3' NH does not hamper tubulin binding. Computational studies of the conformational behavior of the macrocyclic taxoids 3 indicate that the 18-, 20-, and 21-membered-ring 3a-c adopt mainly conformations that are not recognized by tubulin. The most active taxoid 3d appears to adopt a conformation that is between the "nonpolar" and T-shaped forms.

The bioactive Taxol conformation on β-tubulin: Experimental evidence from highly active constrained analogs

“…The second point follows, which is that the present results contrast sharply with those derived by bridging from either the C-3Ј phenyl (25,28,29) or the benzamido (26,30,31) side chain directions to the C-2 position of the baccatin core; cases in which the activity is either nonexistent or at best one-tenth that of Taxol. The fundamental reason for activity in the present series and its absence in other bridging schemes is related to the location of ␤-tubulin's His-227 in the taxoid binding pocket.…”

“…Examination of the computationally refined tubulin binding site illustrates that His-227 resides between these two rings. This accounts for the fact that previous attempts to bridge the C-2 and C-3Ј positions have delivered either inactive Taxol analogs (28) or compounds that are one or two orders of magnitude less active than Taxol itself (25,26,29,30,31). By contrast, inspection of T-Taxol reveals that the C-4 acetate methyl hydrogens are just 2.5-2.9 Å and 4.3-4.9 Å distant from the o-and m-hydrogens of the C-3Ј phenyl, respectively (Fig.…”

“…On the other hand, it can provide a conceptual model for the synthesis of simplified analogs that may well retain the full activity of the parent compound. Several experimental attempts to identify this conformation have been made by NMR measurement of internuclear distances within Taxol bound to microtubules (23,24), and by the synthesis of various conformationally restricted Taxol analogs (25)(26)(27)(28)(29)(30). In addition, studies have compared the conformations of Taxol and epothilone B by molecular modeling and other methods (29,(31)(32)(33).…”

Recent Progress in the Chemistry and Biology of Paclitaxel (TaxolTM) and Related Taxanes

“…Three similar studies [178][179][180] were published describing several panels of N-linked macrocyclicpaclitaxel analogs that were designed and synthesized. The first series of compounds can be illustrated by structure 3.2.18, in which n varies from 3 to 7 (Figure 8.35).…”

“…In a related study [179], macrocyclic analogs bearing only carbon tethers such as 3.2.20 were built because of a suspicion that sulfur may be deleterious to tubulin binding (Figure 8.36). Eleven cyclic compounds were evaluated for inhibition of microtubule disassembly, and among them compound 3.2.21 was only sevenfold less active than paclitaxel.…”