Khalid Yousuf - Academia.edu (original) (raw)

Papers by Khalid Yousuf

(A) HeLa cells (0.5×105 cells/well) were grown to confluence in s... more (A) HeLa cells (0.5×105 cells/well) were grown to confluence in six well tissue culture plate and scratched with sterile tip; 3-azidoWA was added to cultures as indicated. Scratched areas were photographed (magnification 100x) at zero hour and then subsequently again 24 h later to assess the degree of wound healing. (B) The scratched areas were quantified in three random fields in each treatment, and data were calculated from three independent experiments. (C) HeLa (1×103) cells/well were cultured and treated with various concentration of compound 3-azidoWA for 5 days at 37°C and then stained with crystal violet (for details see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044039#s2" target="_blank">materials and methods</a>), numbers of stained colonies were counted, photographed (100x) and (D) data were calculated from three independent experiments. Columns mean; bars SD of three independent experiments. P<0.05, **P<0.01 compared with untreated control. (E) Cell migration was determined via the modified Boyden chamber assay as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044039#s2" target="_blank">Materials and Methods</a>. HeLa cells (2×105) were seeded in top chamber in the presence or absence of 0.25, 0.50, and 0.75 µM of 3-azidoWA. Cells were allowed to migrate for 24 h, at which point migratory cells on the bottom half of the insert membrane were stained with 0.1% crystal violet and counted under 200x magnification. (F) Invasive cells were counted using image software as the number of migrated cells per high-power field (HPF). Five fields were counted in triplicate (n = 3) from each insert. Cell images were obtained using microscope Nikon Eclipse E200 inbuilt with camera. Columns mean; bars SD of three independent experiments. P<0.05, **P<0.01 compared with untreated control.</p

MedChemComm, 2017

The present study utilised whole cell based phenotypic screening of thousands of diverse small mo... more The present study utilised whole cell based phenotypic screening of thousands of diverse small molecules against H37Rv () and identified the cyclohexane-1,3-dione-based structures and as hits. The selected hit molecules were used for further synthesis and a library of 37 compounds under four families was synthesized for lead generation. Evaluation of the library against lead to the identification of three lead antituberculosis agents (, and ). The most potential compound, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione () showed an MIC of 2.5 μg mL, which falls in the range of MICs values found for the known antituberculosis drugs ethambutol, streptomycin and levofloxacin. Additionally, this compound proved to be non-toxic (<20% inhibition at 50 μM concentration) against four human cell lines. Like first line antituberculosis drugs (isoniazid, rifampicin and pyrazinamide) this compound lacks activity against general Gram positive and Gram negative bacteria...

Microbial pathogenesis, Jan 24, 2017

Tuberculosis continues to be the most dangerous infectious disease globally and need for developm... more Tuberculosis continues to be the most dangerous infectious disease globally and need for development of new therapies is of utmost importance. In this study we describe the rationale design for synthesis using molecular hybridization and subsequent in-vitro antimycobacterial activity of various indolo-pyridone hybrid molecules against Mycobacterium tuberculosis H37Rv. A total of 16 indolo-pyridone hybrid molecules were synthesized with 85-90% yields and characterized by various spectroscopic techniques. Four compounds were ineffective with MIC >256 μg/ml (highest concentration tested), six exhibited poor activity with MIC > 100 μg/ml, four showed moderate activity with MIC > 50 μg/ml and two had notable anti-TB activity with MIC values 32 μg/ml. Interestingly the last two compounds were observed equally effective against drug susceptible and various drug resistant strains including multidrug-resistant (MDR) strains, thereby clearly demonstrating their potential against MDR-...

Carbohydrate research, Jan 13, 2017

One-pot carbon-Ferrier rearrangement of glycals with unactivated aryl methyl ketones has been dev... more One-pot carbon-Ferrier rearrangement of glycals with unactivated aryl methyl ketones has been developed under mild Silyl triflate catalysis. Keto methyl group of various aryl methyl ketones without being converted into silyl enol ether could directly attack anomeric position of glycals to form keto functionalized C-glycosides in moderate to good yields with high α-selectivity. The versatility of this method has been extended to the synthesis of a small library of chromanone 3-C-glycosides.

