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Shiradkar M.,Lupin Research Park | Pawankumar G.,Nethaji Institute of Pharmaceutical science
International Journal of Pharma and Bio Sciences | Year: 2011

This project was designed with the objective of investigating glucose lowering potential, anti-mutagenic activity and anti-fertility activity of Cassia auriculata bark extract in the diabetic animals. The albino rats were treated with methanolic extract. The extracts were found to posses promising anti-diabetic, antimutagenic and anti-fertility activities.


Shiradkarb M.R.,Lupin Research Park | Botharac K.G.,Sinhgad Institute of Pharmacy
Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry | Year: 2011

The reaction of ethyl 2-amino-4-methylthiazole-5-carboxylate 1 with acetic anhydride followed by reaction with hydrazine hydrate yields the ethyl 2-acetamido-4-methylthiazole-5- carboxylate 2 and N-[5-(hydrazinecarbonyl)-4- methylthiazol-2- yl]acetamide 3, respectively. The compound 3 on further reaction with alcoholic potassium hydroxide-carbon disulphide followed by cyclization with hydrazine hydrate gives N-[5-(4-amino-5- mercapto-4H-1,2,4- triazol-3-yl)-4-methylthiazol-2-yl]acetamide 5. The compound 5 is then condensed with different aromatic aldehydes to offer Schiff bases 6a-h. The Schiff bases on cyclization with chloroacetyl chloride in presence of triethylamine as catalyst furnish the azetidin-2-one 7a-h. The compounds are synthesized in good yield and the chemical structures of the compounds are elucidated from their IR, 1H NMR, and elemental analysis. All the synthesized compounds have been screened for their antimicrobial activity.


Shiradkar M.R.,Lupin Research Park | Hima Bindu V.,Jawaharlal Nehru Technological University Anantapur
International Journal of Pharma and Bio Sciences | Year: 2011

Piperine, an amide alkaloid of black pepper, was investigated for transdermal enhancer activity using human cadaver skin in vitro with aceclofenac as the model drug. Furthermore, FT-IR studies were conducted to understand to possible enhancement mechanism. Piperine, at all three concentrations tested, significantly increased flux of the drug compared to control (p<0.05). Similarly permeability coefficient (Kp), cumulative amount release (Q24) and enhancement ratio (ER) shown significant increase over control sample whereas skin content of aceclofenac and lag-time of enhancer treated epidermal membrane shown proportionate reduction over control. FT-IR studies reveal that piperine reduces peak area by 19.17 % and 16.87 % for symmetric and asymmetric stretching peaks. In addition, piperine significantly reduces percentage of secondary structures of keratin at amide I band. These results indicate that piperine enhances transdermal permeation of aceclofenac by biphasic mechanism involving partial extraction of stratum corneum (SC) lipid and interaction with SC keratin.


Shiradkar M.R.,Lupin Research Park | Hima Bindu V.,Jawaharlal Nehru Technological University Anantapur
Research Journal of Pharmaceutical, Biological and Chemical Sciences | Year: 2011

Saponins rich fraction of Caralluma adscendens, Gymnema sylvestre & their combination (C+G), was investigated for transdermal enhancer activity by using human cadaver skin in vitro with aceclofenac as the model drug. Moreover, FT-IR studies were conducted to understand to possible enhancement mechanism. Results shows significantly increased flux of the drug compared to control (p<0.05). Similarly permeability coefficient (Kp), cumulative amount release (Q 24) and enhancement ratio (ER) shown significant increase over control sample. FT-IR studies reveal that Gymnema & Caralluma combination (C+G) reduces peak area by 89.00 % and 75.76 % for symmetric and asymmetric stretching peaks. In addition significantly reduces percentage of secondary structures of keratin at amide I band. These results indicate that Caralluma & Gymnema enhances transdermal permeation of aceclofenac by biphasic mechanism involving partial extraction of stratum corneum (SC) lipid and interaction with SC keratin.


