Combretastatin A-4: The Antitubulin Agent that Inspired the Design and Synthesis of Styrene and Spiroisatin Hybrids as Promising Cytotoxic, Antifungal and Antiviral Compounds

Yaneth Brand,Liliana Betancur-Galvis,Carlos Puerto,Vladimir Kouznetsov,Verónica Castaño,Vicky Linares

doi:10.21577/0103-5053.20190265

Abstract

The design of a series of styrene and spiroisatin hybrids was based on the structure of combretastatin A-4 1. This library of 20 compounds were synthesized with the pharmacophoric units: 3,4,5-trimethoxy or/and 4-hydroxy-3-methoxy phenyl moities in their structure. Thereby, the libraries of β-nitrostyrenes 10a-10c, spiroisatin-dihydroquinolines 14a-14c, spiroisatin-thiazolidinones 17a-17c and spiroisatin-nitropyrrolizidines 20a-20k were evaluated for their in vitro cytotoxic, anti-proliferative, antifungal and antiviral activities. Biological results revealed that among these compounds, β-nitrostyrenes 10a-10c exhibited significant cytotoxicity (HeLa and Jurkat tumor cells) and antifungal (T. mentagrophytes) activities. Moreover, the spiroisatin-dihydroquinoline 14a and 14c showed promising cytotoxicity (U937 cells). 14a-14c molecules were active against human herpesviruses serotypes 1 and 2 (HHV-1 and HHV-2), but only 14a and 14b were effective against dengue virus serotype 2 (DENV-2). The spiroisatin-nitropyrrolizidine 20c exhibited moderate anti-herpetic activity, while 17c spiroisatin-thiazolidinone derivative also reduced the infection of HHV-1 and DENV-2. Finally, the molecular docking showed that these kind of molecules interact with the subunit α/β-tubulin.

Highlights

Combretastatin A-4 1 (CA-4), the most potent and studied compound isolated from the bark of the South African willow tree Combretum caffrum,[1] stands out among other members of the combretastatin family due to its cytotoxic properties as inhibitor of angiogenesis and tubulin polymerization.[2]
We have found in previous studies that some CA‐4 1 hybrids containing the (Z)-2-(3,4,5-trimethoxystyryl) furan moiety have showed interesting antifungal activity against T. mentagrophytes and T. rubrum, giving minimal inhibitory concentration (MIC) values of 15.7 ± 6.8 and 15.8 ± 6.5 μg mL-1, respectively.[32]
In a previous study carried out in our laboratory,[32] we reported the antiviral activity of combretastatin A-4 hybrid of HHV-2 at concentrations below 25.0 and 3.1 μg mL-1

Summary

Introduction

Combretastatin A-4 1 (CA-4), the most potent and studied compound isolated from the bark of the South African willow tree Combretum caffrum,[1] stands out among other members of the combretastatin family due to its cytotoxic properties as inhibitor of angiogenesis and tubulin polymerization.[2]The constant assembly (polymerization) and disassembly (depolymerization) of microtubules, formed by a heterodimer constituted by α- and β-tubulin subunits,[3] plays a crucial role in mitosis and cell division where they are involved during the spindle formation, migration, Several structure-activity relationship studies of CA-4 has revealed that the cis configuration of the double bond, the 3,4,5-trimethoxy groups on the A-ring, and the meta‐hydroxy and para-methoxy groups on the B-ring are fundamental for its main biological activity.[7].

Results

Conclusion