The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors.

González González,Ramudo Ramudo,Vicente-Blázquez Vicente-Blázquez,Medarde Medarde,Pelaéz Pelaéz,Gallego-Yerga Gallego-Yerga,Ellahioui Ellahioui,Marín Marín,Sanz Sanz,Álvarez Álvarez,Caballero Caballero

doi:10.3390/molecules24234319

Abstract

Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups—termed masked polar group incorporation (MPGI)—was devised and applied to nitrogenated combretastatin analogues. Bulky ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket while increasing molecular polarity. The resulting analogues show improved aqueous solubilities and highly potent antiproliferative activity against several cancer cell lines of different origin. The more potent compounds showed moderate tubulin polymerization inhibitory activity, arrested the cell cycle of treated cells at the G2/M phase, and subsequently caused apoptotic cell death represented by the cells gathered at the subG0/G1 population after 48 h of treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 72 h confirmed the induction of apoptosis. Docking studies suggest binding at the colchicine site of tubulin in a similar way as combretastatin A4, with the polar groups masked by the vicinal substituents. These results validate the proposed strategy for the design of colchicine site ligands and open a new road to increasing the aqueous solubility of ligands binding in apolar environments.

Highlights

The microtubule filament system of eukaryotic cells is an important drug target for pesticides, antiparasitic and anticancer agents [1]
We propose the introduction of polar moieties on the structure of combretastatin analogues, such as the previously attempted pyridines, but masking them in the apolar environment by means of substituents, which hide them from the molecular surface: a strategy we have called masked polar group incorporation (MPGI)
A new strategy for increasing molecular polarity without exposing polar groups termed masked polar group incorporation (MPGI) has been proposed as a means to increase the aqueous solubility of ligands binding at hydrophobic pockets

Summary

Introduction

The microtubule filament system of eukaryotic cells is an important drug target for pesticides, antiparasitic and anticancer agents [1]. The microtubule targeting agents (MTAs) bind to the main constituent of the microtubules, the αβ-tubulin dimers, in several different domains and alter their polymerization–depolymerization equilibria. They are often referred to as antimitotics, as their most patent effect is interference with the highly dynamic mitotic spindle, and depending on the effect they show on microtubule mass, they are often classified as microtubule stabilizing (MSA) or microtubule destabilizing agents (MDA). Attempts to find alternatives to the 3-hydroxy-4-methoxyphenyl ring (B-ring) of combretastatin A4 have resulted in highly potent derivatives, such as indole [10,11,12,13] or naphthalene [13] analogues but with reduced water solubilities

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