Synthesis of Novel 2‐O,3′‐N‐Linked Macrocyclic Taxoids with Variable Ring Size

Abstract

A series of macrocyclic taxoids was prepared by connecting the 2‐OH and 3′‐NH moieties with aliphatic chains to mimic the docetaxel solid‐state conformation. The synthesis was achieved by acylation of both positions with various bromoalkanoic acids, and ring closure was carried out with sodium sulfide. Nine 19‐ to 27‐membered macrocyclic taxoids were obtained and evaluated as inhibitors of microtubule disassembly as well as for their cytoxicity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

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.…”

“…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). Separate investigations have proposed distinguishable conformations of the Taxol side chain, with a T-shaped conformation being favored on the basis of its fit with the election-density map of zinc-induced tubulin sheets (34,35).…”

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).…”

“…This suggested that the presence of the macrocyclic disulfide did not account for the weak interaction with tubulin. However, a specific interaction between the disulfide and the protein was proposed to explain the difference in activity between analogs containing S-S bonds and C-S bonds [178]. A conformational study was not reported.…”