Synthesis and Biological Evaluation of Combretastatin A-4 and Three Combretastatin-Based Hybrids

Abstract

The syntheses of combretastatin A-4 from gallic acid and of three combretastatin-based hybrids are described. Starting from commercial gallic acid, the phosphonium salt (3,4,5-trimethoxybenzylphosphonium bromide) is synthesized and coupled, through a Wittig reaction, with several aldehydes, including methoxymethyl-protected isovanillin, the aldehyde γ-bicyclohomofarnesal having a labdane skeleton, 3-(3-pyridyl) propanal, and furfural. The biological properties of the cis-coupled compounds as cytotoxic, antiviral and antifungal agents are also reported. In addition, pyrogallol, gallic and 3,4,5-trimethoxybenzoic acids have been studied biologically.

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

“…CA-4 and hybrid 9 revealed activities against HHV-1, and HHV-2. The antiviral activities of CA-4 against HHV-1, and HHV-2 are 50 and 25 µg/mL, respectively [38].…”

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

“…The determination of the reduction factor (R f ), which corresponds to the value obtained by dividing the viral titer in the absence of compound over the viral titer obtained in the presence of compound was employed as an end point of this antiviral bioassay (Table 3). 34 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 . This background is important and establishes a guide for continue exploring antiviral activity.…”

“…31 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 MIC values of 15.7 ± 6.8 and 15.8 ± 6.5 µg mL -1 , respectively. 32 Furthermore, the antifungal activity of 10c was previously determined against C. albicans ATCC 90028 giving an MIC value of 32.0 µg mL -1 . 33 The results of this study confirm that the 3,4,5-trimethoxy phenyl moiety should be the fragment, which improves the antifungal activity, especially against T. mentagrophytes, allowing to conclude that this pharmacophoric subunit of CA-4 1 is also relevant for the development of novel antidermatophytes agents.…”

“…This background is important and establishes a guide for continue exploring antiviral activity. 32 In order to determine the relevant or moderate antiviral activity of tested compounds, the reduction of R f was established as a criterion to classify their potency according to the standard parameters. 30 Nevertheless, only the spiroisatin-dihydroquinoline hybrids 14b-14c exhibited moderate anti-herpetic activity, classifying them according to those parameters as follows: 14c > 14b > 14a.…”

Anticancer Activity of Stilbene‐Based Derivatives

“…The combretastatin‐based hybrid 45 (Figure ) and its analogues were tested in vitro for potential antitumor and cytotoxic activities on HeLa tumor cell line and non‐tumor Vero cell line. This derivative showed a high potential antitumor activity with an IC 50 value in the low micromolar range …”