Design of Combretastatin A-4 Analogs as Tubulin Targeted Vascular Disrupting Agent with Special Emphasis on Their Cis-Restricted Isomers

Abstract

Tubulin protein is a highly imperative and feasible goal for anticancer drug discovery. Hundreds of naturally occurring, semi synthetic and synthetic antitubulin agents have been reported till now. Among these, Combretastatin A - 4 (CA - 4) is effective antimitotic agent possessing potent cytotoxicity against a panel of cancer cells, including multi-drug resistant cancer cell lines. The inadequate water solubility and inactivation of these analogs during storage limit their use as clinical anticancer agents. To overcome these shortcomings, numerous water soluble amino analogs, amino acid derivative, phosphate prodrug (CA - 4P) and cis-locked CA - 4 have been developed with distinctive attributes of antitubulin and antivascular properties in a wide variety of preclinical tumor models. Subsequently, several heterocycle based cis restricted CA - 4 analogs are being reported for antitumor activity against collection of cancer cell lines. This review recapitulates the rational design, structure activity relationship, pharmacokinetic and pharmacodynamic profile of synthesized cis restricted CA - 4 analogs.

Tubulin-interactive stilbene derivatives as anticancer agents

“…A specific action of ombrabulin towards intratumoral vessels rather than to the peritumoral vasculature was demonstrated by means of immunochemical staining of HNSCC tumors [92]. The design of CA-4 analogs as VDAs was the subject of a concise review by Rajak et al, who paid special attention to cis-restricted isomers [93]. Resveratrol's anti-angiogenic activity has been shown in in vitro assays and preclinical animal models [94,95].…”

Combretastatins: More Than Just Vascular Targeting Agents?

“…Although clinical evaluation of the combretastatins is primarily focused on their pronounced vascular targeting properties, the combretastatins are naturally tubulin-targeting agents and can directly target cancer cells. To date, reviews on this interesting class of compounds have focused on their primary role as VTAs (Tozer et al, , 2008Siemann et al, 2004Siemann et al, , 2009Porcù et al, 2014), strategic chemical modifications (Hsieh et al, 2005;Rajak et al, 2013), their natural origin (Kingston, 2009;Pereira et al, 2012), or their stilbene moiety (Mikstacka et al, 2013). In this work, although acknowledging the former, we also extend our review to include other less conversed, but equally compelling direct anticancer properties endowed by the combretastatins.…”

“…CA-1 and CA-4 are cis stilbenes and can readily isomerize into inactive trans-isomers in response to heat, light, or acidic conditions. Stability issues were addressed by extensive alkene substitutions to a conformationally restricted structure: many in the form of heterocyclic groups (rings containing elements other than carbon) (Rajak et al, 2013;Lipeeva et al, 2014;Galli et al, 2015). Examples of alkene modifications include the following: imidazoles, furanones, thiazoles, pyrazoles, indoles, isoxazoles, and b-lactams (Medarde et al, 1999;Kaffy et al, 2006;O'Boyle et al, 2010;Banimustafa et al, 2013;Lin et al, 2013;Tsyganov et al, 2013;Mahal et al, 2015).…”

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth

“…A superposition of their binding modes can be seen in Figure 16b. The second group collects a number of ligands (40,48,55,56, and 58, Figure 13) that mimic the binding of the pyrrolidinedione 53, occupying zones 2 and 3, and whose superpositions are shown in Figure 16c. When comparing the superposition in Figure 16b,c, it could be argued that planar compounds tend to locate deeper into the β-subunit making use of zones 2 and 3, whereas more globular or butterfly like shaped ligands occupy zones 1 and 2, mimicking the colchicine-binding mode.…”