Correction: Direct access to the optically active VAChT inhibitor vesamicol and its analogues via the asymmetric aminolysis of meso-epoxides with secondary aliphatic amines.

Correction for 'Direct access to the optically active VAChT inhibitor vesamicol and its analogues via the asymmetric aminolysis of meso-epoxides with secondary aliphatic amines' by Arun Sharma et al., Org. Biomol. Chem., 2017, 15, 1913-1920, https://doi.org/10.1039/C6OB02479C.

Ultrasonication-Assisted Synthesis of a d-Glucosamine-Based ß-CD Inclusion Complex and Its Application as an Aqueous Heterogeneous Organocatalytic System.

For the first time, an inclusion complex has been crafted between a carbohydrate-based molecule and a ß-cyclodextrin (CD) hydrophobic cavity for asymmetric catalytic applications. This novel d-glucosamine-based inclusion compound has been synthesized in high yields using an innovative and proficient acoustic cavitation technology and well characterized using various techniques, such as infrared spectroscopy, nuclear magnetic resonance spectroscopy, ultraviolet-visible spectroscopy, thermogravimetric analysis, scanning electron microscopy, and other spectroscopic techniques. It was observed that the inclusion of a d-glucosamine derivative into the hydrophobic cavity of ß-CD increased its surface area and thermal stability. This catalytic system worked well in water for the direct aldol reaction to afford the products in excellent yields with high diastereo- and enantioselectivities.

Mechanistic details of amino acid catalyzed two-component Mannich reaction: experimental study backed by density functional calculations.

The role of pH-dependent ionic structures of L-amino acids in catalysis has been investigated for the two-component Mannich reactions between dimethyl malonate (DMM)/ethyl acetoacetate (EAA) and imines. As catalysts, L-amino acids performed well, even better than corresponding base catalysts and provided the ß-amino carbonyl compounds in very high yields. Density functional calculations were used to gain the mechanistic insight of the reaction. High catalytic efficiency of amino acids was attributed to the facile formation of carbanion intermediate through barrierless transition state TS1 (- 19.43 kcal/mol) and then its stabilization owing to carbanion interaction with protonated amino acid.

Direct access to the optically active VAChT inhibitor vesamicol and its analogues via the asymmetric aminolysis of meso-epoxides with secondary aliphatic amines.

First highly enantioselective synthesis of biologically important vesamicol, benzovesamicol, and their derivatives was achieved via the desymmetrization of meso-epoxides with secondary aliphatic amines (4-phenylpiperidine derivatives) using a chiral [salenCo(iii)-BF4] catalyst at room temperature. All products were obtained in good yield and with excellent optical induction.

Progress in aminosugar derived asymmetric organocatalysis.

In the last decade aminosugars, especially d-glucoamine based organocatalysts, have been applied to catalyze various asymmetric reactions such as aldol reactions, Michael addition, Strecker reactions, Biginelli reactions, epoxidation, fluorination, and imine reduction, and for the synthesis of various biologically important molecules such as 3-alkylnitro-2-hydroxynaphthoquinones, trans-dihydrobenzofurans etc. Immense growth has been also observed in the structural modification of aminosugar based organocatalysts to obtain the best results from them. This review sheds light on such organocatalytic transformations reported in last the decade including the effect of the structural modification of sugar amines on their catalytic efficiency and the stereoselectivity of the reaction.

Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance.

Drug resistance remains a major obstacle to successful cancer treatment. A database of drug-associated gene expression profiles was screened for molecules whose profile overlapped with a gene expression signature of glucocorticoid (GC) sensitivity/resistance in acute lymphoblastic leukemia (ALL) cells. The screen indicated that the mTOR inhibitor rapamycin profile matched the signature of GC sensitivity. We tested the hypothesis that rapamycin would induce GC sensitivity in lymphoid malignancy cells and found that it sensitized to GC-induced apoptosis via modulation of antiapoptotic MCL1. These data indicate that MCL1 is an important regulator of GC-induced apoptosis and that the combination of rapamycin and glucocorticoids has potential utility in lymphoid malignancies. Furthermore, this approach represents a strategy for identification of promising combination therapies for cancer.

Giant Cell Tumor of Mandible : A Case Report.

