Synergy trap for guardian angels of DNA: Unraveling the anticancer potential of phthalazinone-thiosemicarbazone hybrids through dual PARP-1 and TOPO-I inhibition.

Targeting DNA repair, like PARP-1 and TOPO-I, shows promise in cancer therapy. However, resistance to single agents requires complex and costly combination strategies with significant side effects. Thus, there's an urgent need for single agents with dual inhibition.

Development of new thieno[2,3-d]pyrimidines as dual EGFR and STAT3 inhibitors endowed with anticancer and pro-apoptotic activities.

In part due to the resilience of cellular feedback pathways that develop therapeutic resistance to targeting the EGFR alone, using EGFR inhibitors alone was demonstrated to be unsuccessful in clinical trials. The over-activation of the signal transducer/activator of transcription 3 (STAT3) during the administration of an EGFR inhibitor is expected to play a substantial part in the failure and resistance of EGFR inhibitor treatment. Therein, we proposed a hypothesis that induced STAT3-mediated resistance to EGFR inhibition therapy could be addressed by a dual inhibition of EGFR and STAT3 method.

Novel 4-(2-arylidenehydrazineyl)thienopyrimidine derivatives as anticancer EGFR inhibitors: Design, synthesis, biological evaluation, kinome selectivity and in silico insights.

The current study discovered fifteen new thieno[2,3-d]pyrimidine derivatives with potential anticancer action, including 5a-l, 6, and 7a-b. Results from the NCI screening revealed that compounds 5f-i and 7a significantly inhibited the proliferation of MDA-MB-468 cells at mean GI% and GI levels. Compared to staurosporine, these compounds (5f-i and 7a) demonstrated better safety towards typical WI-38 cells.

The mystery of titan hunter: Rationalized striking of the MAPK pathway via Newly synthesized 6-Indolylpyridone-3-Carbonitrile derivatives.

MAPK pathway sparkles with RTK activation, passes through subsequent downstream RAS-RAF-MEK-ERK signaling cascades, with consequent direct and indirect CDK4/6 signaling activation, and ends with cell survival, division, and proliferation. However, the emergence of anomalies such as mutations or overexpression in one or more points of the pathway could lead to cancer development and drug resistance. Therefore, designing small inhibitors to strike multitudinous MAPK pathway steps could be a promising synergistic strategy to confine cancer.

Discovery of novel enasidenib analogues targeting inhibition of mutant isocitrate dehydrogenase 2 as antileukaemic agents.

Mutant isocitrate dehydrogenase (IDH) 2 "IDH2m" acquires a neo-enzymatic activity reducing α-ketoglutarate to an oncometabolite, D-2-hydroxyglutarate (2-HG). Three -triazine series were designed and synthesised using enasidenib as a lead compound. anticancer screening National Cancer Institute "NCI" revealed that analogues , , and were most potent, with mean growth inhibition percentage "GI%" = 66.

Mechanistic Insight of Synthesized 1,4-Dihydropyridines as an Antidiabetic Sword against Reactive Oxygen Species.

The pharmacologically privileged DHP derivatives were synthesized using the pragmatic multicomponent Hantzsch synthesis to screen the antidiabetic activity. Initially, the candidates were screened using an blood glucose test, where compound showed the most prominent antidiabetic effect (% potency = 218%) compared to glimepiride. Then, a propositioned structure-activity relationship study was executed to reveal that longer side chains decreased the DHP's antidiabetic action.

New Genetic Bomb Trigger: Design, Synthesis, Molecular Dynamics Simulation, and Biological Evaluation of Novel BIBR1532-Related Analogs Targeting Telomerase against Non-Small Cell Lung Cancer.

Telomeres serve a critical function in cell replication and proliferation at every stage of the cell cycle. Telomerase is a ribonucleoprotein, responsible for maintaining the telomere length and chromosomal integrity of frequently dividing cells. Although it is silenced in most human somatic cells, telomere restoration occurs in cancer cells because of telomerase activation or alternative telomere lengthening.

