鉴定具有抗直肠癌活性的7-氨基酸或7-氨基硫脲衍生物为选择性拓扑异构酶I抑制剂
Identification of 7-aminourea or 7-aminothiourea derivatives of camptothecin as selective topoisomerase I inhibitors with anti-colorectal cancer activities
影响因子:4.70000
分区:医学2区 / 有机化学1区 生化与分子生物学2区
发表日期:2024 Nov
作者:
Lixue Tu, Zhongkun Zhou, Yunhao Ma, Liqian Du, Zhenzhen Si, Yuqi Yue, Hua Zhang, Hongmei Zhu, Yingqian Liu, Peng Chen
摘要
结直肠癌（CRC）仍然是消化系统最普遍的恶性肿瘤之一，但可用于临床使用的安全有效的化学治疗剂仍然有限。 Camptothecin（CPT）及其衍生物虽然被批准用于癌症治疗，但由于其生物利用度低和全身性毒性高，在临床应用中遇到了重大挑战。 CPT的7位处的战略修改使具有高活性的新型CPT衍生物的发展。在本研究中，筛选了一系列含有氨基酸，氨基硫菌和酰基氨基硫菌作为7位的取代基的化合物。随后对这些化合物的细胞毒性对人胃癌（GC）细胞系AG和CRC细胞系HCT116进行了评估。两个衍生物XSJ05（IC50 = 0.006±0.003μm）和XSJ07（IC50 = 0.013±0.003μm）表现出非常有效的抗CRC活性，比TPT更好。此外，它们具有更好的安全性。体外机械研究表明，XSJ05和XSJ07通过抑制拓扑异构酶I（TOPO I）的活性对CRC细胞增殖产生了抑制作用。这种抑制会触发DNA双链断裂，导致DNA损伤，并随后导致CRC细胞在G2/M期停滞。最终，细胞会凋亡。总的来说，这些发现表明XSJ05和XSJ07具有出色的活性以及有利的安全概况，这表明它们作为CRC疗法开发的铅化合物的潜力。
Abstract
Colorectal cancer (CRC) remains one of the most prevalent malignant tumors of the digestive system, yet the availability of safe and effective chemotherapeutic agents for clinical use remains limited. Camptothecin (CPT) and its derivatives, though approved for cancer treatment, have encountered significant challenges in clinical application due to their low bioavailability and high systemic toxicity. Strategic modification at the 7-position of CPT enables the development of novel CPT derivatives with high activity. In the present study, a series of compounds incorporating aminoureas, amino thioureas, and acylamino thioureas as substituents at the 7-position were screened. These compounds were subsequently evaluated for their cytotoxicity against the human gastric cancer (GC) cell line AGS and the CRC cell line HCT116. Two derivatives, XSJ05 (IC50 = 0.006 ± 0.003 μM) and XSJ07 (IC50 = 0.013 ± 0.003 μM), exhibited remarkably effective anti-CRC activity, being better than TPT. In addition, they have a better safety profile. In vitro mechanistic studies revealed that XSJ05 and XSJ07 exerted their inhibitory effects on CRC cell proliferation by suppressing the activity of topoisomerase I (Topo I). This suppression triggers DNA double-strand breaks, leads to DNA damage and subsequently causes CRC cells to arrest in the G2/M phase. Ultimately, the cells undergo apoptosis. Collectively, these findings indicate that XSJ05 and XSJ07 possess superior activity coupled with favorable safety profiles, suggesting their potential as lead compounds for the development of CRC therapeutics.