Chemical Insights in the Concept of Hybrid Drugs:  The Antitumor Effect of Nitric Oxide-Donating Aspirin Involves A Quinone Methide but Not Nitric Oxide nor Aspirin

• Published in: Journal of medicinal chemistry Vol. 50; no. 10; pp. 2424 - 2431
• Main Authors: Hulsman, Niels, Medema, Jan Paul, Bos, Carina, Jongejan, Aldo, Leurs, Rob, Smit, Martine J, de Esch, Iwan J. P, Richel, Dick, Wijtmans, Maikel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.05.2007; Amer Chemical Soc
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Aspirin - analogs & derivatives; Aspirin - pharmacology; Biological and medical sciences; Cell Line, Tumor; Chemistry, Medicinal; Drug Screening Assays, Antitumor; General aspects; Humans; Indolequinones - chemical synthesis; Indolequinones - chemistry; Indolequinones - pharmacology; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Nitric Oxide - analogs & derivatives; Nitric Oxide - chemical synthesis; Nitric Oxide - chemistry; Nitric Oxide - pharmacology; Nitric Oxide Donors - chemical synthesis; Nitric Oxide Donors - chemistry; Nitric Oxide Donors - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; APOPTOSIS; COLON-CANCER CELLS; IN-VITRO; GROWTH-INHIBITION; ENERGY; FUNCTIONAL-ACTIVITY; APPROXIMATION; GLUTATHIONE; PHOSPHODIESTERASE TYPE-5; EXPRESSION; Antineoplastic agent; Human; Drug; Acetylsalicylic acid; Biological activity; Nitric oxide donor; Cell line; Cell death; Nitric oxide; Organic nitrate; Quinonemethide; Salicylates; Colon; Mechanism of action; Chemical synthesis; Tumor cell; Apoptosis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061371e

Hybrid drug 1 (NO-ASA) continues to attract intense research from chemists and biologists alike. It consists of ASA and a −ONO2 group connected through a spacer and is in preclinical development as an antitumor drug. We report that, contrary to current beliefs, neither ASA nor NO contributes to this antitumor effect. Rather, an unsubstituted QM was identified as the sole cytotoxic agent. QM forms from 1 after carboxylic ester hydrolysis and, in accordance with the HSAB theory, selectively reacts with cellular GSH, which in turn triggers cell death. Remarkably, a derivative lacking ASA and the −ONO2 group is 10 times more effective than 1. Thus, our data provide a conclusive molecular mechanism for the antitumor activity of 1. Equally importantly, we show for the first time that a “presumed invisible” linker in a hybrid drug is not so invisible after all and is in fact solely responsible for the biological effect.