Influence of Proline Chirality on Neighbouring Azaproline Residue Stereodynamic Nitrogen Preorganization.

We report herein the first systematic crystal structural investigation of azaproline incorporated in homo- and heterochiral diprolyl peptides. The X-ray crystallography data of peptides 1-5 illustrates that stereodynamic nitrogen in azaproline adopted the stereochemistry of neighbouring proline residue without depending on its position in the peptide sequence. Natural bond orbital analysis of crystal structures indicates OazPro -C'Pro of peptides 4 and 5 participating in n→π* interaction with stabilization energy about 1.21-1.33 kcal/mol. Density functional theory calculations suggested that the endo-proline ring puckering favoured over exo-conformation by 6.72-7.64 kcal/mol. NBO and DFT data reveals that the n→π* interactions and proline ring puckering stabilize azaproline chirality with the neighbouring proline stereochemistry. The CD, solvent titration, variable-temperature and 2D NMR experimental results further supported the crystal structures conformation.

Transition metal-free reductive coupling of allylic sulfonylhydrazones with aryl boronic acids for C(sp3)-C(sp2) bond formation.

The reductive coupling between allylic sulfonylhydrazones and aryl boronic acids gives 1,3-diarylpropene systems with good to excellent yields. Simple reaction conditions, high yields, and good functional group tolerance are the salient features of this reaction which takes place without using any transition-metal catalysts and an inert atmosphere. The substituents on aryl boronic acid or allylic sulfonylhydrazone play a role in the isomerization of the double bond. The 3,3-diphenylacrylaldehyde derived allylic sulfonylhydrazone gives almost exclusively a single isomer.

NMR-Based Metabolomic Imprinting Elucidates Macrophage Polarization of THP-1 Cell Lines Stimulated by Zinc Oxide Nanoparticles.

Zinc oxide (ZnO) nanoparticles (NPs) have been widely used in industry, cosmetics, drugs, bioimaging, and drug delivery. ZnO NPs have been found to interact and interfere with cellular physiology via macrophages, thereby resulting in macrophage polarization. The functional reprogramming of the cells is synchronized through cellular metabolic adaptations. The current study, therefore, aims to establish crosstalk between ZnO-NP-induced metabolic alterations and macrophage polarization in PMA-activated THP-1 cell lines. We observed moderate to heightened cytotoxic response in terms of cell viability and proliferation. The results also revealed increased Th1-type cytokine and chemokine expression. In order to characterize the changes in metabolite concentration in treatment groups, we employed multivariate data analysis (principal component analysis and partial least-squares discriminant analysis) of 1H NMR spectra. The results revealed biologically relevant patterns and alterations in many metabolic pathways. These alterations and patterns were found to be in line across the immune-cytotoxic axis. Furthermore, the results also implicate the role of carbon metabolism toward the classical activation of macrophage polarization. The omics approach could identify the markers involved in NP-induced toxicity, thus elaborating our vision of cytotoxicity that is currently limited to end-point and cytokine assays. Also, it could be emphasized that metabolic reconfiguration upon NP stimulation could direct macrophage polarization toward classical activation.

Partially saturated canthaxanthin alleviates aging-associated oxidative stress in D-galactose administered male wistar rats.

It has been earlier reported that partially saturated canthaxanthin (PSC) from Aspergillus carbonarius mutant is non-toxic, has anti-lipid peroxidation activity and can induce apoptosis in prostate cancer cell lines. In the present study, the antiaging effect of PSC was explored in D-galactose administered male wistar rats. 8-10 weeks old, male wistar rats were randomly divided into (i) Vehicle Control Group (VCG), (ii) Aged Control Group (ACG), (iii) Aged + α Lipoic Acid Group (ALG) and (iv) Aged + Partially saturated canthaxanthin Group (APG). Rats received D-galactose (300 mg /kg bwt/day; i.p.) alone (ACG) or together with PSC (APG) (20 mg/kg bwt/day; oral) and α Lipoic Acid (ALG) (80 mg/kg bwt/day; oral) for 10 weeks. Rats in VCG were injected with the same volume of physiological saline (i.p.) and fed with olive oil (vehicle). In vitro protein oxidation and DNA oxidation inhibition, in vivo malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), acetylcholinesterase (AChE) and monoamine oxidase (MAO) activities were determined. In addition, brain neurotransmitters, dopamine and serotonin were estimated by NMR. PSC treatment showed inhibition against protein and DNA oxidation. PSC effectively improved D-galactose induced aging rats by inducing a protective effect through up-regulation of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and brain neurotransmitters and downregulated malondialdehyde (MDA) and monoamineoxidase (MAO) levels. Thus, PSC appears to be a functional compound having antioxidant and antiaging properties.

