Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche "STEBICEF", Sezione di Chimica Farmaceutica e Biologica, Università di Palermo, Via Archirafi 32, I-90123 Palermo, Italy.
Eur J Med Chem. 2013 Jul;65:381-8. doi: 10.1016/j.ejmech.2013.05.012. Epub 2013 May 20.
An unusual Dimroth rearrangement occurring in the reaction leading to annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core allowed the isolation of the linear isomer thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidine. By decorating the linear isomer with the same chains that improved the biological activity of the angular isomers, new annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines were designed and synthesized. They were selected by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) for the anticancer screening against a panel of 60 human tumor cell lines. The biological results showed that the new derivatives exhibited strong antiproliferative activity up to nanomolar concentration. In vivo screenings of the most active compound, the N-[2-(1H-imidazol-4-yl)ethyl]-4-(3-phenyl-10-oxo-4,10-dihydrobenzothieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidin-4-yl)butanamide, showed its low toxicity and high potency.
一种不寻常的 Dimroth 重排反应发生在导致稠合噻吩并[2,3-e][1,2,3]三唑并[1,5-a]嘧啶核心的反应中，允许分离出线性异构体噻吩并[3,2-d][1,2,3]三唑并[1,5-a]嘧啶。通过用相同的链修饰线性异构体，提高了角型异构体的生物活性，设计并合成了新的稠合噻吩并[3,2-d][1,2,3]三唑并[1,5-a]嘧啶。它们被国家癌症研究所（NCI）的发展治疗药物计划（DTP）选择用于针对 60 个人类肿瘤细胞系的抗癌筛选。生物结果表明，新衍生物在纳摩尔浓度下表现出强烈的抗增殖活性。最活跃化合物的体内筛选，N-[2-(1H-咪唑-4-基)乙基]-4-(3-苯基-10-氧代-4,10-二氢苯并噻吩并[3,2-d][1,2,3]三唑并[1,5-a]嘧啶-4-基)丁酰胺，显示其低毒性和高效力。
