Spiro-bicyclo[2.2.2]octane derivatives as paclitaxel mimetics. Synthesis and toxicity evaluation in breast cancer cell lines

Abstract

Paclitaxel is one of the most important anti-cancer agents introduced during the last 20 years. However, the use of paclitaxel is limited by undesirable side effects as well as the development of drug resistance. Here, we report a synthetic strategy towards spiro-bicyclo[2.2.2]octane derivatives, which includes double Michael addition and ring-closing metathesis as key synthetic steps. This strategy was used to synthesize a series of spiro-bicyclic compounds designed to be paclitaxel mimetics, which were evaluated in human breast-derived cell lines. One of these paclitaxel mimetics showed toxicity, although at higher concentrations than paclitaxel itself. In addition, two other spiro-bicyclic compounds, lacking the paclitaxel side chain, showed toxicity.

Effects of Spiro-bisheterocycles on Proliferation and Apoptosis in Human Breast Cancer Cell Lines

“…Our results clearly showed that the spiroheterocyclic compounds substituted by isoxazole (3), diazepine (4) and oxazepine (6) significantly reduced the proliferation of MCF-7 and MDA-MB-231 cells in a dose-dependent manner. These results were consistent with other studies demonstrating the cytotoxicity of spiro-bicyclic compounds in human cancer cell lines (5,24). Our data are further supported by another report which demonstrated similar in vivo anticancer potential of a spiro-heterocyclic compound on the development on MCF-7 human breast cancer cells (25).…”

Reactions of Allylmagnesium Reagents with Carbonyl Compounds and Compounds with C═N Double Bonds: Their Diastereoselectivities Generally Cannot Be Analyzed Using the Felkin–Anh and Chelation-Control Models

“…Even for a hindered exocyclic aldehyde, diastereoselectivity was modest (Scheme 324). 466 Addition to the hindered βalkoxy aldehyde 822 occurred with low diastereoselectivity, which was established after conversion to the resulting cyclic products by ring-closing metathesis. The aldehyde 822 resembles an aldehyde discussed earlier (Scheme 120).…”

Metal Complex Catalysis in the Synthesis of Spirocarbocycles

“…64 A domino of two consecutive Michael additions was used to construct the skeleton 162 of the bicyclo[2.2.2]octane derivative 163, which, by a subsequent ring-closing metathesis, gave the spirocyclohexenone-annelated bicyclo[2.2.2]octane 165 as precursor to paclitaxel mimetics (Scheme 34). 65 These examples demonstrate that ring-closing intramolecular metatheses of various gem-diallyl-or gem-dialkenylcycloalkane and -bicycloalkane derivatives induced by Grubbs catalysts can be successfully employed for one-pot syntheses of valuable, both natural and synthetic spiroannelated carbocycles and carbobicycles with intricate structures.…”

“…Scheme 34. Formation of Spirocyclohexenone-Annelated Bicyclo[2.2.2]octanes by Ring-Rearrangement Metathesis (RRM)65 …”