Combretastatins: In vitro structure-activity relationship, mode of action and current clinical status

Abstract

For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways. The combination of both elements makes combretastatin an anticancer compound of high efficiency. The cis-configuration is crucial for its biological activity. To date, many derivatives were synthesized. The attempts to resolve spontaneous isomerization to less active trans-stilbene derivative are still in progress. This issue seems to be overcome by incorporation of the ethene bridge with heterocyclic moiety in combretastatins structure. This modification retains the cis-configuration and prevents isomerization. Nevertheless, combretastatin A4 phosphate disodium is still the most potent compound of this group. The combination therapy, which is the most effective treatment, includes combretastatin A4 phosphate (CA4P) and conventional chemotherapeutics and/or radiotherapy. CA4P is relatively well tolerated giving adverse events of moderate severity, which includes: nausea, vomiting, headache, and tumor pain. The aforementioned effects subside on the day of drug administration or on the following day.

Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

“…As shown in Figure , the hydroxy group at position 3 of the B‐ring is not essential for activity, which makes this position attractive for the attachment of prodrug moieties. A phosphoric acid ester attached at this position yields a prodrug with increased aqueous solubility (fosbretabulin) which showed potent antitumor activity in phase II clinical trials …”

“…Ap hosphorica cid ester attached at this position yields ap rodrug with increased aqueous solubility (fosbretabulin) which showedp otent antitumor activity in phase II clinical trials. [26] The main problem regarding the use of colchicine and other tubulin polymerization destabilizers as antiviral drugs is their high systemic toxicity.C olchicine causes ac omplete inhibition of tubulin assembly at sub-stoichiometric concentrations [31] and has stronga nti-angiogenic effects, at ypical feature of microtubule disruptinga gents, which is now seen to providea promising approachfor the treatment of cancer. [32,33] Previous attempts to decrease the systemic toxicity of colchicine often resulted in as ignificant drop or total loss of biological activity.…”

Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers

“…(3) Vasoconstriction and shutdown of the established tumor vessels: after blebbing; endothelial cells die by apoptosis, and rapid collapse of tumor vessels is observed (for details, see reviews by Jaroch et al. , Chase et al. , and Tozer et al.…”

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

“…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). …”