Synthesis and biological evaluation of 5-membered spiro heterocycle-benzopyran derivatives against myocardial ischemia

• Published in: European journal of medicinal chemistry Vol. 46; no. 3; pp. 966 - 973
• Main Authors: Rapposelli, Simona, Breschi, Maria Cristina, Calderone, Vincenzo, Digiacomo, Maria, Martelli, Alma, Testai, Lara, Vanni, Michael, Balsamo, Aldo
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.03.2011; Elsevier
• Subjects: Animals; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - therapeutic use; Biological and medical sciences; Cardiotonic Agents - chemical synthesis; Cardiotonic Agents - chemistry; Cardiotonic Agents - therapeutic use; Cardiovascular system; Cell Line; Chemistry, Medicinal; Imino-spirooxazolidindiones; KATP Channels - metabolism; Life Sciences & Biomedicine; Male; Medical sciences; Miscellaneous; Mito-KATP channel openers; Mitochondrial ATP-sensitive potassium channels; Myocardial ischemia; Myocardial Ischemia - drug therapy; Myocytes, Cardiac - drug effects; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Wistar; Science & Technology; Spiro oxazolidinones; Spiro-substituted benzopyrans; Imino-spirooxazolidindiones; Mito-KATP channel openers; RPP; Spiro-substituted benzopyrans; Myocardial ischemia; Mitochondrial ATP-sensitive potassium channels; MPTP; IPC; Spiro oxazolidinones; MITOCHONDRIAL K-ATP; Mito-K-ATP channel openers; SENSITIVE POTASSIUM CHANNEL; OPENERS; CARDIOPROTECTION; Heart; Rat; Organic carbamate; Potassium channel agonist; Mitochondria; Structure activity relation; Mito-K; channel openers; Aromatic compound; Chemical synthesis; Oxygen nitrogen heterocycle; Rodentia; Cardioprotective agent; Aniline derivatives; Tricyclic compound; In vitro; Spiran; Vertebrata; Mitochondrial ATP-sensitive potassium; Mammalia; Cell line; channels; Cardiomyocyte; Oxazolidinone derivative; Antiïschemic; Aromatic amine
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.01.003

The activation of ATP-sensitive potassium channels (KATP), play a key role in an endogenous “self-defence” mechanism, known as ischemic preconditioning (IPC), which is fundamentally involved in the protection of the heart against the ischemia/reperfusion injury. Presently, it is widely accepted that IPC is mainly (albeit not exclusively) mediated by the activation of KATP channels expressed in the mitochondrial inner membrane (mito-KATP) rather than the sarcoplasmatic ones (sarc-KATP). Consistently, exogenous activation of KATP channels by pharmacological tools can be viewed as one of the most promising strategies for the therapy of myocardial ischemia. As part of our research program devoted to the synthesis and the evaluation of new cardioprotective agents, we extensively studied several six-membered spiro-heterocycle-benzopyran compounds endowed of a significant anti-ischemic activity. The positive results obtained, prompted us to further explore the influence on the biopharmacological effects, of the spiro-substitution at C4 benzopyran nucleus by replacing the six-membered spirocycle of the most active compounds with 5-membered-one. The preliminary evaluation of the new compounds on cultured H9c2 cardiomyoblasts exposed to anoxia/reperfusion and on Langendorff-perfused rat hearts submitted to ischemia/reperfusion cycles, showed that some of them can exert a cardioprotective effect. This anti-ischemic activity was antagonized by 5-hydroxydecanoic acid, a selective blocker of mito-KATP channels, confirming the involvement of this channel in the cardioprotective activity. [Display omitted] ► We synthesised a limited series of 5-membered spiroheterocycles-benzopyran as new potential tool to study myocardial-ischemia. ► The compounds were evaluated for their cardioprotective activity on cultured H9c2 cardiomyoblasts. ► The evaluation of the activity of the most active compound 1a on rat hearts submitted to ischemia/reperfusion cycles showed that mitoKATP channel is involved in cardioprotection. ► The structural contraction of the lead compound A does not affect the cardioprotective activity, thus indicating that also the spiro-oxazolidinone scaffold represents a valid structural motif to offer cardioprotection.