Synthesis and Chemical and Biological Comparison of Nitroxyl- and Nitric Oxide-Releasing Diazeniumdiolate-Based Aspirin Derivatives

被引：63

作者：

Basudhar, Debashree ^{[1
]}

Bharadwaj, Gaurav ^{[1
]}

Cheng, Robert Y. ^{[2
]}

Jain, Sarthak ^{[3
]}

Shi, Sa ^{[4
,5
]}

Heinecke, Julie L. ^{[2
]}

Holland, Ryan J. ^{[6
]}

Ridnour, Lisa A. ^{[2
]}

Caceres, Viviane M. ^{[4
,7
]}

Spadari-Bratfisch, Regina C. ^{[7
]}

Paolocci, Nazareno ^{[4
,8
]}

Velazquez-Martinez, Carlos A. ^{[3
]}

Wink, David A. ^{[2
]}

Miranda, Katrina M. ^{[1
]}

机构：

[1] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA

[2] NIH, Radiat Biol Branch, Bethesda, MD 20892 USA

[3] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2E1, Canada

[4] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21287 USA

[5] Harbin Med Univ, Dept Pathophysiol, Harbin 150081, Heilongjiang, Peoples R China

[6] NCI, Biol Chem Lab, Frederick, MD 21702 USA

[7] Fed Univ Sao Paulo UNIFESP, Dept Biosci, BR-04021001 Santos, SP, Brazil

[8] Univ Perugia, Dept Clin & Expt Med, I-06100 Perugia, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 20期

基金：

美国国家卫生研究院;

关键词：

NONSTEROIDAL ANTIINFLAMMATORY DRUGS; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; THERAPEUTIC TARGETS; UP-REGULATION; CANCER; CYCLOOXYGENASE-2; HNO; COX-2; NO; PROSTAGLANDINS;

D O I：

10.1021/jm400196q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structural modifications of nonsteroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but they may increase the risk of myocardial infarction with chronic use. The fact that nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction, and enhances contractility led us to synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. In addition to protection against stomach ulceration, these prodrugs exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward nonsmall cell lung carcinoma cells (A549), but they were not appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening on murine ventricular myocytes compared to control. Together, these anti-inflammatory, antineoplasic, and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure.

引用

页码：7804 / 7820

页数：17

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