ABSTRACT
Herein, we report the synthesis and cytotoxicity of a series of substituted 6,7-dimethoxyquinazoline derivatives. The cytotoxic activity of all synthesized compounds has been evaluated against HCT116p53(+/+) and HCT116p53(-/-) colon cancer cells and a HEY ovarian cancer cell line naturally resistant to cisplatin. Nine of the tested compounds showed significant cytotoxicity in all cell lines at 10µM. The most promising derivative (7c) showed IC(50)values of 0.7 and 1.7µM in the two colon cancer cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Colonic Neoplasms/drug therapy , Ovarian Neoplasms/drug therapy , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Antineoplastic Agents/chemistry , Cell Survival/drug effects , Female , HCT116 Cells , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mass Spectrometry , Quinazolines/chemistry , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
Cathepsins have been found to have important physiological roles. The implication of cathepsin L in various types of cancers is well established. In a search for selective cathepsin L inhibitors as anticancer agents, a series of 2-cyanoprrolidine peptidomimetics, carrying a nitrile group as warhead, were designed. Two series of compounds, one with a benzyl moiety and a second with an isobutyl moiety at P(2) position of the enzyme were synthesized. The synthesized compounds were evaluated for inhibitory activity against human cathepsin L and cathepsin B. Although, none of the compounds showed promising inhibitory activity, (E)N-{(S)1-[(S)2-cyano-1-pyrrolidinecarbonyl]-3-methylbutyl}-2,3-diphenylacrylamide (24) with an isobutyl moiety at P(2) was found to show selectivity as a cathepsin L inhibitor (Ki 5.3 microM for cathepsin L and Ki > 100 microM for cathepsin B). This compound could act as a new lead for the further development of improved inhibitors within this inhibitor type.