Discovery of 2-(2-aminobenzo[d]thiazol-6-yl) benzo[d]oxazol-5-amine derivatives that regulated HPV relevant cellular pathway and prevented cervical cancer from abnormal proliferation

Eur J Med Chem. 2020 Oct 15:204:112556. doi: 10.1016/j.ejmech.2020.112556.

Peili Jiao ¹, Yuxi Wang ², Beibei Mao ³, Bingding Wang ⁴, Yi Zhong ⁵, Hongwei Jin ⁶, Lihe Zhang ⁷, Liangren Zhang ⁸, Zhenming Liu ⁹

Affiliations

1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: pelly@bjmu.edu.cn.
2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: yuxiwang@bjmu.edu.cn.
3 College of Pharmaceutical Science, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. Electronic address: maobeibei89@163.com.
4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: 1710307424@pku.edu.cn.
5 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: yi_zhong@pku.edu.cn.
6 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: jinhw@bjmu.edu.cn.
7 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: zdszlh@bjmu.edu.cn.
8 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: liangren@bjmu.edu.cn.
9 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: zmliu@bjmu.edu.cn.

PMID: 32739649 DOI: 10.1016/j.ejmech.2020.112556

Abstract

Human papillomavirus (HPV) is a well-established etiological factor for cervical Cancer, and the expression of oncogenic protein E7 is crucial for carcinogenesis. Herein, virtual screening was performed and 2-(2-aminobenzo[d]thiazol-6-yl) benzo[d]oxazol-5-amine derivatives were designed, synthesized as antineoplastic agents, and evaluated for their anti-tumor activities. Among them, the most promising compound H1 showed specific anti-proliferation ability against HeLa cells (IC₅₀ = 380 nM) as well as excellent inhibition of tumor growth in the HeLa xenograft model without inducing obvious side effects. It is interesting that compound H1 displayed significant inhibition against HPV18-positive cervical cell lines (HeLa) but not for HPV16-positive cervical cell lines (SiHa). Further study demonstrated that a low concentration of compound H1 could lead to a cell cycle blockage at the G1 phase and promote cell Apoptosis slightly (8.77%). Compound H1 also exhibited transcription repression, especially those associated with the oncoprotein E7 cellular pathway like E7/Rb/E2F-1/DNMT1, which were essential in tumorigenesis. Proteomics analysis revealed that E7 might be degraded through E3 ubiquitin ligases, which aligned with decreasing expression of E7 following the treatment of compound H1. Taken together, it indicated that compound H1 could be a promising potential agent for cervical Cancer treatment.

Keywords

2-(2-aminobenzo[d]thiazol-6-yl) benzo[d]oxazol-5-amine derivatives; Cellular pathway; Cervical cancer; Human papillomavirus E7.

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