期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 29, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115890
关键词
Phosphoinositide 3-kinase inhibitors; Thieno[2,3-d]pyrimidine; Thiazolo[5,4-d]pyrimidine; Fraction of sp(3) carbon atoms (Fsp(3)); Anti-tumor activities
资金
- Drug Innovation Major Project [2018ZX09711-001-005]
- CAMS Innovation Fund for Medical Sciences [2017-I2M-3-011, 2019-I2M-1-005]
- Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2018PT35003]
- Fundamental Research Funds for the Central Universities [3332020041]
A new series of PI3K inhibitors were designed and synthesized, showing promising anti-cancer activity and in vivo efficacy. Among them, thiazolo [5,4-d]pyrimidine 7a demonstrated superior anti-cancer activity compared to other compounds, warranting further pre-clinical evaluation.
As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp(3) carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo [5,4-d] pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antipmliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo [5,4-d]pyrimidine 7a had better anti-cancer activity than thieno [2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.
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