Rivello Bárbara Gonçalves, Willig Julia Biz, Gotardi Jéssica, Machado Michele Resende, da Silva Gloria Narjara Santos, Gomides Christian Dias, de Oliveira Gisele Augusto Rodrigues, Lião Luciano Morais, Pilger Diogo André, Menegatti Ricardo
Laboratory of Medicinal Pharmaceutical Chemistry (LQFM), School of Pharmacy, Federal University of Goiás, Goiânia, Brazil.
Laboratory of Biochemical and Cytological Analysis, Postgraduate Program in Pharmaceutical Sciences, School of Pharmacy, Federal University of Rio Grande Do Sul, Porto Alegre, Brazil.
Chem Biol Drug Des. 2025 Jul;106(1):e70151. doi: 10.1111/cbdd.70151.
Eight new LQFM's Aplysinopsin analogs (12a-h) were synthesized and were evaluated for their anticancer profile on MCF-7 (breast cancer), SiHA and HeLa (cervical cancer). The compounds were obtained through the rational drug design strategy, bioisosterism, by changing the indole scaffold of Aplysinopsin by phenylpyrazole, a subunit extensively explored for designing potent and selective anticancer agents. The synthesis was performed in three simple steps, followed by structural elucidation through nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry, and global yield ranged from 10% to 93%. Regarding the biological assay, the best result was achieved with 12g, which showed antiproliferative activity against all cell lines evaluated, with IC 59.22, 58.33, and 55.32 μM for MCF-7, SiHA and HeLa, respectively. The safety profile, in the Zebrafish-based model, showed the mortality rate for 12g in concentration-time-dependent, from 87 μM, over 120 h. All Aplysinopsin analogs demonstrated drug-likeness in agreement to Lipinski and Veber rules. Although the moderate antiproliferative activity displayed by 12g, our results include new Aplysinopsin analogs that may be promising lead compounds for further studies, since chemical structures related to this marine compound have provided satisfactory results as anticancer agents against a variety of human tumor cell lines.
合成了8种新型LQFM的阿朴lysopsin类似物（12a - h），并评估了它们对MCF - 7（乳腺癌）、SiHA和HeLa（宫颈癌）的抗癌活性。这些化合物是通过合理药物设计策略、生物电子等排体，用苯基吡唑取代阿朴lysopsin的吲哚骨架而获得的，苯基吡唑是一种广泛用于设计强效和选择性抗癌剂的亚基。合成过程分三个简单步骤进行，随后通过核磁共振、红外光谱和质谱进行结构解析，总产率在10%至93%之间。关于生物测定，12g取得了最佳结果，它对所有评估的细胞系均显示出抗增殖活性，对MCF - 7、SiHA和HeLa的IC50分别为59.22、58.33和55.32 μM。在基于斑马鱼的模型中，安全性分析表明，12g在浓度 - 时间依赖性下的死亡率从87 μM起，持续120小时。所有阿朴lysopsin类似物均符合Lipinski和Veber规则，具有类药性质。尽管12g显示出中等抗增殖活性，但我们的结果包括新的阿朴lysopsin类似物，它们可能是有前途的先导化合物，可用于进一步研究，因为与这种海洋化合物相关的化学结构作为针对多种人类肿瘤细胞系的抗癌剂已取得了令人满意的结果。
