Boronic Analogues of (R)-6-O-Desmethylantofine as Anticancer Agents.

Phenanthroindolizidines are naturally occurring alkaloids mainly isolated from different species of Asclepiadaceae. These alkaloids are characterized by an excellent anticancer activity against a very wide range of cancerous cell lines including those who are multi drug resistant. Nevertheless, phenanthroindolizidines are associated with sever neurotoxicity that prevented any candidate from this family to pass the clinical trials. A number of boron-based analogues of (R)-6-O-desmethylantofine have been synthesised. Their physochemical properties were evaluated, same as their in-vitro antiproliferative activity. The pinacol boronate ester derivative (3) showed interesting cytotoxicity against a panel of cancerous cell lines attested by a cancer cell growth-inhibitory potency (GI50) as low as 30 nM.

Design, Synthesis, and in Vitro Biological Evaluation of 14-Hydroxytylophorine-dichloroacetate Co-drugs as Antiproliferative Agents.

Co-drug, or mutual-prodrug, is a drug design approach consisting of covalently linking two active drugs so as to improve the pharmacokinetics and/or pharmacodynamics properties of one or both drugs. Co-drug strategy has proven good success in overcoming undesirable properties such as absorption, poor bioavailability, nonspecificity, and gastrointestine tract (GIT) side effects. In this work, we successfully developed a co-drug of 14-hydroxytylophorine, a phenanthroindolizidine derivative with remarkable antiproliferative activity, and dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate steers tumour cell metabolism from glycolysis back to glucose oxidation, which in turn reverses the Warburg effect and renders tumour cells with a proliferative disadvantage. The obtained co-drugs retained the cytotoxicity of 14-hydroxytylophorine. However, they showed similar unselectivity towards normal cells.