The Synthesis of a c(RGDyK) Targeted SN38 Prodrug with an Indolequinone Structure for Bioreductive Drug Release

• DOI: 10.1021/ol1002626
• Publication Date: 2010-03-01T19:53:22Z
• Authors: Baohua Huang; Ankur Desai; Shengzhuang Tang; Thommey P. Thomas; James R. Baker
• Keywords: Time Factors; Dose-Response Relationship, Drug; Molecular Structure; Uterine Cervical Neoplasms; Integrin alphaVbeta3; Peptides, Cyclic; 01 natural sciences; KB Cells; 3. Good health; 0104 chemical sciences; Structure-Activity Relationship; NAD(P)H Dehydrogenase (Quinone); Humans; Camptothecin; Female; Prodrugs; Drug Screening Assays, Antitumor; Indolequinones; Oxidation-Reduction; Cell Proliferation

Preparation of a novel c(RGDyK) targeted SN38 prodrug incorporating an indolequinone structure for bioreductively triggered drug release is described. This design yields a prodrug that targets surface molecules on tumor cells (alpha(v)beta(3) integrins) and releases drug under bioreductive conditions. There are three moieties in the prodrug design, namely a therapeutic drug SN38, an indolequinone structure serving as a drug releasing trigger, and an alpha(v)beta(3) integrin targeting peptide c(RGDyK). Preliminary studies showed that SN38 is released in the presence of a bioreductive enzyme (DT-diaphorase).