Novel therapeutics with enhanced biological activity generated by the strategic introduction of silicon isosteres into known drug scaffolds

Abstract The strategic replacement of carbon with silicon within biologically prevalidated drug scaffolds can generate focused libraries of pharmaceutically relevant agents with novel, durable and marketable intellectual property. This approach can be cost‐effective and of lower developmental risk because known drugs have recognized pharmacology and toxicity profiles, proven safety in humans, and established manufacturing and formulation methods. The change in shape, charge, and lipophilicity that can result from the addition of silicon can favorably alter the biological activity and toxicology of the parent drug. Silicon‐containing derivatives of indomethacin are COX‐2 selective, suggesting they will not be associated with the classical toxicities associated with nonselective inhibition of the cyclooxygenases. The silicon‐indomethacin derivatives also demonstrated superior anti‐cancer activity at clinically achievable concentrations when tested in vitro against a human pancreatic cancer cell line, MiaPaCa‐2, and a panel of 14 human multiple myeloma cell lines. Bioorganosilicon chemistry represents an attractive approach for emerging biopharmaceutical organizations seeking to rapidly develop a portfolio of novel pharmacological agents that have the potential for enhanced therapeutic and pharmacological benefit. Drug Dev Res 68:156–163, 2007. ©2007 Wiley‐Liss, Inc.