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.Electric Literature of C14H18ClN3O2S This article mentions the following:
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鈥瞫 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. In the experiment, the researchers used many compounds, for example, 5-((1,4-Diazepan-1-yl)sulfonyl)isoquinoline hydrochloride (cas: 105628-07-7Electric Literature of C14H18ClN3O2S).
5-((1,4-Diazepan-1-yl)sulfonyl)isoquinoline hydrochloride (cas: 105628-07-7) belongs to isoquinoline derivatives. Although isoquinoline derivatives can be synthesized by several methods, relatively few direct methods deliver the unsubstituted isoquinoline. The Pomeranz鈥揊ritsch reaction provides a method for the preparation of isoquinoline. This reaction uses a benzaldehyde and aminoacetoaldehyde diethyl acetal, which in an acid medium react to form isoquinoline.Electric Literature of C14H18ClN3O2S
Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem