Biomimetic synthesis and anti-HIV activity of dimeric phloroglucinols

Plants are an important source of a variety of bioactive compounds with different modes of action. Anti-HIV agents from plant sources can be useful in developing novel therapies for inhibiting HIV infection. Based on the reported anti-HIV activity of plant derived phloroglucinols, several new dimeric phloroglucinols were synthesized in the present study by varying substitution on aromatic ring and at methylene bridge. Some of the synthesized compounds have shown good HIV inhibitory activity in a human CD4+ T cell line (CEM-GFP) infected with HIV-1 NL4.3 virus isolate. Structure–activity studies indicate that phenyl, 4-benzyloxy-1-phenyl and cyclohexyl substitution at methylene bridge gave compounds with better anti-HIV activity. Compounds 22 and 24 showed highest anti-HIV activity with an IC50 of 0.28 μM and 2.71 μM, respectively, former was more active than the positive standard AZT in cell based assay

TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes