Boronic Analogues of (<i>R</i>)-6-<i>O</i>-Desmethylantofine as Anticancer Agents

Abstract

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 (GI 50) as low as 30 nM.

Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

“…Prototype compounds, such as tylocrebrine, tylophorine, and antofine ( Figure 1 ), exhibit low nanomolar to picomolar half-maximal growth inhibition (GI 50 ) values, as well as effectiveness against multidrug-resistant human cancerous cell lines [ 6 ]. Phenanthroindolizidines exert their anticancer activity through a combination of diverse mechanisms [ 7 ] such as the inhibition of hypoxia-inducible factor-1 (HIF-1) [ 8 ], the inhibition of DNA, RNA and protein synthesis [ 9 , 10 , 11 , 12 ], the inhibition of thymidylate synthase [ 13 , 14 , 15 ], the inhibition of dihydrofolate reductase [ 13 , 14 , 15 ], the inhibition of Activator Protein-1, and NF-κB, and the down-regulation of cyclin D1 [ 16 , 17 ].…”