KRAS inhibitors in drug resistance and potential for combination therapy.

Kirsten Rat Sarcoma (KRAS) is a potent target for cancer therapy because it acts as a signaling hub, engaging in various signaling pathways and regulating a number of cellular functions like cell differentiation, proliferation, and survival. Recently, an emergency approval from the US-FDA has been issued for KRAS inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. However, clinical studies on covalent KRAS inhibitors have rapidly confronted resistance in patients.

Novel Pyrazole-Chalcone Hybrids: Synthesis and Computational Insights Against Breast Cancer.

More women die of breast cancer than of any other malignancy. The resistance and toxicity of traditional hormone therapy created an urgent need for potential molecules for treating breast cancer effectively. Novel biphenyl-substituted pyrazole chalcones linked to a pyrrolidine ring were designed by using a hybridization approach.

Discovery of Novel Pyrimidine Based Small Molecule Inhibitors as VEGFR-2 Inhibitors: Design, Synthesis, and Anti-cancer Studies.

Background: Receptor tyrosine kinases (RTKs) are potent oncoproteins in cancer that, when mutated or overexpressed, can cause uncontrolled growth of cells, angiogenesis, and metastasis, making them significant targets for cancer treatment. Vascular endothelial growth factor receptor 2 (VEGFR2), is a tyrosine kinase receptor that is produced in endothelial cells and is the most crucial regulator of angiogenic factors involved in tumor angiogenesis. So, a series of new substituted N-(4-((2-aminopyrimidin-5-yl)oxy)phenyl)-N-phenyl cyclopropane- 1,1-dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized.

Emerging perspectives: unraveling the anticancer potential of vitamin D.

Vitamin D, a fat-soluble vitamin known for its critical function in calcium homeostasis and bone health, is gaining interest for its anticancer properties. Observational studies have suggested a negative relationship between vitamin D levels and the incidence of some malignancies throughout the years, prompting substantial investigation to find its anticancer effects. The purpose of this comprehensive review is to investigate the diverse function of vitamin D in cancer prevention and therapy.

Discovery of New Quinazoline Derivatives as VEGFR-2 Inhibitors: Design, Synthesis, and Anti-proliferative Studies.

Background: In cancer, Receptor tyrosine kinases (RTKs) are powerful oncoproteins that can lead to uncontrolled cell proliferation, angiogenesis, and metastasis when mutated or overexpressed, making them crucial targets for cancer treatment. In endothelial cells, one of them is vascular endothelial growth factor receptor 2 (VEGFR2), a tyrosine kinase receptor that is produced and is the most essential regulator of angiogenic factors involved in tumor angiogenesis. So, a series of new N-(4-(4-amino-6,7-dimethoxyquinazolin-2-yloxy)phenyl)-N-phenyl cyclopropane-1,1- dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized.

Recent progress in targeting KRAS mutant cancers with covalent G12C-specific inhibitors.

KRAS has been identified as a potential target in the treatment of solid tumors. One of the most often transformed proteins in human cancers is the small Kirsten rat sarcoma homolog (KRAS) subunit of GTPase, which is typically the oncogene driver. KRAS is altered to keep the protein in an active GTP-binding form.

Design, Synthesis, Molecular Docking, and Preliminary Pharmacological Screening of some New Benzo[d]thiazol-2-ylamino Containing Chromen-2- one Derivatives with Atypical Antipsychotic Profile.

Introduction: Mental disorders are very serious complicated disorders. Schizophrenia is one of the most baffling mental disorders. The new series 7-(2-(benzo[d]thiazol-2- ylamino)ethoxy)-4-methyl-2H-chromen-2- synthesized in search of newer compounds for Schizophrenia.

Bio-Actives as ESR Signaling Pathway Inhibitor for Breast Cancer Treatment: A Network Pharmacology Approach.

In our previous study (AV) has appeared as a promising target for breast cancer hence we have screened potential targets by , In Vitro and In Vivo methods. A network pharmacology (NP) approach involves prediction and validating of targets via molecular modeling, western blotting and In Vivo MNU-induced mammary cancer. The PPI network showed the 573 edges between 214 nodes (targets) that are involved in breast cancer and important one are ESR-1, ESR-2, AR, EGFR, NOS3, MAPK, KDR, SRC and MET.

Benzimidazole-1,2,3-triazole hybrid molecules: synthesis and study of their interaction with G-quadruplex DNA.

