The Synthesis And Antitumor Activity Of Combretastatin A-4 Derivatives

Context and Objectives:In recent years both the morbidity and mortality rates associated with certain types of cancer have been increasing.While a wide range of relevant,clinically-deployed,anti-cancer drugs is now available,a significant number of these display adverse side-effects and/or suffer from poor bioavailability.As a consequence,the search continues for ever more efficacious tumor-fighting drugs.Natural products have proven to be a remarkable source of inspiration in this regard.So,for example,combretastatin A-4（CA-4）（see Figure 1）,a natural product embodying a cis-stilbene sub-structure,can inhibit the progression of mitosis and disrupt the formation of new blood vessels（a phenomenon known as angiogenesis）and so leading to apoptosis within various tumor cells.Although it has been suggested that CA-4（or pro-drug forms there-of）has the potential to become a broad-spectrum anti-tumor drug,its poor water solubility,as well as its propensity for structural isomerization in vivo（and resulting in inactive trans-configured compounds）,limits its clinical applications.Accordingly,structural modifications to CA-4 are being investigated in efforts to identify configurationally stable congeners with superior pharmacokinetic properties and thereby providing a source of safer and more effective CA-4-type anti-cancer agents.Approach:In view of the instability of the cis-configured stilbene framework associated with CA-4,a strategy of replacing the ethylene bridge with the chemically robust and pharmaceutically-privileged pyrrole ring became the focus of the study detailed herein and that was informed by structure-activity relationship profiles revealed by previous research in the area.So,using abundant pyrrole-2-carboxaldehyde as starting material,a library of new CA-4 analogues was prepared by deploying bromination,Suzuki-Miyaura cross-coupling and other reliable chemical transformations.These analogues were then subjected to structural characterization using,inter alia,nuclear magnetic resonance and high-resolution mass spectrometric techniques.They were then tested for their cytotoxic effects against the tumor cell lines MCF-7,A549,Hep G2,Caco-2 and N2A using MTT assays conducted in-house.Outcomes:A total of 58 CA-4 analogues embodying the pyrrole framework were synthesized and the MTT assays conducted on them revealed that the B-,D-and F-series compounds had no inhibitory effects on any of the five cancer cells lines tested.In contrast,most of the C-series compounds incorporating a 3’,4’,5’-trimethoxyphenyl residue as the A-ring exerted strong anti-proliferative effects on Caco-2 and N2A cell lines.For example,the IC₅₀ values for compounds 19a and 26a（see Figure 1）against the N2A cell-line were 2.1±0.8μM and 2.2±0.3μM,respectively,while that for compound 27a against the Caco-2 cell line was 4.9±0.5μM.Conclusions:Certain of the C-and E-series CA-4 analogues prepared during the course of this study,and containing the pyrrole framework,exhibited potentially useful cytotoxic properties.In particular,this work has revealed that the incorporation of a3’,4’,5’-trimethoxyphenyl residue within such a framework was crucial for activity.More broadly speaking,it would appear that 4,5-diarylated pyrrole-2-carboxaldehydes and related compounds represent a class of compound worthy of further investigation as cytotoxic agents because of their potential for deployment as anti-cancer agents.（?）...