Synthesis of C2−C3‘N-Linked Macrocyclic Taxoids. Novel Docetaxel Analogues with High Tubulin Activity

Abstract

Novel C2-C3'N-linked macrocyclic taxoids 4 bearing an aromatic ring at position C2 were synthesized. These compounds, tethered between N3' and the C2-aromatic ring at the ortho, meta, or para position, were constructed by ring-closing metathesis. The para-substituted derivatives were unable to stabilize microtubules, whereas the ortho- and meta-substituted compounds show significant activity in cold-induced microtubule disassembly assay. The meta derivative 4c is the first C2-C3'-linked cyclic analogue to be equipotent to paclitaxel in this assay and to show significant cytotoxicity. Computational studies of the conformational behavior of these compounds indicate that they can adopt several conformations including mainly the "T-shaped" forms. Docking experiments have shown that the "T-shaped" form is preferred for a good interaction of these compounds with the beta-tubulin binding pocket.

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).…”

C‐3′‐Cyclopropanated Taxol Analogs: Synthesis, Bioassay and Biostructural Analysis

“…The compounds proved to match and surpass taxol in both their microtubule-stabilizing capacity and cytotoxicity. [12,13] More recently, the French team reported an efficient route to a highly active series of taxol analogs bridged between the C-2 benzoyl phenyl group and an alkyl replacement of the 3Ј-benzamido functionality. [14] While all the compounds were significantly weaker cytotoxins than docetaxel, unsaturated (E) and (Z) analogs with a C 7 spacer linking the 3Ј-NHC(=O) carbon atom and the meta position of the ter-minal 2-phenyl group proved to be as active as PTX in the tubulin aggregation assay.…”

“…After removal of the solvent, the residual colorless solid was filtered through silica gel (11 g, 1.5 × 6 cm) eluting with dichloromethane to remove residual acetic acid, then eluting the product with ether/methanol (10:1 55 (m, 1 H), 7.91-7.95 (m, 2 H) ppm. 13 …”

“…[11] The initial computationally refined electron crystallographic model [11] was employed in the design, synthesis and subsequent bioanalysis of a novel and highly active series of C-4 to C-3Ј bridged analogs providing clearcut experimental confirmation of the model. [12] A synthetic approach employing less constrained C-2 to C-3Ј linkers complemented by protein docking, conceived around the same time by the French group, furnishes parallel support for the T-concept, [13] while another recent approach based on a REDOR-taxol structure gives support to aspects of the T-concept. [14] An additional successful application of the model was inspired by the observation that tubulin from yeast (S. cerevisiae) is not polymerized by taxol.…”

Novel C2–C3′ N-peptide linked macrocyclic taxoids. Part 1: Synthesis and biological activities of docetaxel analogues with a peptide side chain at C3′

“…Moreover, this superposition could be related to that of the conformationally restricted macrocyclic taxoids synthesized in our group to mimic the ÔnonpolarÕ and ÔT-shapedÕ conformation of paclitaxel and docetaxel. [10][11][12] As shown earlier, bioactive taxoids bind to the b-tubulin subunit in a specific binding conformation, and several studies (X-rays, NMR, and molecular modeling) have been performed to elucidate the nature of the bioactive conformation as ÔnonpolarÕ, 13,14 ÔpolarÕ 15 or Bioorganic & Medicinal Chemistry Letters 15 (2005) 4722-4726 0960-894X/$ -see front matter Ó…”