Letters in Drug Design & Discovery, 2012

Organic & Biomolecular Chemistry, 2013

Journal of Medicinal Chemistry, 2013

A set of nine trans disubstituted dihydropyran based medium ring macrolides has been synthesised ... more A set of nine trans disubstituted dihydropyran based medium ring macrolides has been synthesised using D-glucal as chiral pool and evaluated against a panel of three human cancer cell lines and a normal cell line. The synthetic route to the targeted molecule is simple, concise and high yielding compare to other reported methods. Bio evaluation studies have resulted in the identification of potent cytotoxic molecule (10) exhibiting dose dependent growth inhibition against HL-60 cell line with IC 50 value of 1.10± 0.75µM which is lower than the naturally occurring molecules of this class and comparable activity to the synthetic drug fludarubin. The compound 10 inhibits PI3K/AKT signaling pathway by selectively targeting p110α subunit of PI3Kα. This leads to mitochondrial stress that causes translocation of cytochrome c from

(A) Synthesis of 3-azidoWA. (B) Effects of 3-azidoWA on the cell proliferation of A549 (... more (A) Synthesis of 3-azidoWA. (B) Effects of 3-azidoWA on the cell proliferation of A549 (lung cancer), PC-3, DU-145 (prostrate cancer) and HeLa (cervical cancer) cell lines were determined by MTT assay. (C) 3-azidoWA along with vehicle DMSO and positive control staurosporine treated cells were analyzed by FACS, (as indicated); graphical representation of the results show proportion of non-apoptotic cells (Q3), early apoptotic (Q4), necrotic (Q1) and late apoptotic (Q2) cells. (D) HeLa cells (5×104) were cultured in chamber slides and treated with 3-azidoWA (0.25, 0.50 and 1.0 µM) along with vehicle DMSO and positive control staurosporine (25 nM) for 24 h. After fixation, cells were stained with nuclear stain DAPI and photographed under fluorescence microscope (100x magnifications) to identify the apoptotic nuclei (white arrowheads). (E) HeLa cells were treated with increasing concentrations of 3-azidoWA as indicated, procaspase-3 and cleaved caspase-3 expressions were determined by Western blotting along with loading control β-actin.</p

Journal of Chemical Sciences, 2022

A highly chemo- and diastereoselective vic -dibromination of olefins has been developed. The proc... more A highly chemo- and diastereoselective vic -dibromination of olefins has been developed. The process employs a readily available N-Bromosuccinimide (NBS)/DMSO reagent system as a bromine source. High substrate scope, simple reaction conditions, application to natural products and glycals makes the process very attractive. Graphical abstract A highly chemo- and diastereoselective vic -dibromination of olefins has been developed. The process employs a readily available N-Bromosuccinimide (NBS)/DMSO reagent system as a bromine source. High substrate scope, simple reaction conditions, application to natural products and glycals makes the process very attractive.

Biomedicine & Pharmacotherapy, 2017

Tuberculosis is the leading infectious disease responsible for an estimated one and a half millio... more Tuberculosis is the leading infectious disease responsible for an estimated one and a half million human deaths each year around the globe. HIV-TB coinfection and rapid increase in the emergence of drug resistant forms of TB is a dangerous scenario. This underlines the urgent need for new drugs with novel mechanism of action. A plethora of literature exist that highlight the importance of enzymes involved in the biosynthesis of mycobacterial cell wall responsible for its survival, growth, permeability, virulence and resistance to antibiotics. Therefore, assembly of cell wall components is an attractive target for the development of chemotherapeutics against Mycobacterium tuberculosis. The aim of this review is to highlight novel sets of enzyme inhibitors that disrupt its cell wall biosynthetic pathway. These include the currently approved first and second line drugs, candidates in clinical trials and current structure activity guided endeavors of scientific community to identify new potent inhibitors with least cytotoxicity and better efficacy against emergence of drug resistance till date.

