In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.

Background Prunella vulgaris, commonly known as self-heal, has been extensively used in the traditional system of medicines. The plant has been found to contain a number of bioactive molecules including those having radical scavenging property which indicates its potential for the treatment of those diseases which are induced by free radical damage like drug-induced hepatotoxicity. Objective The current study was undertaken to investigate the flavonoid and total phenolic content and evaluate the hepatoprotective potential of various extracts obtained from floral spikes of P. vulgaris . Material and methods Flavonoid and otal phenolic contents were obtained from the standard curves of Gallic acid as per the reported methods. The extent of hepatotoxicity induced by paracetamol (500 mg/kg b.w, p.o daily for 14 days), hepatoprotective potential of extracts (200 mg/kg b.w/day, orally) and standard drug silymarin (50 mg/kg b.w/day, orally) were evaluated by analyzing various biochemical parameters like Serum Glutamic Oxaloacetic Transaminase, Serum Glutamic Pyruvic Transaminase, Alkaline Phosphatase, Total Proteins, Total and Direct Bilirubin and detailed histopathology of rat livers. Results Methanolic extract showed higher quantity of flavonoids and total phenolic content followed by ethanolic, hydroalcoholic and aqueous extracts. Treatment of rats with extracts showed a highly significant reduction in the enzyme activities of Serum Glutamic Oxaloacetic Transaminase, Serum Glutamic Pyruvic Transaminase, Alkaline Phosphatase, and serum levels of Total, Direct Bilirubin (P < 0.01) and highly significant elevation in Total Proteins (P < 0.01) when compared with the toxic control group. This was further confirmed by histopathological evaluation, where almost normal hepatic architecture or very less hepatic damage was observed in groups treated with extracts and silymarin compared to paracetamol treated group. Results from biochemical and histopathological evaluation indicated that among the extracts methanolic extract was most effective. Conclusion From the results, it can be concluded that the extracts obtained from floral spikes of P. vulgaris possess highly significant hepatoprotective activity which could be attributed to its radical scavenging potential and hepatic regeneration. This is further authenticated by the presence of phenolic and flavonoids which are known to possess radical scavenging properties.

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Lysosomal biogenesis plays a vital role in cell fate. Under certain conditions, excessive lysosomal biogenesis leads to susceptibility for lysosomal membrane permeabilization resulting in various pathological conditions including cell death. In cancer cells apoptosis machinery becomes dysregulated during the course of treatment, thus allows cancer cells to escape apoptosis. So it is therefore imperative to identify cytotoxic agents that exploit non-apoptotic mechanisms of cell death. Our study showed that pancreatic cancer cells treated with SDS-203 triggered an incomplete autophagic response and a nuclear translocation of transcriptional factor TFEB. This resulted in abundant biosynthesis and accumulation of autophagosomes and lysosomes into the cells leading to their death. It was observed that the silencing of autophagy genes didn’t alter the cell fate, whereas siRNA-mediated silencing of TFEB subdued SDS-203 mediated lysosomal biogenesis and associated cell death. Further mouse tumors treated with SDS-203 showed a significant reduction in tumor burden and increased expression of lysosomal markers. Taken together this study demonstrates that SDS-203 treatment triggers non-apoptotic cell death in pancreatic cancer cells through a mechanism of lysosome over accumulation.