Klein Brittney A, Robertson Ian M, Reiz Béla, Kampourakis Thomas, Li Liang, Sykes Brian D
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Ministry of Health, Government of Alberta, Edmonton, Alberta T5J 1S6, Canada.
ACS Med Chem Lett. 2019 May 15;10(6):1007-1012. doi: 10.1021/acsmedchemlett.9b00168. eCollection 2019 Jun 13.
We have investigated the mechanism and reactivity of covalent bond formation between cysteine-84 of the regulatory domain of cardiac troponin C and compounds containing a nitrile moiety similar to the calcium sensitizer levosimendan. The results of modifications to the levosimendan framework ranged from a large increase in covalent bond formation to complete inactivity. We present the biological activity of one of the most potent compounds. Limitations, including compound solubility and degradation at acidic pH, have prevented thorough investigation of the potential of these compounds. Our studies reveal the efficacious nature of the malononitrile moiety in targeting cNTnC and its potential in future cardiotonic drug design.
我们研究了心肌肌钙蛋白C调节结构域的半胱氨酸-84与含有类似于钙增敏剂左西孟旦的腈基部分的化合物之间形成共价键的机制和反应活性。对左西孟旦框架进行修饰的结果从共价键形成大幅增加到完全无活性不等。我们展示了其中一种最有效化合物的生物活性。包括化合物溶解度和在酸性pH下的降解等局限性，阻碍了对这些化合物潜力的全面研究。我们的研究揭示了丙二腈部分靶向心肌肌钙蛋白C的有效性质及其在未来强心药物设计中的潜力。
