Novel antiproliferative analogs of the Taq DNA polymerase inhibitor catalpol

The naturally occurring iridoid catalpol (1) is a Taq DNA Polymerase inhibitor. However, its poor lipophilicity might account for the lack of biological activity against human solid tumor cell lines. The traditional prodrug approach by means of peracetylation of the free hydroxyl groups led to a compound, which showed a marginal growth inhibition against the most sensitive cell line A2780 (ovarian Cancer). However, the formation of analogs bearing one to three silyl ether groups led to antiproliferative compounds against a panel of six human solid tumor cell lines, with GI50 values in the range 1.8-4.8 microM. Cell cycle studies revealed arrest in G0/G1 phase that is consistent with DNA Polymerase inhibition.