Su Qing, Xu Baolin, Tian Zhoubin, Gong Ziling
Department of Orthopedic Oncology, Yantai Shan Hospital, Yantai, 264003 China.
Department of Orthopedics The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou, 310006, China.
Acta Pharm. 2022 Apr 13;72(3):389-402. doi: 10.2478/acph-2022-0026. Print 2022 Sep 1.
Osteosarcoma (OS) is an uncommon tumour that mainly affects bone in children and adolescents. The current treatment options of OS are of limited significance due to their immense side effects. In the present manuscript, we have developed a novel series of 1,2,3-triazole chalcone derivatives as potential agents against OS. The compounds were synthesized and evaluated for their PI3K and mTOR inhibitory activity using luminescent kinase assay, and Lance ultra assay, resp. The entire set of compounds showed significant to moderate inhibition of both kinases in the nanomolar range. The three most active compounds: (-(4-(3-(1-(4-bromophenyl)-1-1,2,3-triazol-4-yl)acryloyl)phenyl)-4-nitrobenzamide), (-(4-(3-(1-(4-bromophenyl)-1-1,2,3-triazol-4-yl)acryloyl)phenyl)-4-chlorobenzamide) and (4-bromo--(4-(3-(1-(4-bromophenyl)-11,2,3-triazol-4-yl)acryloyl)phenyl)benzamide), were evaluated for anticancer activity against human OS cancer cell line (MG-63), liver cancer cell line (HepG2), lung cancer cell line (A549) and cervical cancer (HeLa), using MTT assay. Among the tested series, compound showed a better inhibitory profile than gedatolisib against PI3K and was approximately comparable to that of gedatolisib against mTOR. The most significant inhibitory activity was observed for compound against all cell lines (MG-63, HepG2, A549 and HeLa), still somewhat lower to comparable to that of gedatolisib, but with the highest potency against MG-63 cells. Compound was further tested for anti-cancer activity against other OS cells and showed to be equipo-tent to gedatolisib against U2OS and Saos-2 cells. Moreover, it was also found non-toxic to normal cells (BEAS-2B and MCF 10A). The effect of compound was further determined on apoptosis of Saos-2 cells by Annexin-PI assay, where it significantly amplified the percentage of apoptotic cells. Novel 1,2,3-triazole chalcone derivatives are potential agents against OS.
骨肉瘤（OS）是一种罕见的肿瘤，主要影响儿童和青少年的骨骼。由于其巨大的副作用，目前骨肉瘤的治疗选择意义有限。在本手稿中，我们开发了一系列新型的1,2,3 - 三唑查尔酮衍生物作为抗骨肉瘤的潜在药物。使用发光激酶测定法和Lance超敏测定法分别合成并评估了这些化合物对PI3K和mTOR的抑制活性。所有化合物在纳摩尔范围内对这两种激酶均表现出显著至中等程度的抑制作用。三种活性最高的化合物：（-（4 - （3 - （1 - （4 - 溴苯基）-1,2,3 - 三唑 - 4 - 基）丙烯酰基）苯基）-4 - 硝基苯甲酰胺）、（-（4 - （3 - （1 - （4 - 溴苯基）-1,2,3 - 三唑 - 4 - 基）丙烯酰基）苯基）-4 - 氯苯甲酰胺）和（4 - 溴 - -（4 - （3 - （1 - （4 - 溴苯基）-1,2,3 - 三唑 - 4 - 基）丙烯酰基）苯基）苯甲酰胺），使用MTT测定法评估了它们对人骨肉瘤癌细胞系（MG - 63）、肝癌细胞系（HepG2）、肺癌细胞系（A549）和子宫颈癌（HeLa）的抗癌活性。在所测试的系列中，化合物对PI3K的抑制作用比吉地替尼更好，对mTOR的抑制作用与吉地替尼大致相当。观察到化合物对所有细胞系（MG - 63、HepG2、A549和HeLa）具有最显著的抑制活性，仍略低于吉地替尼但与之相当，不过对MG - 63细胞的效力最高。进一步测试了化合物对其他骨肉瘤细胞的抗癌活性，结果显示其对U2OS和Saos - 2细胞的活性与吉地替尼相当。此外，还发现它对正常细胞（BEAS - 2B和MCF 10A）无毒。通过Annexin - PI测定法进一步确定了化合物对Saos - 2细胞凋亡的影响，结果表明它显著增加了凋亡细胞的百分比。新型1,2,3 - 三唑查尔酮衍生物是抗骨肉瘤的潜在药物。
