Novel approaches to prodrugs of anticancer diaminodichloroplatinum(II) complexes activated by stereoselective enzymatic ester hydrolysis.
A series of dichloro(ethylenediamine)-type platinum complexes bearing ester-, amide- and ether-bonded alkyl straight chains (C2-C18) was prepared as a model for the prodrug of cis-diamminedichloroplatinum (CDDP). Evaluation of cytotoxic activity of the complexes against the S-180 cell line proved that their enzymatic hydrolysis in the cells lowered the permeability to the cell membranes resulting in an increase of pharmacological activity. Optically active isomers of dichloro(N-2(2-phenylpropanoyloxy)ethyl)-2,3-diaminopropanamide )platinum(II) were prepared. They were re-activated stereoselectively, and a tenfold difference in activity was observed based on the differences in chiral discrimination by enzymes.
Kageyama
Y
Y
National Institute of Bioscience and Human Technology, Agency of Industrial Science and Technology, Ibaraki, Japan.
Yamazaki
Y
Y
Okuno
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D002463:Cell Membrane Permeability / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D006868:Hydrolysis; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D012510:Sarcoma 180 / Q000188:drug therapy / Q000378:metabolism; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011355:Prodrugs; D002945:Cisplatin