Scientific reports, Jan 5, 2016

The eukaryotic translation initiation factor 4E (eIF4E) is considered as a key survival protein i... more The eukaryotic translation initiation factor 4E (eIF4E) is considered as a key survival protein involved in cell cycle progression, transformation and apoptosis resistance. Herein, we demonstrate that medicinal plant derivative 3-AWA (from Withaferin A) suppressed the proliferation and metastasis of CaP cells through abrogation of eIF4E activation and expression via c-FLIP dependent mechanism. This translational attenuation prevents the de novo synthesis of major players of metastatic cascades viz. c-FLIP, c-Myc and cyclin D1. Moreover, the suppression of c-FLIP due to inhibition of translation initiation complex by 3-AWA enhanced FAS trafficking, BID and caspase 8 cleavage. Further ectopically restored c-Myc and GFP-HRas mediated activation of eIF4E was reduced by 3-AWA in transformed NIH3T3 cells. Detailed underlying mechanisms revealed that 3-AWA inhibited Ras-Mnk and PI3-AKT-mTOR, two major pathways through which eIF4E converges upon eIF4F hub. In addition to in vitro studies, w...

Molecular Carcinogenesis, 2015

Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated... more Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating b-catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. This study, for the first time, reveals 3-AWA treatment consistently sequestered nuclear b-catenin and augmented its cytoplasmic pool as evidenced by reducing b-catenin transcriptional activity in these cells. Moreover, 3-AWA treatment triggered robust induction of pro-apoptotic intracellular Par-4, attenuated Akt activity and rescued Phospho-GSK3b (by Akt) to promote b-catenin destabilization. Further, our in vitro studies demonstrate that 3-AWA treatment amplified Ecadherin expression along with sharp downregulation of c-Myc and cyclin D1 proteins. Strikingly, endogenous Par-4 knock down by siRNA underscored 3-AWA mediated inhibition of nuclear b-catenin was Par-4 dependent and suppression of Par-4 activity, either by Bcl-2 or by Ras transfection, restored the nuclear b-catenin level suggesting Par-4 mediated b-catenin regulation was not promiscuous. In vivo results further demonstrated that 3-AWA was effective inhibitor of tumor growth and immunohistochemical studies indicated that increased expression of total b-catenin and decreased expression of phospho-b-catenin and Par-4 in breast cancer tissues as compared to normal breast tissue suggesting Par-4 and b-catenin proteins are mutually regulated and inversely co-related in normal as well as cancer condition. Thus, strategic regulation of intracellular Par-4 by 3-AWA in diverse cancers could be an effective tool to control cancer cell metastasis. Conclusively, this report puts forward a novel approach of controlling deregulated b-catenin signaling by 3-AWA induced Par-4 protein.

European Journal of Organic Chemistry, 2014

The palladium-catalyzed stereoselective synthesis of 2,3-deoxy-C-aryl glycosides was investigated... more The palladium-catalyzed stereoselective synthesis of 2,3-deoxy-C-aryl glycosides was investigated. The strategy is based on the Pd-catalyzed desulfitative Heck coupling of arylsulfonyl chlorides and glycals with good leaving groups. An attempt was made to establish the reaction mechanism, which may involve PdII/Pd0 interconversion under basic conditions.

RSC Advances, 2013

ABSTRACT A fast, solvent-free solid acid mediated synthetic strategy for the synthesis of bisindo... more ABSTRACT A fast, solvent-free solid acid mediated synthetic strategy for the synthesis of bisindolylmethanes has been developed. The process is applicable to a wide range of substrates with different protecting group survival properties. Reusability of Fe/Al pillared clay for more than 5 cycles without significant loss of catalytic activity adds to the features of the reaction.

Org. Biomol. Chem., 2014

Zinc mediated alkynylation reaction was studied for the preparation of C-glycosides from unactiva... more Zinc mediated alkynylation reaction was studied for the preparation of C-glycosides from unactivated aromatic and aliphatic acetylenes. Different glycosyl donors such as glycals and anomeric acetates were tested towards in situ generated alkynyl zinc reagent using zinc dust and ethyl bromoacetate. The method provides a simple, mild and stereoselective access of alkynyl glycosides.

Organic & Biomolecular Chemistry, 2012

Azidotrimethylsilylation of carbohydrates (monosaccharides and disaccharides) has been achieved i... more Azidotrimethylsilylation of carbohydrates (monosaccharides and disaccharides) has been achieved in high yields under Mitsunobu conditions. The azidation of carbohydrates is effected at 0 °C essentially only at the primary alcoholic position in mono, di- and triols in protected/unprotected glycosides, whereas the remaining secondary hydroxyl groups got silylated. Surprisingly, no azidation of the secondary hydroxyls was observed in all the carbohydrate substrates. Applications of the methodology for the synthesis of amino sugars, triazoles and azasugars are reported.