Synthesis of Nonracemic Pyrrolo-allocolchicinoids Exhibiting Potent Cytotoxic Activity

An efficient eight-step semisynthetic approach towards nonracemic pyrrolo-allocolchicinoids starting from natural colchicine was developed by exploiting Pd-catalyzed domino Sonogashira coupling/5-endo-dig cyclization of a 2-iodo-trifluoroacetanilide intermediate to build up the heterocyclic ring system. The N-Me substitution of the pyrrole ring enhanced the antitumor activity of the prepared molecules by 2–3 orders of magnitude. Among the active compounds, the N-methylated colchicinoid exhibited powerful cytotoxic and antiproliferative properties at concentrations < 1 nm.