1. N- and s-substituted Pyrazolopyrimidines: A promising new class of potent c-Src kinase inhibitors with prominent antitumor activity.
- Author
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Awaji AA, Zaloa WAZE, Seleem MA, Alswah M, Elsebaei MM, Bayoumi AH, El-Morsy AM, Alfaifi MY, Shati AA, Elbehairi SEI, Almaghrabi M, Aljohani AKB, and Ahmed HEA
- Subjects
- Humans, Apoptosis, Cell Line, Tumor, Cell Proliferation, CSK Tyrosine-Protein Kinase metabolism, Drug Screening Assays, Antitumor, Molecular Structure, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, src-Family Kinases, Structure-Activity Relationship, Pyrimidines chemistry, Pyrimidines pharmacology, Pyrazoles chemistry, Pyrazoles pharmacology, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Triple Negative Breast Neoplasms
- Abstract
In this work, readily achievable synthetic pathways were utilized for construction of a library of N/S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC
50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N-substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N-propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N-substitution as promising candidates for the treatment of TNBC type of breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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