A series of new benzimidazole-1,2,3-triazole hybrid derivatives have been synthesized 'click' reaction and evaluated for their cytotoxicity as well as DNA binding affinity. MTT assay showed that all the six compounds are cytotoxic to PC3 and B16-F10 cancer cell lines. Though all the compounds showed moderate interaction with G4, c-Myc promoter DNA and dsDNA, exhibited selective interaction with G-quadruplex DNA over duplex DNA as demonstrated by spectroscopic experiments like UV-vis spectroscopy, fluorescence spectroscopy, CD spectroscopy, thermal melting and fluorescence lifetime experiments.

Network analysis and molecular mapping for SARS-CoV-2 to reveal drug targets and repurposing of clinically developed drugs.

Novel coronavirus (SARS-CoV-2), turned out to be a global pandemic with unstoppable morbidity and mortality rate. However, till date there is no effective treatment found against SARS-CoV-2. We report on the major in-depth molecular and docking analysis by using antiretroviral (Lopinavir and ritonavir), antimalarial (Hydroxychloroquine), antibiotics (Azithromycin), and dietary supplements (Vitamin C and E) to provide new insight into drug repurposing molecular events involved in SARS-CoV-2.

A network pharmacology-based approach to explore potential targets of Caesalpinia pulcherima: an updated prototype in drug discovery.

Caesalpinia pulcherima (CP) is a traditional herb used for the treatment of asthma, bronchitis, cancer, anti-bacterial, anti-fungal and as abortifacient. In the present study, bioactive components and potential targets in the treatment of breast cancer validated through in silico, in vitro and in vivo approach. The results for the analysis were as among 29 components, only four components were found active for further study which proved the use of CP as a multi-target herb for betterment of clinical uses.

A Validated Stability-Indicating Liquid Chromatographic Method for the Determination of Lorcaserin and Related Impurities in DRUG Substance Supported by Quality by Design.

Lorcaserin (LOR) is selective and potent antiobesity drug that targets the activation of the serotonin 5HT2C receptor. Here a novel, specific, sensitive stability indicating method was developed and validated for the quantitative determination of LOR and its process-related impurities using quality by design principles. By applying experimental design, the authors examine the multifactorial effect of parameters on the critical resolution pair and generated design space representing the robust design.

Immunomodulatory dose of clindamycin in combination with ceftriaxone improves survival and prevents organ damage in murine polymicrobial sepsis.

Sepsis is a life-threatening organ dysfunction resulting from inflammatory responses instigated by toxins secreted by bacteria. Immunomodulatory effect of clindamycin is earlier reported in a murine lipopolysaccharide (LPS)-induced sepsis model. There are no studies demonstrating the immunomodulatory effect of clindamycin in combination with ceftriaxone in a clinically relevant murine polymicrobial sepsis model induced by cecal ligation and puncture (CLP).

Chemomodulatory effects of extract via mitochondria-dependent apoptosis and necroptosis in breast cancer.

The present study intended to assess the anticancer potential of ethyl acetate fraction (AVEAF) in breast cancer cell lines (MCF-7 and MDA-MB-453) and against -methyl--nitrosourea (MNU) induced mammary carcinoma in Sprague-Dawley rats which resemble the human estrogen dependent breast cancer. The SRB assay showed that the maximum growth inhibition rate of AVEAF on MCF-7 cell was 27.12 at 100 µg/ml.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery.

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases.

Synthesis, Biological Investigation and Docking Study of Novel Chromen Derivatives as Anti-Cancer Agents.

Background: According to the latest global cancer data, cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018.

Liquid chromatographic separation and thermodynamic investigation of lorcaserin hydrochloride enantiomers on immobilized amylose-based chiral stationary phase.

A novel liquid chromatographic method was developed for enantiomeric separation of lorcaserin hydrochloride on Chiralpak IA column containing chiral stationary phase immobilized with amylose tris (3.5-dimethylphenylcarbamate) as chiral selector. Baseline separation with resolution greater than 4 was achieved using mobile phase containing mixture of n-hexane/ethanol/methanol/diethylamine (95:2.

Design, Synthesis and Anti-breast Cancer Activity of Some Novel Substituted Isoxazoles as Anti-breast Cancer Agent.

Methods: A novel series of isoxazole (S21-S30) derivatives were designed, synthesized and screened for their anticancer activity against estrogen receptor-positive MCF-7 and negative MDA-MB-435 breast cancer cell lines. The synthesized derivative has the ability to inhibit the growth of the human breast cancer cell line at low concentrations. In vivo anticancer activity was performed on virgin female sprague dawley rats.

