识别7-氨基尿素或7-氨基硫脲衍生物的喜树碱作为选择性拓扑异构酶I抑制剂，具有抗结直肠癌活性

Identification of 7-aminourea or 7-aminothiourea derivatives of camptothecin as selective topoisomerase I inhibitors with anti-colorectal cancer activities

BIOORGANIC CHEMISTRY

影响因子:4.7

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

DOI: 10.1016/j.bioorg.2024.107723

摘要

结直肠癌（CRC）仍是消化系统中最常见的恶性肿瘤之一，但临床上安全有效的化疗药物有限。喜树碱（CPT）及其衍生物虽已获批用于癌症治疗，但由于其低生物利用度和高系统毒性，临床应用面临重大挑战。通过在CPT的7位点进行战略性修饰，开发出具有高活性的新型CPT衍生物。本研究筛选了一系列在7位点引入氨基尿素、氨基硫脲和酰氨基硫脲的化合物，并评估其对人胃癌细胞系AGS和CRC细胞系HCT116的细胞毒性。结果显示，两个衍生物XSJ05（IC50=0.006±0.003μM）和XSJ07（IC50=0.013±0.003μM）在抗CRC方面表现出色，优于TPT，并具有更好的安全性。机制研究表明，XSJ05和XSJ07通过抑制拓扑异构酶I（Topo I）活性，阻断DNA双链断裂，导致DNA损伤，促使CRC细胞在G2/M期停滞，最终诱导细胞凋亡。综上，这些化合物具有优越的活性和良好的安全性，具有作为CRC新药候选化合物的潜力。

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.