Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
Molecules. 2020 Jul 5;25(13):3066. doi: 10.3390/molecules25133066.
The burden of neoplastic diseases is widely recognized as a severe cause of mortality. The clinical inadequacy of most anticancer therapeutics urgently prompted intense drug discovery efforts toward the identification of new chemical entities endowed with a potent and safe antitumor profile. In this scenario, targeting cancer cells apoptosis machinery has emerged as a relevant strategy, useful for tackling the emergence of drug resistance. On this basis, a small library of naturally inspired hybrid molecules was obtained by combining, through a click chemistry approach, "privileged" synthons such as curcumin scaffold and 1,2,3-triazole building block. Compound , bearing a -fluoro phenyl moiety, showed low-micromolar potency against T acute lymphoblastic leukemia cell growth. More in-depth biologic studies demonstrated, for this analog, cell death-inducing properties associated with its capability to simultaneously activate both the receptor and the mitochondrial apoptosis cascades. This peculiar behavior offers promises for achieving an expanded anticancer effect, namely intense cytotoxic response coupled with reduced predisposition of chemoresistance insurgence. Altogether, this study allowed the identification of compound as a lead compound worth to be progressed as an anticancer drug candidate.
肿瘤疾病的负担被广泛认为是导致死亡率升高的一个严重原因。大多数抗癌疗法的临床效果不足，这迫切促使人们开展了激烈的药物发现工作，以寻找具有强大且安全的抗肿瘤特性的新化学实体。在这种情况下，针对癌细胞凋亡机制已成为一种相关策略，有助于解决耐药性的出现。在此基础上，通过点击化学方法将姜黄素支架和 1,2,3-三唑砌块等“优势”合成子组合在一起，得到了一个由天然启发的混合分子组成的小分子库。化合物 带有一个-氟苯基团，对 T 急性淋巴细胞白血病细胞生长具有低微摩尔效力。更深入的生物学研究表明，该类似物具有诱导细胞死亡的特性，与其能够同时激活受体和线粒体凋亡级联反应的能力有关。这种特殊的行为为实现更广泛的抗癌效果提供了希望，即强烈的细胞毒性反应，同时降低了化学抗性出现的倾向。总的来说，这项研究鉴定了化合物 作为一种值得进一步开发为抗癌药物候选物的先导化合物。