Design, synthesis and anticancer screening of 3-(3-(substituted phenyl) acryloyl)-2H-chromen-2ones as selective anti-breast cancer agent.

By utilizing concept of molecular hybridization, involving combination of various Pharmacophore, novel substituted coumarin-chalcone hybrids was synthesized and evaluated for anti-proliferative activity against estrogen receptor-positive MCF-7 and negative MDA-MB-435 breast cancer cell lines. In-vivo study was carried out by N-methyl nitrosourea (MNU) induced mammary carcinoma in virgin female Spraque Dawly (SD) rats. The compound 5b has highest potential than standard drug Adriamycin, comparable against Tamoxifen against ER-positive MCF-7 breast cancer cell lines.

Design and Synthesis of Some Novel Estrogen Receptor Modulators as Anti-Breast Cancer Agents: In Vitro & In Vivo Screening, Docking Analysis.

A series of novel coumarin-chalcone hybrids have been synthesized in good yields and evaluated for their in vitro & in vivo anticancer activity. Cytotoxicity study was done against MCF-7 and Zr-75-1 human cancer cell lines. All compounds exhibited significant antiproliferative properties on both cell lines.

Design, synthesis and in vivo screening of some novel quinazoline analogs as anti-hyperlipidemic and hypoglycemic agents.

A novel series of substituted quinazoline derivatives were designed, synthesized and evaluated for their hypolipidemic activity in cholesterol induced hyperlipidemic rats. In vivo screening concluded that compounds A-4, C-5 and C-6 have shown potent antihyperlipidemic activity by decreasing the plasma level of triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL), followed by increase in level of high density lipoprotein (HDL).

Synthesis, in Vitro, and in Vivo Biological Evaluation and Molecular Docking Analysis of Novel 3-(3-oxo-substitutedphenyl-3-)4-(2-(piperidinyl)ethoxy)phenyl)propyl)-2H-chromen-2-one Derivatives as Anti-breast Cancer Agents.

The analogs of coumarin-chalcones have been reported to exhibit antineoplastic, anti-allergic, antihepatoprotective, and estrogenic activity. Herein, we have reported 3-(3-oxo-substitutedphenyl-3-)4-(2-(piperidinyl)ethoxy)phenyl)propyl)-2H-chromen-2-one derivatives as a new class of compounds that exhibit selectivity for ER-α binding along with antiproliferative and cytotoxic activity on human breast cancer cell line. The active compounds which show prominent activity against estrogen receptor-alpha-positive (ER+) human breast cancer cell lines MCF-7 and Zr-75-1 are subjected to in vivo screening.

Synthesis and in-vivo hypolipidemic activity of some novel substituted phenyl isoxazol phenoxy acetic acid derivatives.

The present study was undertaken to evaluate in-vivo hypolipidemic activity of a novel series of 2-methyl-2-(substituted phenyl isoxazol)phenoxyacetic acid derivatives by triton induced hyperlipidemia in rats. The newly synthesized compounds 5a, 5d and 5g showed significant decrease in the serum TCH, TG, LDL and VLDL along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index and increase in % protective activity compared to control group.

Synthesis and biologic evaluation of substituted 5-methyl-2-phenyl-1H-pyrazol-3(2H)-one derivatives as selective COX-2 inhibitors: molecular docking study.

The present study reported the synthesis and biologic evaluation of new pyrazolone derivatives for COX-2 inhibitory activities and investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model as well as in vitro using HRBC membrane stabilization and protein denaturation method. Eight derivatives showed pronounced COX-2 inhibition, and 5a, 5d, and 5f exhibited the highest COX-2 inhibition. The derivatives were further evaluated for antioxidant activity wherein 5a and 5b showed potent free radical-scavenging activity against DPPH, nitric oxide, and hydrogen peroxide radicals.

3D QSAR studies based in silico screening of 4,5,6-triphenyl-1,2,3,4-tetrahydropyrimidine analogs for anti-inflammatory activity.

The 3D QSAR studies based on generation of common pharmacophore hypotheses (CPHs) were performed separately for the series of 1,2,3,4-tetrahydropyrimidin-5-yl-acetic acid and 2-(4-sulfonylphenyl)pyrimidine analogs for their in-vivo anti-inflammatory activity and in-vitro COX-2 inhibitory activity respectively. The main idea of selecting two different series was to develop two 3D QSAR models for same scaffold (1,2,3,4-tetrahydropyrimidine/pyrimidine) for same target, but with different aspects of activity. The aim of study was to screen designed compounds and select new compounds with increased COX-2 selectivity.