A pharmacophore modeling approach to design new taxol® mimics: towards the synthesis of potential anticancer and MDR-reversing agent

Michela L. Renzulli,Stanislava I. Avramova,Girolamo Cirrincione,Maurizio Botta,Luc Rocheblave,Laura Maccari,Fabrizio Manetti,Federico Corelli,Stefano Forli,Elena Galletti,Daniele Castagnolo

doi:10.3998/ark.5550190.0007.812

Abstract

The remarkable therapeutic importance of taxane diterpenoids as anticancer drugs and their challenging structural complexity have stimulated worldwide enormous efforts. Our group developed a theoretic quantitative model describing the relationship between structure and biological activity of microtubules-stabilizing anticancer agents (MSAAs) aimed at gaining an insight into the specific structural features required for the ligand-receptor binding. The model was demonstrated to be able to estimate/predict the microtubule-stabilising activity for a series of taxanes and provided further details about the influence of each pharmacophore point on the ligand binding affinity. Molecular modeling studies from our group revealed that modified Taxuspines U and X could adopt a conformation similar to the bioactive conformation of paclitaxel and can be well accommodated within the pseudoreceptor model. Following the suggestions coming from the model we rationally designed and synthesized new simplified taxuspine U analogues. In particular, we developed a new methodology for the synthesis of such compounds involving a macrocyclisation reaction via RCM in presence of different functional groups.

Highlights

The emergence of Paclitaxel (Taxol®)[1] as one of the most promising anticancer natural products[2,3] has stimulated worldwide interest in phytochemical studies of Taxus species
Our group developed a theoretic quantitative model describing the relationship between structure and biological activity of microtubules-stabilizing anticancer agents (MSAAs) aimed at gaining an insight into the specific structural features required for the ligand-receptor binding
Molecular modeling studies from our group revealed that modified Taxuspines U and X could adopt a conformation similar to the bioactive conformation of paclitaxel and can be well accommodated within the pseudoreceptor model

Summary

Introduction

The emergence of Paclitaxel (Taxol®)[1] as one of the most promising anticancer natural products[2,3] has stimulated worldwide interest in phytochemical studies of Taxus species. Paclitaxel (1) and its semisintetic analogue docetaxel (2, Taxotere®) (Figure 1 and Table 1) exhibit potent antitumor activity against different cancers which have not been effectively treated by existing antitumor drugs. This is due to their unique ability to inhibit microtubules depolymerisation process by promoting the polymerisation of tubulin α,β-heterodimers and stabilizing the resulting polymer. This mechanism of action differs from that of antimitotic drugs such as colchicines, podophyllotoxin and the Vinca alkaloids, which inhibit microtubule assembly. Microtubules formed in the presence of Taxol® are resistant to depolymerisation by Ca2+ ions.[3]

Results and Discussion

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