Konduri S.D.,Roswell Park Cancer Institute | Konduri S.D.,Cancer Research Institute | Medisetty R.,Roswell Park Cancer Institute | Liu W.,Roswell Park Cancer Institute | And 14 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Estrogen receptor α (ERα) plays an important role in the onset and progression of breast cancer, whereas p53 functions as a major tumor suppressor. We previously reported that ERα binds to p53, resulting in inhibition of transcriptional regulation by p53. Here, we report on the molecular mechanisms by which ERα suppresses p53's transactivation function. Sequential ChIP assays demonstrated that ERα represses p53-mediated transcriptional activation in human breast cancer cells by recruiting nuclear receptor core-pressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). RNAi-mediated down-regulation of NCoR resulted in increased endogenous expression of the cyclin-dependent kinase (CDK)-inhibitor p21Waf1/Cip1 (CDKN1A) gene, a prototypic transcriptional target of p53. While 17β-estradiol (E2) enhanced ERα binding to p53 and inhibited p21 transcription, antiestrogens decreased ERα recruitment and induced transcription. The effects of estrogen and antiestrogens on p21 transcription were diametrically opposite to their known effects on the conventional ERE-containing ERα target gene, pS2/TFF1. These results suggest that ERα uses dual strategies to promote abnormal cellular proliferation: enhancing the transcription of ERE-containing proproliferative genes and repressing the transcription of p53-responsive antiproliferative genes. Importantly, ERα binds to p53 and inhibits transcriptional activation by p53 in stem/progenitor cell-containing murine mammospheres, suggesting a potential role for the ER-p53 interaction in mammary tissue homeostasis and cancer formation. Furthermore, retrospective studies analyzing response to tamoxifen therapy in a subset of patients with ER-positive breast cancer expressing either wild-type or mutant p53 suggest that the presence of wild-type p53 is an important determinant of positive therapeutic response.


Aneja R.,Georgia State University | Asress S.,Emory University | Dhiman N.,University of Delhi | Awasthi A.,Lupin Research Park | And 5 more authors.
International Journal of Cancer | Year: 2010

(S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4, 5-g]isoquino-lin-5-yl)-6,7-dimethoxyisobenzofuran-1(3H)-one (EM011) is a tubulin-binding agent with significant anticancer activity. Here we show that EM011 modulates microtubule dynamics at concentrations that do not alter the total polymer mass of tubulin. In particular, EM011 decreases the transition frequencies between growth and shortening phases and increases the duration microtubules spend in an idle 'pause' state. Using B16LS9 murine melanoma cells, we show that EM011 briefly arrests cell-cycle progression at the G2/M phase by formation of multiple aster spindles. An aberrant mitotic exit without cytokinesis then occurs, leading to the accumulation of abnormal multinucleated cells prior to apoptosis. Our pharmacokinetic studies conformed to a linear doseresponse relationship upto 150 mg/kg. However, non-linearity was observed at 300 mg/kg. In a syngeneic murine model of subcutaneous melanoma, better antitumor responses were seen at 150 mg/kg compared to 300 mg/kg of EM011. Unlike currently available chemotherapeutics, EM011 is non-toxic to normal tissues and most importantly, does not cause any immunosuppression and neurotoxicity. Our data thus warrant a clinical evaluation of EM011 for melanoma therapy. © 2009 UICC.


Dinda M.,Indian Central Salt and Marine Chemicals Research Institute | Agrawal M.K.,Indian Central Salt and Marine Chemicals Research Institute | Agrawal M.K.,Lupin Research Park | Gandhi M.R.,Indian Central Salt and Marine Chemicals Research Institute | And 4 more authors.
RSC Advances | Year: 2012

2:1:3 NaBr-NaBrO 3-NaCl (obtainable as a low cost and eco-friendly reagent from an alkaline bromine intermediate) has been utilized previously in a number of bromination reactions. One such reaction is the conversion of p-nitrotoluene (PNT) to p-nitrobenzyl bromide (PNBBr) used widely for functional group protection. In the present work, selective cold (0-5 °C) crystallization of PNBBr from the reaction mixture containing ca. 2.5 M PNBBr along with 2.5-5.0 M PNT in ethylene dichloride (EDC) was found to be a winning move which led to gains in two fronts. It allowed the bromination reaction to be carried out cleanly and also enabled direct recycling of the mother liquor in the subsequent batch. Para NO 2-Ph-CHBr 2 impurity, which built up gradually in the reaction mixture over 8 batches, was converted into PNBBr/PNT through treatment of the mother liquor with NaBH 4, thereby helping to recycle the liquor perpetually and eliminate organic waste. EDC was the sole solvent in the entire process and its losses were minimal. The combined yield of isolated and recoverable PNBBr was 98.30% with respect to PNT consumed. The reagent utilization efficiency was 98.26%. This journal is © 2012 The Royal Society of Chemistry.


