Design, Synthesis, and Biological Evaluation of Novel C14−C3′BzN-Linked Macrocyclic Taxoids

Abstract

Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3'Nbenzoyl group (C3'BzN), which are ca. 7.5 Å apart, with a short linker (4−6 atoms). 7-TES-14β-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-β-lactams were selected as key components and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ringclosing metathesis (RCM) of paclitaxel-dienes gave the designed 15-and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.

Application of REDOR NMR in natural product chemistry

“…For example, 7 and 8 in Scheme 2 show potent anticancer activity superior to that of 1. 51,52 Further MD analysis of the tubulin-bound paclitaxel has been performed on the basis of REDOR restraints to provide the REDOR-taxol conformation. 53…”

The Synthesis of Macrocycles for Drug Discovery

“…As a route to more highly functionalized molecules, MCR of a sugar amino acid or alcohol, an aldehyde, and an isocyanoacetamide was used to prepare the acyclic precursor (240) for an acid-promoted cyclization that produced interesting macrodepsipeptides 241 (Scheme 11.31). 333 In this approach, the 5-aminooxazole in 240 acts as an internal activator of the terminal carboxylic acid to facilitate the macrolactonization.…”

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

“…80 The microtubules formed with 16 and paclitaxel were found to be very similar, while those formed with GTP are known to be longer and more uniform. Mimic SB-T-2053 ( 18 ), a double-bond regioisomer of 19 , showed slightly better activity than paclitaxel in the tubulin polymerization assay, but exhibited slightly weaker cytotoxicity than paclitaxel.…”

“…73 Both macrocyclic mimics take a virtually perfect “REDOR-Taxol” structure in computer modeling, and those structures are very stable in the MD simulations. 75,80 …”