Triggering Breast Cancer Apoptosis via Cyclin-Dependent Kinase Inhibition and DNA Damage by Novel Pyrimidinone and 1,2,4-Triazolo[4,3-a]pyrimidinone Derivatives.

Combinations of apoptotic inducers are common clinical practice in breast cancer. However, their efficacy is limited by the heterogeneous pharmacokinetic profiles. An advantageous alternative is merging their molecular entities in hybrid multitargeted scaffolds exhibiting synergistic activities and uniform distribution. Herein, we report apoptotic inducers simultaneously targeting DNA and CDK-2 (cyclin-dependent kinase-2) inspired by studies revealing that CDK-2 inhibition sensitizes breast cancer to DNA-damaging agents. Accordingly, rationally substituted pyrimidines and triazolopyrimidines were synthesized and assayed by MTT against MCF-7, MDA-MB231, and Wi-38 cells compared to doxorubicin. The N-(4-amino-2-((2-hydrazinyl-2-oxoethyl)thio)-6-oxo-1,6-dihydropyrimidin-5-yl)acetamide 5 and its p-nitrophenylhydrazone 8 were the study hits against MCF-7 (IC50 = 0.050 and 0.146 µM) and MDA-MB231 (IC50 = 0.826 and 0.583 µM), induced DNA damage at 10.64 and 30.03 nM, and inhibited CDK-2 (IC50 = 0.172 and 0.189 µM). 5 induced MCF-7 apoptosis by 46.75% and disrupted cell cycle during S phase. Docking and MD simulations postulated their stable key interactions.

Halting colorectal cancer metastasis via novel dual nanomolar MMP-9/MAO-A quinoxaline-based inhibitors; design, synthesis, and evaluation.

Matrix metalloproteinase-9 (MMP-9) and monoamine oxidase-A (MAO-A) are central signaling nodes in CRC and promotors of distant metastasis associated with high mortality rates. Novel series of quinoxaline-based dual MMP-9/MAO-A inhibitors were synthesized to suppress CRC progression. The design rationale combines the thematic pharmacophoric features of MMP-9 and MAO-A inhibitors in hybrid scaffolds. All derivatives were initially screened via MTT assay for cytotoxic effects on normal colonocytes to assess their safety profiles, then evaluated for their anticancer potential on HCT116 cells overexpressing MMP-9 and MAO-A. The most promising derivatives 8, 16, 17, 19, and 28 exhibited single digit nanomolar IC50 against HCT116 cells within their safe doses (EC100) on normal colonocytes. They suppressed HCT116 cell migration by 73.32, 61.29, 21.27, 28.82, and 27.48%, respectively as detected by wound healing assay. Enzymatic assays revealed that the selected derivatives were superior to the reference MMP-9 and MAO-A inhibitors (quercetin and clorgyline, respectively). The nanomolar dual MMP-9/MAO-A inhibitor 19 was identified as the most potent and balanced dual inhibitor among the evaluated series with considerable selectivity against MAO-A over MAO-B. Besides, qRT-PCR analysis was conducted to explore the hit compounds' potential to downregulate hypoxia-inducing factor (HIF-1α) in HCT116 cells being correlated with MAO-A mediated CRC migration and invasion. The five above-mentioned compounds significantly downregulated HIF-1α by more than 5 folds. Docking simulations predicted their possible binding modes with MMP-9 and MAO-A and highlighted their essential structural features. Finally, they recorded drug-like in silico physicochemical parameters and ADMET profiles.

Synthesis and activity against HBV of novel Tetra-seconucleoside analogues of dyphlline having the acyclic chains of ACV and HBG.

Selective alkylation of dyphylline (1) with (2-acetoxyethoxy)methyl bromide (2a) or 4-acetoxybutyl bromide (2b) afforded 3'-O-[(acetoxyethoxy)methyl]dyphylline (3a) and 3'-O-(4-acetoxybutyl)-dyphylline (3b), respectively. A trans esterification process rather than alkylation of the dihydroxy-propyl side chain in 1 had taken place during the reaction with 2-p-toluoyloxy)ethyl chloride (5) to afford the respective 3'-toluoyloxy derivative 7 and not the anticipated 3'-O-[(p-toluoyloxy)ethyl]-dyphylline (6). Deacylation of 3a,b and 7 afforded 4a,b and 1, respectively. Viral screening of selected compounds against HBV has been investigated.

Synthesis of AZT analogues: 7-(3-azido-2-hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-,7-(3-triazolyl-2-hydroxypropyl)theophylline.

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph3P/Py/NH4OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N1-propargyl thymine (6) afforded the regioisomeric triazole 7.