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烟云听雨铁杆木虫 (正式写手)
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求翻译一段英文文献（药化）
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As part of our efforts toward greater skeletal diversity, additional ring systems were introduced through modifications of the ketone carbonyl on scaffolds constructed by a Diels–Alder/ Schmidt reaction sequence.We applied the isocyanide multicomponent reaction (MCR) methodology developed by Shaabani et al. to transform the ketone carbonyl to the spirocyclic nitrogen heterocycles shown (Scheme 4) (45). This protocol smoothly incorporated three elements of diversity in a single operation to afford 44 heterocyclic analogues synthesized from the fragment pool in Scheme 4. This chemotype possesses an intriguing, complex spirocyclic molecular architecture not reported from any natural sources and incorporating three additional basic nitrogen sites. Although the MCR was not completely diastereoselective, a trend we had previously observed in the reductive amination at the same ketone carbonyl (39), the reaction did afford a dominant diastereomer that was assigned based on the X-ray crystal structure of the isolated compound 14{44}. Screening the full compound set for κ opioid, sigma 1, and sigma 2 receptor binding (Ki values) revealed a number of compounds with modest binding for these targets. Thus, compound 14{11} emerged as the most potent Sig-R binding candidate (Ki ¼ 867, 280 nM for sigma 1 and sigma 2, respectively) and compound 14{15} was found to possess the most potent κ opioid binding (Ki ¼ 407 nM) along with modest sigma 1 binding (Ki ¼ 1;158 nM). Sixteen of the 44 compounds were also evaluated for 5HT1A binding, with only compound 14{26} found to possess significant 5HT1A binding activity (Ki ¼ 431 nM). In addition, four compounds were screened against the full 43 GPCR assay panel as described previously for neostenine. The results showed this compound subset to be free from promiscuous binding, and compound 14{41} was discovered to possess selective adrenergic binding affinity (Ki ¼ 1;156, 7,588 nM for Alpha1A and Alpha1B, respectively). Representative structures of this chemotype and associated binding activity are shown in Scheme 4 (for complete data on all compounds, see SI Appendix). |
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