Title : Development of nitroreductase/prodrug system for cancer therapy
Abstract:
Conversion of an inactive drug (prodrug) into an active drug is the starting point of the Enzyme Prodrug Therapy (EPT), one of the novel strategies attracted attention increasingly over 20 years to develop new solutions for various illness. Nitroreductases reduce aromatic nitro groups and convert prodrugs to hydroxylamine derivatives (active drug) which can bind to DNA and inhibit tumuor formation. The best known example in the enzyme mediated cancer therapy is probably the use of E.coli NTR in combination with the prodrug CB1954 (5-aziridinyl-2-4-dinitrobenzamide). In this study, first of all, we explored and characterized a novel nitroreductase (Ssap-NtrB-cloned from S. saprophyticus) with enhanced activity-selectivity and implemented various applications. Different type of nitro group containing compounds were designed, synthesized and the interaction of prodrugs with Ssap-NtrB were investigated by HPLC analysis. Resulting metabolites were analyzed by LC-MS/MS. Michaelis-Menten kinetic parameters were calculated for reduction reactions of prodrugs and compared common known prodrugs like as CB1954 and SN23862. The prodrugs were evaluated by MTT and SRB assay in three different cancer cell lines, Human Hepatoma Cancer (Hep3B), Human Colon Cancer (HT-29) and Human Prostate Cancer (PC3) in addition to non-cancer cell, HUVEC. Promising results along this side are going to be discussed.
Takeaway Notes
•How to use prodrug approach for expanding their research or teaching,
•Realize importance of nitroreductase to drug design and other applications,
•Design new projects with collaboration for cancer therapy.
