Discovery of New Pyrrolo[2,3-d]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers

In the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(E)-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N’-benzylidenebenzohydrazides’, were successfully synthesized in three steps with high yields. Among these nov...

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Published inPharmaceuticals (Basel, Switzerland) Vol. 16; no. 9; p. 1324
Main Authors Alotaibi, AbdulAziz A, Alanazi, Mohammed M, Rahman, A. F. M. Motiur
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 01.09.2023
MDPI
Subjects
Amino acids
Antimitotic agents
Antineoplastic agents
Apoptosis
apoptosis inducer
Cancer
Cancer therapies
Care and treatment
Cytotoxicity
Drugs
Hypertension
Leukemia
Lung diseases
multiple kinase inhibitor
Mutation
Nilotinib
Proteins
Pyrimidines
Pyrrolo[2,3-d]pyrimidine
Structure
Testing
Toxicity
tyrosine kinase inhibitor
Saudi Arabia
Thailand
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Summary:In the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(E)-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N’-benzylidenebenzohydrazides’, were successfully synthesized in three steps with high yields. Among these novel compounds, namely 5e, 5h, 5k, and 5l, promising cytotoxic effects were observed against four different cancer cell lines, with IC50 values ranging from 29 to 59 µM. Notably, compound 5k emerged as the most potent inhibitor, exhibiting significant activity against EGFR, Her2, VEGFR2, and CDK2 enzymes, with IC50 values ranging from 40 to 204 nM, comparable to the well-known TKI sunitinib (IC50 = 261 nM). Mechanistic investigations of compound 5k revealed its ability to induce cell cycle arrest and apoptosis in HepG2 cells, accompanied by a notable increase in proapoptotic proteins caspase-3 and Bax, as well as the downregulation of Bcl-2 activity. Furthermore, molecular docking studies indicated similar binding interactions between compound 5k and the four enzymes, as observed with sunitinib. These findings highlight the potential of compound 5k as a promising candidate for further development as a multi-targeted kinase inhibitor with enhanced potency.
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These authors contributed equally to this work.
ISSN:1424-8247
1424-8247
DOI:10.3390/ph16091324