Recent Advancement in Discovery and Development of Natural Product Combretastatin-inspired Anticancer Agents

Abstract

The natural stilbenoids combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent antitubulin agents demonstrating antimitotic activity as well as tumor vascular disruption property. Due to structural simplicity and potent cytotoxicity of CA4 and CA1, they are considered as promising leads for the development of potent anticancer agents. In fact, scientific fraternity is motivated to synthesize several derivatives of CA4 and CA1 as novel therapeutic agents. In the literature, several studies have been carried out to evaluate the medicinal chemistry, pharmacology and structure-activity relationships (SAR) of a variety of modified combretastatin derivatives. The present report aimed at comprehensively revising the recent advancements (2006-2014) in the medicinal chemistry and SAR of diversified combretastatin analogues. The published data concerning new combretastatin A-4 analogues as antimitotic anticancer agents are presented and SAR is reviewed and discussed.

Conformational mimetics of the α-methyl chalcone TUB091 binding tubulin: Design, synthesis and antiproliferative activity

“…In addition, the Lys-Pro prodrug of TUB091 (11), that strongly enhanced the aqueous solubility, showed potent antitumor activity in melanoma and cancer xenograft models as well as antimetastatic activity [18]. The active conformation of these chalcones when binding at the colchicine site is the s-trans conformer, as initially propose by Ducki [16] and unequivocally confirmed by the resolution of the complex of the hydroxyl derivative TUB092 (12) with tubulin [18].…”

“…The low solubility issue has been addressed through the synthesis of prodrugs, of which the phosphate of CA-4 (fosbretabulin, 4) [8] or the diphosphate of CA-1 (OXi4503, 5) [9] are being tested in clinical trials. Concerning the stability of the cis stilbene, many efforts have been performed to fix the cis conformation by incorporation of the stilbene into a restricted bridge or by replacing it by other linkers, as recently reviewed [10][11][12][13].…”

Harnessing Plant Biodiversity for the Discovery of Novel Anticancer Drugs Targeting Microtubules

“…Combretastatin selectively suppresses tumor angiogenesis, a process crucial for cancer growth and metastasis. Importantly, combretastatin is not recognized by the ATP-dependent efflux transporters associated with drug resistance, making it a promising lead molecule for chemotherapy (Patil et al, 2015). This agent is currently being investigated for the treatment of several cancer types, such as anaplastic thyroid cancer and medullary thyroid cancer ( Table 1 ) (Garon et al, 2016; Jaroch et al, 2016).…”

Synthesis and biological activity of pyrrole analogues of combretastatin A-4

“…This cis-trans isomerisation results in a loss of antimitotic activity and cytotoxicity. 1,2,5,7,9,14 The low water-solubility of CA-4 results in its low efficacy in vivo and therefore the water-soluble sodium phosphate prodrug of CA-4, fosbretabulin (CA-4P), was designed and is currently in phase II/III clinical trials. [5][6][7][8][9][10][11] Efforts to remove the possibility of cis-trans isomerisation have been attempted by replacing the cis-olefin with a five-membered heterocycle which result in a cis-like constrained configuration.…”

“…CA-4 analogues having five-membered heterocyclic rings such as oxazoles, imidazoles and triazoles have been reported to have increased potency and bioactivity. 2,3,13,14 Pyrrole-linked heterocyclic analogues have also been previously synthesised and their antimitotic activity evaluated with 3,4-diaryl-1H-pyrrole-2-carboxylates, 15 4,5-diaryl-1H-pyrrole-2-carboxylates, 7 3,5-diaryl-1H-pyrrole-2-carboxylates 16 and 1,2-diaryl-1H-pyrroles 10 being reported.…”