Department of Chemistry, Faculty of Sciences, Atatürk University, Erzurum, Turkey.
Department of Chemistry, Faculty of Science, Cumhuriyet University, Sivas, Turkey.
J Biochem Mol Toxicol. 2024 Sep;38(9):e23837. doi: 10.1002/jbt.23837.
Synthesis of novel unnatural amino acids (UAAs) from 4-oxo-4-phenylbut-2-enoic acid derivatives with intramolecular aza-Michael addition reaction in the presence of chlorosulfonyl isocyanate (CSI) was reported in soft conditions without any metal catalyst. Acids and base as a catalyst, and solvents effects were investigated for the synthesis of novel UAAs. This novel method provides inexpensive, practicable, and efficient approach to generate UAAs. The use of UAAs has attracted great interest in the development of therapeutic agents and drug discovery to improve their properties. In this context, in addition to the synthesis of new UAAs, their inhibition effects on important metabolic enzymes of acetylcholinesterase (AChE) and carbonic anhydrases I and II (hCA I and II) enzymes were investigated. The compound 2g showed the best inhibition for CA I and AChE enzymes, while compound 2i exhibited the best inhibition profile against CA II isoenzyme. The inhibition values of these compounds were found as 1.85 ± 0.64 for AChE, 0.53 ± 0.07 for hCA I, 0.44 ± 0.15 µM for hCA II, respectively, and they showed a stronger inhibitory property than acetazolamide (standard inhibitor for hCA I and II) and tacrine (standard inhibitor for AChE) molecules. The activity of the studied molecule against different proteins that are hCA I (PDB ID: 2CAB), hCA II (PDB ID: 5AML), and AChE (PDB ID: 1OCE) was examined. Finally, the drug properties of the studied molecule were examined by performing absorption, distribution, metabolism, excretion, and toxicity analysis.
在无任何金属催化剂存在的条件下，通过氯磺酰异氰酸酯（CSI）引发的分子内氮杂迈克尔加成反应，从 4-氧代-4-苯基-2-丁烯酸衍生物合成新型非天然氨基酸（UAAs）的方法被报道。在温和条件下，考察了酸和碱作为催化剂以及溶剂效应对新型 UAAs 合成的影响。该新方法为生成 UAAs 提供了一种廉价、实用且高效的方法。UAAs 的应用在治疗剂的开发和药物发现中引起了极大的兴趣，以改善它们的性质。在这种情况下，除了合成新的 UAAs 外，还研究了它们对乙酰胆碱酯酶（AChE）和碳酸酐酶 I 和 II（hCA I 和 II）酶的重要代谢酶的抑制作用。化合物 2g 对 CA I 和 AChE 酶表现出最好的抑制作用，而化合物 2i 对 CA II 同工酶表现出最好的抑制作用。这些化合物的抑制值分别为 1.85±0.64 对 AChE、0.53±0.07 对 hCA I、0.44±0.15µM 对 hCA II，并且它们表现出比乙酰唑胺（hCA I 和 II 的标准抑制剂）和他克林（AChE 的标准抑制剂）更强的抑制性质。研究分子对不同蛋白质的活性进行了测试，这些蛋白质是 hCA I（PDB ID：2CAB）、hCA II（PDB ID：5AML）和 AChE（PDB ID：1OCE）。最后，通过进行吸收、分布、代谢、排泄和毒性分析，研究了研究分子的药物特性。
