Synthesis and mechanism of action of new purine derivatives against triple negative breast cancer

Qian Zhang; Guoyang Sun; Yuna Huang; Shanshan Cui; Tingshen Li; Lianbo Zhao; Kui Lu; Peng Yu; Yongmin Zhang; Herve Galons; Nassima Oumata; Yuou Teng

doi:10.1016/j.ejmech.2023.115797

Synthesis and mechanism of action of new purine derivatives against triple negative breast cancer

Eur J Med Chem. 2023 Dec 5:261:115797. doi: 10.1016/j.ejmech.2023.115797. Epub 2023 Sep 7.

Authors

Qian Zhang¹, Guoyang Sun¹, Yuna Huang¹, Shanshan Cui¹, Tingshen Li¹, Lianbo Zhao¹, Kui Lu¹, Peng Yu¹, Yongmin Zhang², Herve Galons³, Nassima Oumata⁴, Yuou Teng⁵

Affiliations

¹ China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China.
² Sorbonne Université, Institut Parisien de Chimie Moléculaire, UMR8232 CNRS, 4 place Jussieu, 75005, Paris, France.
³ China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China; Université Paris Cité, 4, avenue de l'Observatoire, 75006, Paris, France.
⁴ Université Paris Cité, 4, avenue de l'Observatoire, 75006, Paris, France.
⁵ China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China; Université Paris Cité, 4, avenue de l'Observatoire, 75006, Paris, France. Electronic address: tyo201485@tust.edu.cn.

PMID: 37708799
DOI: 10.1016/j.ejmech.2023.115797

Abstract

Triple negative breast cancer (TNBC) is considered to be the most difficult subtype of breast cancer to treat because of its extremely prone to metastasis and the lack of targeted therapy drugs. New purine derivatives were synthesized and evaluated in a series of kinases and cell lines. The most active compounds 3g and 3j were selected based on their antiproliferative activities, then their pharmaceutical activity and mechanism in MDA-MB-231 cells were analyzed. The results in vitro indicated that compounds 3g and 3j can induce MDA-MB-231 cells apoptosis, and inhibit its migration and angiogenesis through influencing protein expression such as Bcl-2, Bax, Bcl-xl, P38, MMP2, MMP9, AKT and EGFR. In vivo results indicate that compounds 3g and 3j can inhibit tumor growth and metastasis and reduce the expression of Ki67 and CD31 protein in TNBC xenograft models. These findings not only broaden our understanding of the anti-TNBC effects and mechanisms of compounds 3g and 3j, but also provide new ideas and reference directions for the treatment of TNBC.

Keywords: CDK7; CLKs; MDA-MB-231 cells; TNBC.

MeSH terms

Apoptosis
Cell Line, Tumor
Cell Proliferation
Humans
Purines / pharmacology
Purines / therapeutic use
Triple Negative Breast Neoplasms* / pathology

Substances

Purines