Revisiting ageless antiques; synthesis, biological evaluation, docking simulation and mechanistic insights of 1,4-Dihydropyridines as anticancer agents.

The historic DHP nucleus was serendipitously discovered by Arthur Hantzsch about 130 years ago and is still considered a hidden treasure for various pharmacological activities. Twenty-one DHP analogues were synthesized using the expedient one pot Hantzsch synthesis for screening as anticancer agents. Initially, the in vitro anti-proliferative single dose against a panel of 18 cancer cell lines showed that compounds 11b and 8f were the superlative candidates regarding their antitumor effect (GI% mean = 66.

Identification of potential inhibitors for HCV NS5b of genotype 4a by combining dynamic simulation, protein-ligand interaction fingerprint, 3D pharmacophore, docking and 3D QSAR.

HCV NS5B polymerase has been one of the most attractive targets for developing new drugs for HCV infection and many drugs were successfully developed, but all of them were designed for targeting Hepatitis C Virus genotype 1 (HCV GT1). Hepatitis C virus genotype 4a (HCV GT4a) dominant in Egypt has paid less attention. Here, we describe our protocol of virtual screening in identification of novel potential potent inhibitors for HCV NS5B polymerase of GT4a using homology modeling, protein-ligand interaction fingerprint (PLIF), docking, pharmacophore, and 3D CoMFA quantitative structure activity relationship (QSAR).

Structurally Diverse Histone Deacetylase Photoreactive Probes: Design, Synthesis, and Photolabeling Studies in Live Cells and Tissue.

Histone deacetylase (HDAC) activity is modulated in vivo by post-translational modifications and formation of multiprotein complexes. Novel chemical tools to study how these factors affect engagement of HDAC isoforms by HDAC inhibitors (HDACi) in cells and tissues are needed. In this study, a synthetic strategy to access chemically diverse photoreactive probes (PRPs) was developed and used to prepare seven novel HDAC PRPs 9-15.

Identification of potential inhibitors for HCV NS3 genotype 4a by combining protein-ligand interaction fingerprint, 3D pharmacophore, docking, and dynamic simulation.

HCV NS3 protease domain has been one of the most attractive targets for developing new drugs for HCV infection and many drugs were successfully developed, but all of them were designed for targeting HCV genotype 1 infection. HCV genotype 4a dominant in Egypt has paid less attention. Here, we describe our protocol of virtual screening in identification of novel potential potent inhibitors for HCV NS3 of genotype 4a using homology modeling, PLIF (protein-ligand interaction fingerprint), docking, pharmacophore, and dynamic simulation.

Ellagic acid protects against carrageenan-induced acute inflammation through inhibition of nuclear factor kappa B, inducible cyclooxygenase and proinflammatory cytokines and enhancement of interleukin-10 via an antioxidant mechanism.

There are several hypotheses that explain the process of acute inflammation, including free radical overproduction, pro-inflammatory enzyme activation, and release of pro-inflammatory cytokines. In this study, the protective role of ellagic acid against carrageenan-induced acute inflammation was assessed. In addition, the immunomodulatory action, the antioxidant effects, and the role of COX-2 and NF-κB were also investigated.

Molecular dynamics simulations of wild-type and point mutation human prion protein at normal and elevated temperature.

This paper describes molecular dynamics simulations of prion protein at 300 and 500 K. This was undertaken to gain insight into the factors involved in the stability of prion protein. Simulations were done using the Particle Mesh Ewald (PME) method using a homology model of the C-terminal fragment of human prion protein and the NMR structure of the human prion protein.

Selective inhibition of 6-phosphogluconate dehydrogenase from Trypanosoma brucei.

A number of triphenylmethane derivatives have been screened against 6-phosphogluconate dehydrogenase from Trypanosoma brucei and sheep liver. Some of these compounds show good inhibition of the enzymes and also selectivity towards the parasite enzyme. Modelling was undertaken to dock the compounds into the active sites of both enzymes.