title: Nitrobenzocyclophosphamides as potential prodrugs for bioreductive activation: synthesis, stability, enzymatic reduction, and antiproliferative activity in cell culture.
abstract: In efforts to obtain potential anticancer prodrugs for gene-directed enzyme prodrug therapy using Eschericia coli nitroreductase, a series of four benzocyclophosphamide analogues were designed and synthesized incorporating a strategically placed nitro group in a position para to the benzylic carbon for reductive activation. All four analogues were found to be stable in phosphate buffer at pH 7.4 and 37 degrees C and were good substrates of E. coli nitroreductase with half lives between 7 and 24 min at pH 7.0 and 37 degrees C. However, only two analogues 6a and 6c, both with a benzylic oxygen in the phosphorinane ring para to the nitro group, showed a modest 33-36-fold enhanced cytotoxicity in E. coli nitroreductase-expressing cells. These results suggest that good substrate activity and the para benzylic oxygen are required for activation by E. coli nitroreductase. Compounds 6a and 6c represent a new structure type for reductive activation and a lead for further modification in the development of better analogues with improved selective toxicity to be used in gene-directed enzyme prodrug therapy.
authors.affiliation: Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
authors.forename: Zhuorong
authors.initials: Z
authors.lastname: Li
authors.forename: Jiye
authors.initials: J
authors.lastname: Han
authors.forename: Yongying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Patrick
authors.initials: P
authors.lastname: Browne
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Knox
authors.forename: Longqin
authors.initials: L
authors.lastname: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D004795:Enzyme Stability; D004926:Escherichia coli / Q000201:enzymology; D020128:Inhibitory Concentration 50; D009601:Nitroreductases / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D003520:Cyclophosphamide; D009601:Nitroreductases