Pd-catalyzed synthesis of hetero 1,2-interlinked C-disaccharides by coupling of iodo glycals with glycals.

A facile synthesis of C1-C2 interlinked disaccharides is achieved from readily available iodo-glycals and unsubstituted glycals. Ester-protected donors reacted with ether-protected acceptors under Pd-Ag catalysis to access C-disaccharides bearing C-3 vinyl ether, which upon ring opening by Lewis acid furnished pi-extended conjugated orthogonally protected chiral ketones. Benzyl deprotection and reduction of the double bonds resulted in a fully saturated disaccharide stable toward acid hydrolysis.

Comparison of Miniplate and K-wire in the Treatment of Metacarpal and Phalangeal Fractures.

Introduction Metacarpal and phalangeal fractures are common upper limb fractures due to direct blows, axial loading, and torsional loading injuries. The universal goal in treating all fractures for the patient to achieve normal motion, but the ideal technique for stabilization is still debated. For internal fixation, Kirschner wires (K-wires) or miniplates can be used, and each carries certain advantages. No previous study has compared K-wire use to miniplate use in treating metacarpal and phalangeal fractures. Therefore, we conducted this randomized control trial to evaluate the outcomes of K-wire and miniplate use in treating metacarpal and phalangeal fractures. Materials and methods This randomized controlled trial was conducted in the Department of Orthopaedic Surgery, Bahawal Victoria Hospital, from February 2017 to February 2018. Seventy-five patients were included in this study and randomly assigned into two groups. One group was treated with K-wire fixation, and the other group was treated with miniplate fixation. We assessed total active motion (TAM), range of motion (ROM), duration of injury, and complication rate. Data were analyzed using IBM SPSS Statistics for Windows, Version 23.0 (Armonk, NY: IBM Corp). P values ≤ 0.05 were considered significant. Results Mean surgical time, pain scale, and time of union of K-wire treated patients was 38.63±3.64 minutes, 4.17±1.11, and 12.95±3.38 weeks, respectively. The success of the union was noted in 38 K-wire patients (95%). Total active ROM was greater in miniplate fixation patients compared with K-wire treated patients, but this difference was statistically significant. Similarly, TAM was also greater in the miniplate fixation patients compared to the K-wire treated patients, but this difference was also not statistically significant. Conclusion Both K-wire fixation and miniplate fixation are equally effective in terms of TAM, ROM, and complications when used to treat metacarpal and phalangeal fractures.

Synthesis and Investigation of the Role of Benzopyran Dihydropyrimidinone Hybrids in Cell Proliferation, Migration and Tumor Growth.

BACKGROUND: Cancer is the second leading cause of mortality worldwide after heart diseases, and lung cancer is the topmost cause of all cancer-related deaths in both sexes. Dihydropyrimidinones (DHPMs) are medicinally important class of molecules with diverse pharmacological activities including anticancer activity. The present study focuses on the molecular hybridization of novel Benzopyran with Dihydropyrimidinone and evaluation of the resulting hybrids for cancer cell proliferation, migration and tumor growth. METHODS: We have synthesized a focused library of dihydropyrimidinone benzopyran hybrids (compounds 1-11) by joining the aromatic as well as pyran portions of the benzopyran core with dihydropyrimidinone. All the synthesized hybrid molecules were evaluated for their cytotoxic activities against a panel of four human cancer cell lines of diverse tissue origin, viz: A549 (lung carcinoma), MCF7 (mammary gland adenocarcinoma), HCT-116 (colorectal carcinoma), and PANC-1 (pancreatic duct carcinoma) with the help of MTT cell viability assay. A structure-activity relationship was made on the basis of IC50 values of different hybrids. Effect on cell proliferation was examined through colony formation assay, reactive oxygen species generation and mitochondrial membrane potential studies. Wound healing assays and cell scattering assays were employed to check the effect on cell migration. Western blotting experiments were performed to find out the molecular mechanism of action and anti-tumor studies were carried out to evaluate the in vivo efficacy of the selected lead molecule. RESULTS: Two types of novel hybrids were synthesized efficiently from benzopyran aldehydes, ethylacetoacetate and urea under heteropolyacid catalysis. Compound 3 was found to be the most potent hybrid among the synthesized compounds with consistent cytotoxic activities against four human cancer cell lines (IC50 values: 0.139 - 2.32 µM). Compound 3 strongly inhibited proliferation abilities of A549 cells in colony formation assay. Compound 3 exerted oxidative stress-mediated mitochondrial dysfunction, in which mitochondrial reactive oxygen species (ROS) generation as a mechanism of its anti-proliferative effects was analysed. Further, the molecule abrogated migration and cell scattering properties of aggressive PANC-1 cells. Mechanistic studies revealed that compound 3 modulated NF-kB expression and its downstream oncogenic proteins involved in cancer cell proliferation and invasion. Finally, compound 3 confirmed its in vivo anti-tumor efficacy; there observed 41.87% tumor growth inhibition at a dose of 30 mg/kg/body weight against a mouse model of Ehrlich solid tumor. CONCLUSION: Our study unravels a potential anticancer lead (compound 3) from DHPMs that have opened up new research avenues for the development of promising anticancer therapeutic agents.

Regiospecific Synthesis of Ring A Fused Withaferin A Isoxazoline Analogues: Induction of Premature Senescence by W-2b in Proliferating Cancer Cells.

Induction of premature senescence represents a novel functional strategy to curb the uncontrolled proliferation of malignant cancer cells. This study unveils the regiospecific synthesis of novel isoxazoline derivatives condensed to ring A of medicinal plant product Withaferin-A. Intriguingly, the cis fused products with ß-oriented hydrogen exhibited excellent cytotoxic activities against proliferating human breast cancer MCF7 and colorectal cancer HCT-116 cells. The most potent derivative W-2b triggered premature senescence along with increase in senescence-associated ß-galactosidase activity, G2/M cell cycle arrest, and induction of senescence-specific marker p21Waf1/Cip1 at its sub-toxic concentration. W-2b conferred a robust increase in phosphorylation of mammalian checkpoint kinase-2 (Chk2) in cancer cells in a dose-dependent manner. Silencing of endogenous Chk2 by siRNA divulged that the amplification of p21 expression and senescence by W-2b was Chk2-dependent. Chk2 activation (either by ectopic overexpression or through treatment with W-2b) suppressed NM23-H1 signaling axis involved in cancer cell proliferation. Finally, W-2b showed excellent in vivo efficacy with 83.8% inhibition of tumor growth at a dose of 25 mg/kg, b.w. in mouse mammary carcinoma model. Our study claims that W-2b could be a potential candidate to limit aberrant cellular proliferation rendering promising improvement in the treatment regime in cancer patients.