Total Synthesis of the Antitumor Natural Product Polycarcin V and Evaluation of Its DNA Binding Profile

ABSTRACT: The convergent total synthesis of polycarcin V, a gilvocarcin-type natural product that shows significant cytotoxicity with selectivity for nonsmall-cell lung cancer, breast cancer, and melanoma cells, has been achieved in 13 steps from 7, 8, and 22; the sequence features a stereoselective α-C-glycosylation reaction for the union of protected carbohydrate 7 and naphthol 8. The association constant for the binding of polycarcin V to duplex DNA is similar to that previously reported for gilvocarcin V. The gilvocarcin family of C-aryl glycoside natural products1have been shown to exhibit high antitumor activity with low overall toxicity.2 A likely mode of action of gilvocarcin V, the most studied member of the gilvocarcins, involves intercalation of the aromatic chromophore into DNA, followed by UV-induced covalent linkage of the natural product to DNA by a [2 + 2]-cycloaddition between the vinyl moiety and a thymine residue.3 Photoactivated gilvocarcin V is also able to selectively cross-link DNA and the phosphorylated form of histone H3 an