Giant cell tumor is locally aggressive primary benign neoplasm of bone with tendency of frequent recurrence, metastasis and malignant transformation. Because of the rarity of the disease involving mandible, no definite treatment guideline is established. Surgical treatment is the treatment of choice for giant cell tumor. Due to its proximity to vital structures including skull base, the recurrent disease associated with less invasive procedure could be difficult to manage while more invasive procedure will result in higher morbidity and complex reconstruction. Medical management with denosumab or zoledronic acid has been advocated in surgically unresectable disease. We present a rare case of giant cell tumor of mandible. Patient was a 33 years old lady who presented with gradually progressive painful swelling in chin. After exclusion of distant metastasis by F-18 FDG PET scan, she underwent en-bloc resection of the tumor with free fibula flap reconstruction. During 6 months of follow up visit patient had no recurrence.

Copper ferrite nanoparticles catalyzed the challenging Diels-Alder reaction of aromatic chalcones with cyclopentadiene.

Copper ferrite nanoparticles efficiently transformed the unreactive aromatic chalcones into activated dienophiles for a Diels-Alder reaction with cyclopentadiene/isoprene as dienes. The best results in terms of rate of reaction and product yields were obtained in an eco-friendly solvent i.e. ethanol using 5 mol% catalytic loading. Substrate scope was also investigated for a number of chalcone derivatives, and all the reactions proceeded smoothly to provide the corresponding DA adducts in high yields (up to 89%) and good diastereoselectivities (up to >99%) with endo-preference.

Birth Defects among Newborns in a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Introduction: The incidence of birth defects is 2-3% in the general population but it is increasing. An estimated 303,000 newborns die within 4 weeks of birth every year, worldwide, due to congenital anomalies. The objective of this study was to find out the prevalence of birth defects among newborns in a tertiary care centre. Methods: A descriptive cross-sectional study was done in the Department of Obstetrics and Gynaecology and the Department of Paediatrics from 15 June 2016 and 14 June 2019. Ethical approval was obtained from the Institutional Review Committee (Reference number: 142/077/078-IRC). Data of newborns were collected from the hospital records. Convenience sampling method was used. Point estimate and 99% Confidence Interval were calculated. Results: Among 32,695 newborns, birth defects were seen in 169 (0.51%) (0.41-0.61, 99% Confidence Interval). The most common birth defect was musculoskeletal defects seen in 60 (35.50%) newborns followed by central nervous system defect seen in 30 (17.75%) newborns. Conclusions: The prevalence of birth defects among newborns was lower than in other studies done in a similar setting. Keywords: birth defect; congenital malformation; prevalence.

Glucosamine-based primary amines as organocatalysts for the asymmetric aldol reaction.

Glucosamine derivatives have been synthesized starting from commercially available N-acetyl-D-glucosamine/glucosamine hydrochloride and have been employed successfully as efficient organocatalysts for the direct asymmetric aldol reaction between cyclohexanone and aryl aldehydes having diversified substituents. Furthermore, the anomeric effect of various groups present at the anomeric position on the catalytic activity of these organocatalysts was also studied.

1-Chloro-2-formyl indenes and tetralenes as antitubercular agents.

1-Chloro-2-formyl indenes and tetralenes have been synthesized using Vilsmeier-Haack-Arnold reaction onto indanones and tetralones. Most of these analogues exhibited antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MICs ranging from 30 to 500 µg/mL. Analogue 13 was further modified to some derivatives. The most active analogue 23 showing MIC at 30 µg/mL was further evaluated for acute oral toxicity in Swiss albino mice and was found to be safe up to 300 mg/kg dose.

Antiplasmodial activity of artecyclopentyl mether a new artemisinin derivative and its effect on pathogenesis in Plasmodium yoelii nigeriensis infected mice.

In an effort to evaluate novel derivatives from artemisinin, possessing potential antimalarial activity, a new derivative artecyclopentyl mether (CPM-1) was derivatized and evaluated for its dose-dependent efficacy in Plasmodium yoelii nigeriensis infected mice. The survivability of mice at 7.5 mg/kg was >28 days with negligible parasitaemia and recovered anemia (66.16-72.62%). Artecyclopentyl mether was also found to modulate the pro- and anti-inflammatory cytokines (IFN-γ, 39.64-56.92%; TNF, 49.10-74.31%; IL-4, 11.53-43.22%; IL-10, 37.60-53.52%) favourably besides optimizing the oxidative stress to the infected subjects as evident by the nitric oxide (88.76-95.43%), lipid peroxidation (59.30-76.05%) and glycaemic data (62.70-76.66%). The results indicate the potentiality of the new derivative as an antimalarial against asexual stages of the parasite.

'Chitosan in water' as an eco-friendly and efficient catalytic system for Knoevenagel condensation reaction.

