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CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers that affect humans worldwide. The available therapeutic options suffer from many drawbacks including high toxicity and decreased specificity. Therefore, there is a need for more effective and safer therapeutic agents. A series of new pyrazolo[3,4-d]pyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo[3,4-d]pyrimidinone derivatives bearing N5-2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds 4a and 4b confirmed their CDK2 inhibitory activity. Compound 4a was more potent than the reference roscovitine regarding the CDK2 inhibitory activity (IC50 values: 0.21 and 0.25 µM, respectively). In silico molecular docking provided insights into the molecular interactions of compounds 4a and 4b with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds 4a and 4b were identified as interesting CDK2 inhibitors eliciting antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for future further investigations and development. [ABSTRACT FROM AUTHOR]

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3–24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), also known as hepatoma, is the most prevalent type of primary liver cancer. It begins in the hepatocytes, the liver's major cell type. Cancer that began in another region of the body but has spread to the liver is known as secondary cancer of life; several still unmet demands for better, less toxic therapy to treat this malignant tumor. Several novel pyrazolo[1,5-a]pyrimidine derivatives were synthesized as part of our goal to develop promising anticancer drugs. All the synthesized hybrids have been screened for their cytotoxicity effect against three cancer cell lines which are; HepG-2, HCT-116, and MCF-7. The liver cancer cells were found to be the most sensitive to the effect of the new molecules. A subsequent set of in vitro biological evaluation studies has been conducted on the most promising derivatives to identify their effect on such a cancer type. In HepG-2 cells, four derivatives (8a, 8b, 10c, and 11b) demonstrated good anticancer activity. The most efficacious compounds were 8b and 10c, which had IC50 values of 2.36 ± 0.14 and 1.14 ± 0.063 μM, respectively, higher than the reference medication Imatinib. The latter's putative molecular effect has been investigated further by looking at its influence on the cell cycle, EGFR, and specific apoptotic and anti-apoptotic markers in HepG-2 cells. These findings indicated that 8b and 10c could trigger apoptosis by upregulating BAX and caspase-3 and cell cycle at the Pre-G1 and G2-M stages. The compounds 8b and 10c showed high potency for EGFR with IC50 equal to 0.098 and 0.079 μM, respectively. Compound 10c had the most effective inhibitory activity for EGFR L858R-TK with IC50 (36.79 nM). Additionally, in silico ADMET and docking studies were done for the most active hits, representing good results. [ABSTRACT FROM AUTHOR]

In our attempt to develop effective EGFR-TKIs, two series of 1 H -pyrazolo[3,4- d ]pyrimidine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated in vitro for their inhibitory activities against EGFR WT . Compounds 15 b , 15 j , and 18 d potently inhibited EGFR WT at sub-micro molar IC 50 values comparable to that of erlotinib. Moreover, thirteen compounds that showed promising IC 50 values against EGFR WT were tested in vitro for their inhibitory activities against mutant EGFR T790M . Compounds 17 d and 17 f exhibited potent inhibitory activities towards EGFR T790M comparable to osimertinib. Compounds that showed promising IC 50 values against EGFR WT were further tested for their anti-proliferative activities against three cancer cell lines bearing EGFR WT (MCF-7, HepG2, A549), and two cancer cell lines bearing EGFR T790M (H1975 and HCC827). Compounds 15 g , 15 j , 15 n , 18 d and 18 e were the most potent anticancer agents against the EGFR WT containing cells, while compounds 15 e , 17 d and 17 f showed promising anti-proliferative activities against EGFR T790M containing cells. Furthermore, the most active compound 18 d was selected for further studies regarding to its effects on cell cycle progression and induction of apoptosis in the HepG2 cell line. The results indicated that this compound is good apoptotic agent and arrests G 0 /G 1 and G 2 /M phases of cell cycle. Finally, molecular docking studies were performed to investigate binding pattern of the synthesized compounds with the prospective targets, EGFR WT (PDB: 4HJO) and EGFR T790M (PDB: 3W2O). [ABSTRACT FROM AUTHOR]

A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a-k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like 7b-c, and 7e-g exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC50 values in the 1.65 to 34.28 µM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives 7a-c, 7e, and 7g could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 µM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds 7e and 7g displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets. [ABSTRACT FROM AUTHOR]