Design, synthesis and biological evaluations of a long-acting, hypoxia-activated prodrug of fasudil, a ROCK inhibitor, to reduce its systemic side-effects was written by Al-Hilal, Taslim A.;Hossain, Mohammad Anwar;Alobaida, Ahmad;Alam, Farzana;Keshavarz, Ali;Nozik-Grayck, Eva;Stenmark, Kurt R.;German, Nadezhda A.;Ahsan, Fakhrul. And the article was included in Journal of Controlled Release in 2021.Formula: C4H12ClN The following contents are mentioned in the article:
ROCK, one of the downstream regulators of Rho, controls actomyosin cytoskeleton organization, stress fiber formation, smooth muscle contraction, and cell migration. ROCK plays an important role in the pathologies of cerebral and coronary vasospasm, hypertension, cancer, and arteriosclerosis. Pharmacol.-induced systemic inhibition of ROCK affects both the pathol. and physiol. functions of Rho-kinase, resulting in hypotension, increased heart rate, decreased lymphocyte count, and eventually cardiovascular collapse. To overcome the adverse effects of systemic ROCK inhibition, we developed a bioreductive prodrug of a ROCK inhibitor, fasudil, that functions selectively under hypoxic conditions. By masking fasudil′s active site with a bioreductive 4-nitrobenzyl group, we synthesized a prodrug of fasudil that is inactive in normoxia. Reduction of the protecting group initiated by hypoxia reveals an electron-donating substituent that leads to fragmentation of the parent mol. Under normoxia the fasudil prodrug displayed significantly reduced activity against ROCK compared to its parent compound, but under severe hypoxia the prodrug was highly effective in suppressing ROCK activity. Under hypoxia the prodrug elicited an antiproliferative effect on disease-afflicted pulmonary arterial smooth muscle cells and pulmonary arterial endothelial cells. The prodrug displayed a long plasma half-life, remained inactive in the blood, and produced no drop in systemic blood pressure when compared with fasudil-treated controls. Due to its selective nature, our hypoxia-activated fasudil prodrug could be used to treat diseases where tissue-hypoxia or hypoxic cells are the pathol. basis of the disease. This study involved multiple reactions and reactants, such as Tetramethylammonium chloride (cas: 75-57-0Formula: C4H12ClN).
Tetramethylammonium chloride (cas: 75-57-0) belongs to organic chlorides. Chlorination modifies the physical properties of hydrocarbons in several ways. These compounds are typically denser than water due to the higher atomic weight of chlorine versus hydrogen. Alkanes and aryl alkanes may be chlorinated under free radical conditions, with UV light. However, the extent of chlorination is difficult to control.Formula: C4H12ClN
Referemce:
Chloride – Wikipedia,
Chlorides – an overview | ScienceDirect Topics