Semisynthesis, Biological Activity, and Molecular Modeling Studies of C-Ring-Modified Camptothecins

The synthesis, biological activity, and molecular modeling studies of C-ring-rnodified camptothecins are reported. A general synthetic protocol, based on C-5 camptothecin (C-5-CPT) enolate chemistry, allows one to obtain various C5-substituted analogues. All new Compounds, obtained as 1:1 epimeric mixtures, were tested for their antiproliferative activity. Experimental data showed that all novel derivatives are less active than the reference compounds and that one of the two epimers; is more active than the other. Molecular docking simulations were performed to achieve more insight into the interactions between the new C5-modified CPTs and Topo I. A good correlation was observed when the data of cytotoxicity and the values calculated for the free binding energy were combined.