Augmented Efficacy of Uttroside B over Sorafenib in a Murine Model of Human Hepatocellular Carcinoma.

We previously reported the remarkable potency of uttroside B (Utt-B), saponin-isolated and characterized in our lab from Solanum nigrum Linn, against HCC. Recently, the U.S. FDA approved Utt-B as an 'orphan drug' against HCC. The current study validates the superior anti-HCC efficacy of Utt-B over sorafenib, the first-line treatment option against HCC. The therapeutic efficacies of Utt-B vs. sorafenib against HCC were compared in vitro, using various liver cancer cell lines and in vivo, utilizing NOD.CB17-Prkdcscid/J mice bearing human HCC xenografts. Our data indicate that Utt-B holds an augmented anti-HCC efficacy over sorafenib. Our previous report demonstrated the pharmacological safety of Utt-B in Chang Liver, the normal immortalized hepatocytes, and in the acute and chronic toxicity murine models even at elevated Utt-B concentrations. Here, we show that higher concentrations of sorafenib induce severe toxicity, in Chang Liver, as well as in acute and chronic in vivo models, indicating that, apart from the superior therapeutic benefit over sorafenib, Utt-B is a pharmacologically safer molecule, and the drug-induced undesirable effects can, thus, be substantially alleviated in the context of HCC chemotherapy. Clinical studies in HCC patients utilizing Utt-B, is a contiguous key step to promote this drug to the clinic.

Design, synthesis, and preliminary immunopotentiating activity of new analogues of nojirimycin.

Three new classes of nojirimycin analogues viz. N-alkyl with C1-substituent (4-phenylbutyl), N-substituted 1-deoxynojirimycin and its congener δ-lactam, and a 4-phenylbutyl-ß-C-glycoside were designed and synthesized for immunological studies. The resulting diverse compound library exhibited proliferation of B Cells and T cells induced by LPS and Con A, respectively. The majority of the analogues augmented the secretion of IL-12 in dendritic cells and TNF-α secretion in murine peritoneal macrophages compared to LPS (10 µg/ml). A deoxynojirimycin-triazole conjugate of phytosphingosine analogue was superior in the responses mentioned above and exhibited nitric oxide response equal to LPS. In comparison to findings on its congeners with immunosuppressive action, early immunological tests show that the novel nojirimycin analogues have immunopotentiating effect. Hence, nojirimycin analogues offer tremendous potential in tuning the immunomodulatory activity of iminosugars by subtle to substantial structural variations.

Cu(I)-azidopyrrolo[3,2-d]pyrimidine Catalyzed Glaser-Hay Reaction under Mild Conditions.

The limitation of the CuAAC "click" reaction with a 2-azidopyridine substrate, owing to its equilibrium with a tetrazole isomer, is exploited herein for its utility in the Glaser-Hay reaction. A catalytic combination of a 2-azidopyridine analogue, 4-azido-5H-pyrrolo[3,2-d]pyrimidine, and CuI afforded homocoupled products of terminal alkynes, without any trace of triazole product, under mild conditions with a broad substrate scope. Emphasis on carbohydrate-based substrates appended to a propargylic group led to 1,3-diynes in good to excellent yields.