The catalytic activity of commercially available chitosan has been investigated for the Knoevenagel reaction of ethylacetoacetate (EAA)/dimethylmalonate (DMM) with arylaldehydes. Among all the screened solvents, Chitosan performed the best in water as reaction medium. Substrate scope was evaluated by using various arylaldehydes and it was observed that presence of electron donating groups on aldehydes reduce the yields, while electron-withdrawing groups increase the yields. In case of the reaction of 4-bromobenzaldeyde with EAA, the lower yield of the corresponding product 14 was obtained due to the high stability of imine intermediate formed and this postulate was proved by experiments as well as theoretical calculations. In case of EAA, the E/Z stereochemistry of the corresponding products was assigned based on NOESY experiment.

Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells.

Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.

In silico and in vivo anti-malarial studies of 18ß glycyrrhetinic acid from Glycyrrhiza glabra.

Malaria is one of the most prevailing fatal diseases causing between 1.2 and 2.7 million deaths all over the world each year. Further, development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents possessing novel modes of action. Over the past few years triterpenoids from higher plants have shown a wide range of anti-malarial activities. As a part of our drug discovery program for anti-malarial agents from Indian medicinal plants, roots of Glycyrrhizaglabra were chemically investigated, which resulted in the isolation and characterization of 18ß-glycyrrhetinic acid (GA) as a major constituent. The in vitro studies against P. falciparum showed significant (IC50 1.69 µg/ml) anti-malarial potential for GA. Similarly, the molecular docking studies showed adequate docking (LibDock) score of 71.18 for GA and 131.15 for standard anti-malarial drug chloroquine. Further, in silico pharmacokinetic and drug-likeness studies showed that GA possesses drug-like properties. Finally, in vivo evaluation showed a dose dependent anti-malarial activity ranging from 68-100% at doses of 62.5-250 mg/kg on day 8. To the best of our knowledge this is the first ever report on the anti-malarial potential of GA. Further work on optimization of the anti-malarial lead is under progress.

Delphinidin reduces cell proliferation and induces apoptosis of non-small-cell lung cancer cells by targeting EGFR/VEGFR2 signaling pathways.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) have emerged as two effective clinical targets for non-small-cell lung cancer (NSCLC). In the present study, we found that delphinidin, an anthocyanidin, present in pigmented fruits and vegetables, is a potent inhibitor of both EGFR and VEGFR2 in NSCLC cells that overexpress EGFR/VEGFR2. Using these cells, we next determined the effects of delphinidin on cell growth and apoptosis in vitro and on tumor growth and angiogenesis in vivo. Delphinidin (5-60 µM) treatment of NSCLC cells inhibited the activation of PI3K, and phosphorylation of AKT and MAPKs. Additionally, treatment of NSCLC cells with delphinidin resulted in inhibition of cell growth without having significant toxic effects on normal human bronchial epithelial cells. Specifically, treatment of NCI-H441 and SK-MES-1 cells with delphindin (5-60 µM) resulted in (i) cleavage of PARP protein, (ii) activation of caspase-3 and -9, (iii) downregulation of anti-apoptotic proteins (Bcl2, Bcl-xL and Mcl-1), (iv) upregulation of pro-apoptotic proteins (Bax and Bak), and (v) decreased expression of PCNA and cyclin D1. Furthermore, in athymic nude mice subcutaneously implanted with human NSCLC cells, delphinidin treatment caused a (i) significant inhibition of tumor growth, (ii) decrease in the expression of markers for cell proliferation (Ki67 and PCNA) and angiogenesis (CD31 and VEGF), and (iii) induction of apoptosis, when compared with control mice. Based on these observations, we suggest that delphinidin, alone or as an adjuvant to current therapies, could be used for the management of NSCLC, especially those that overexpress EGFR and VEGFR2.

Gallic acid based steroidal phenstatin analogues for selective targeting of breast cancer cells through inhibiting tubulin polymerization.

Phenstatin analogues were synthesized on steroidal framework, for selective targeting of breast cancer cells. These analogues were evaluated for anticancer efficacy against breast cancer cell lines. Analogues 12 and 19 exhibited significant anticancer activity against MCF-7, hormone dependent breast cancer cell line. While analogues 10-14 exhibited significant anticancer activity against MDA-MB-231, hormone independent breast cancer cell line. Compound 10 showed significant oestrogen antagonistic activities with low agonistic activity in in vivo rat model. These analogues also retain tubulin polymerization inhibition activity. The most active analogue 10 was found to be non-toxic in Swiss albino mice up to 300 mg/kg dose. Gallic acid based phenstatin analogues may further be optimized as selective anti-breast cancer agents.