School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia.
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Molecules. 2019 Apr 12;24(8):1453. doi: 10.3390/molecules24081453.
Purine isosteres present excellent opportunities in drug design and development. Using isosteres of natural purines as scaffolds for the construction of new therapeutic agents has been a valid strategy of medicinal chemistry. Inspired by the similarity to isoguanine, we attempted to develop a practical method for the preparation of 5-aza-isoguanines. Several synthetic approaches were explored to establish a robust general protocol for the preparation of these compounds. The significant difference in the reactivity of the C-5 and C-7 electrophilic centers of 1,2,4-triazolo[1,5-][1,3,5]triazines (5-azapurines) towards nucleophiles was demonstrated. The most practical and general method for the preparation of 5-aza-isoguanines involved a regioselective reaction of ethoxycarbonyl isothiocyanate with a 5-aminotriazole. The intramolecular ring closure of the resulted product followed by the S-methylation afforded 7-methylthio-2-phenyl-1,2,4-triazolo[1,5-][1,3,5]triazin-5-one, which could be effectively aminated with various amines. The resulted 5-aza-isoguanines resemble a known purine nucleoside phosphorylase inhibitor and could be interesting for further investigations as potential anticancer agents.
嘌呤类似物在药物设计和开发中具有极好的应用前景。将天然嘌呤的类似物用作构建新型治疗剂的骨架一直是药物化学的有效策略。受异鸟嘌呤相似性的启发，我们试图开发一种实用的方法来制备 5-氮杂异鸟嘌呤。探索了几种合成方法，以建立一种用于制备这些化合物的稳健通用方案。还证明了 1,2,4-三唑并[1,5-][1,3,5]三嗪（5-氮杂嘌呤）中 C-5 和 C-7 亲电中心对亲核试剂的反应性存在显著差异。制备 5-氮杂异鸟嘌呤的最实用和通用的方法涉及乙氧羰基异硫氰酸酯与 5-氨基三唑的区域选择性反应。所得产物的分子内环化，随后进行 S-甲基化，得到 7-甲硫基-2-苯基-1,2,4-三唑并[1,5-][1,3,5]三嗪-5-酮，可有效与各种胺进行胺化反应。得到的 5-氮杂异鸟嘌呤类似于已知的嘌呤核苷磷酸化酶抑制剂，作为潜在的抗癌药物，可能具有进一步研究的价值。
