结直肠癌（CRC）仍然是消化系统最常见的恶性肿瘤之一，但临床使用的安全有效的化疗药物仍然有限。喜树碱（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毒性高，在临床应用中遇到了重大挑战。对喜树碱7位进行策略修饰，可开发出具有高活性的新型喜树碱衍生物。本研究筛选了一系列7位含有氨基脲、氨基硫脲和酰氨基硫脲作为取代基的化合物。随后评估了这些化合物对人胃癌 (GC) 细胞系 AGS 和 CRC 细胞系 HCT116 的细胞毒性。两种衍生物 XSJ05 (IC50 = 0.006 ± 0.003 μM) 和 XSJ07 (IC50 = 0.013 ± 0.003 μM) 表现出非常有效的抗 CRC 活性，优于 TPT。此外，它们还具有更好的安全性。体外机制研究表明，XSJ05和XSJ07通过抑制拓扑异构酶I（Topo I）的活性来发挥对CRC细胞增殖的抑制作用。这种抑制会触发 DNA 双链断裂，导致 DNA 损伤，随后导致 CRC 细胞停滞在 G2/M 期。最终，细胞发生凋亡。总的来说，这些研究结果表明 XSJ05 和 XSJ07 具有优异的活性和良好的安全性，表明它们作为开发 CRC 疗法的先导化合物的潜力。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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.Copyright © 2024 Elsevier Inc. All rights reserved.