Intramolecular 6-exo-dig Post-Ugi Cyclization of N-Substituted 2-Alkynamides: Direct Access to Functionalized Morpholinone Glycoconjugates.

We herein report a chemo- and regioselective 6-exo-dig catalytic cyclization of Ugi adducts N-substituted 2-alkynamides to access functionalized morpholinone glycoconjugates in the presence of triphenylphosphine. This array allows an interesting multicomponent access to a library of functionalized morpholinone glycoconjugates under mild reaction conditions with regeneration of catalyst triphenylphosphine, supported by 31P nuclear magnetic resonance studies. Density functional theory shows the 6-exo-dig oxocyclization pathway is preferred, which supports our experimental observation.

A prebiotic, short-chain fructo-oligosaccharides promotes peak bone mass and maintains bone mass in ovariectomized rats by an osteogenic mechanism.

In preclinical studies, fructooligosaccharide (FOS) showed beneficial skeletal effects but its effect on peak bone mass (PBM) and bone loss caused by estrogen (E2) deficiency has not been studied, and we set out to study these effects in rats. Short-chain (sc)-FOS had no effect on body weight, body composition, and energy metabolism of ovary intact (sham) and ovariectomized (OVX) rats. scFOS did not affect serum and urinary calcium and phosphorus levels, and on calcium absorption, although an increasing trend was noted in the sham group. Sham and OVX rats given scFOS had better skeletal parameters than their respective controls. scFOS treatment resulted in a higher bone anabolic response but had no effect on the catabolic parameters. scFOS increased serum levels of a short-chain fatty acid, butyrate which is known to have osteogenic effect. Our study for the first time demonstrates that in rats scFOS at the human equivalent dose enhances PBM and protects against E2 deficiency-induced bone loss by selective enhancement of new bone formation, and implicates butyrate in this process.

Increased Bone Marrow-Specific Adipogenesis by Clofazimine Causes Impaired Fracture Healing, Osteopenia, and Osteonecrosis Without Extraskeletal Effects in Rats.

Mycobacterium leprae infection causes bone lesions and osteoporosis, however, the effect of antileprosy drugs on the bone is unknown. We, therefore, set out to address it by investigating osteogenic differentiation from bone marrow (BM)-derived mesenchymal stem cells (MSCs). Out of 7 antileprosy drugs, only clofazimine (CFZ) reduced MSCs viability (IC50 ∼ 1 µM) and their osteogenic differentiation but increased adipogenic differentiation on a par with rosiglitazone, and this effect was blocked by a peroxisome proliferator-activated receptor gamma antagonist, GW9662. CFZ also decreased osteoblast viability and resulted in impaired bone regeneration in a rat femur osteotomy model at one-third human drug dose owing to increased callus adipogenesis as GW9662 prevented this effect. CFZ treatment decreased BM MSC population and homing of MSC to osteotomy site despite drug levels in BM being much less than its in vitro IC50 value. In adult rats, CFZ caused osteopenia in long bones marked by suppressed osteoblast function due to enhanced adipogenesis and increased osteoclast functions. A robust increase in marrow adipose tissue (MAT) by CFZ did not alter the hematologic parameters but likely reduced BM vascular bed leading to osteonecrosis (ON) characterized by empty osteocyte lacunae. However, CFZ had no effect on visceral fat content and was not associated with any metabolic and hematologic changes. Levels of unsaturated fatty acids in MAT were higher than saturated fatty acids and CFZ further increased the former. From these data, we conclude that CFZ has adverse skeletal effects and could be used for creating a rodent ON model devoid of extraskeletal effects.

Synthesis of Structurally Diverse Substituted Aziridinyl Glycoconjugates via Base-Mediated One-Pot Post-Ugi Cyclization.

The base-promoted intramolecular cyclization of Ugi-azide adduct has been demonstrated for the synthesis of highly substituted aziridinyl glycoconjugates in one pot. The reactions are scalable and efficient and have an operationally simple broad substrate scope. To gain insight into the mechanism of aziridine formation, DFT and control experiments show that the cyclization of the aziridine glycoconjugate pathway was preferred, as it proceeds with a low activation energy barrier (0.57 kcal mol-1), which supports our experimental observation.