Kalle A.M.,University of Hyderabad | Mallika A.,University of Hyderabad | Badiger J.,Hkes Smt Vg College For Women | Alinakhi,University of Hyderabad | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2010

Overexpression of SIRT1, a NAD+-dependent class III histone deacetylases (HDACs), is implicated in many cancers and therefore could become a promising antitumor target. Here we demonstrate a small molecule SIRT1 inhibitor, ILS-JGB-1741(JGB1741) with potent inhibitory effects on the proliferation of human metastatic breast cancer cells, MDA-MB 231. The molecule has been designed using medicinal chemistry approach based on known SIRT1 inhibitor, sirtinol. The molecule showed a significant inhibition of SIRT1 activity compared to sirtinol. Studies on the antitumor effects of JGB on three different cancer cell lines, K562, HepG2 and MDA-MB 231 showed an IC50 of 1, 10 and 0.5μM, respectively. Further studies on MDA-MB 231 cells showed a dose-dependent increase in K9 and K382 acetylation of H3 and p53, respectively. Results also demonstrated that JGB1741-induced apoptosis is associated with increase in cytochrome c release, modulation in Bax/Bcl2 ratio and cleavage of PARP. Flowcytometric analysis showed increased percentage of apoptotic cells, decrease in mitochondrial membrane potential and increase in multicaspase activation. In conclusion, the present study indicates the potent apoptotic effects of JGB1741 in MDA-MB 231 cells. © 2010 Elsevier Inc.


Kalle A.M.,University of Hyderabad | Sachchidanand S.,Lupin Research Park | Pallu R.,University of Hyderabad
Leukemia Research | Year: 2010

Our previous studies have shown that overexpression of MDR1 and cyclooygenase-2 (COX-2) resulted in resistance development to imatinib in chronic myelogenous leukemia (CML) K562 (IR-K562) cells. In the present study, the regulatory mechanism of MDR1 induction by COX-2 was investigated. A gradual overexpression of MDR1 and COX-2 during the process of development was observed. Furthermore, down regulation of MDR1 upon COX-2 knockdown by siRNA showed a decrease in the PKC levels and activation of PKC by addition of PGE2 to K562 cells, suggesting a role for PKC in the COX-2 mediated induction of MDR1. The present study demonstrates COX-2 induction by HDACs and MDR1 induction by COX-2 via PGE2-cAMP-PKC-mediated pathway. © 2010 Elsevier Ltd.


Traumatic brain injury (TBI) is one of the leading cause of psychiatric conditions in patients, amongst which, depression and anxiety are more frequent. Despite the preclinical antidepressant-like effects, clinical development of Phospodiesterase-4 (PDE4) enzyme inhibitors has been hampered due to serious side effect profiles, such as nausea and vomiting. Etazolate (ETZ) is a new generation PDE4 inhibitor with encouraging safety and tolerance profiles. In our previous studies we have addressed that ETZ produces antidepressant-like effects in animal models of depression, however, the underlying mechanism(s) following TBI have not been completely explored. Impact accelerated TBI by weight drop method causes depression-like behavioral deficits in modified open field exploration, hyper-emotionality and sucrose consumption paradigms. TBI not only causes immediate mechanical damage to the brain, but also induces biochemical changes that lead to delayed neural cell loss leading to a secondary injury. The present study examines the antidepressant effects of ETZ on the TBI-induced depression-like behavior deficits and attempts to explore the underlying mechanism. In order to understand the underlying pathology of TBI and mechanism(s) of ETZ in TBI molecular markers namely, brain cAMP, cAMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were estimated. Additionally, the level of oxidative (lipid peroxidation) & nitrosative (nitrite) stress markers, along with antioxidant enzymes markers, such as, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured. Furthermore, the involvement of hypothalamic-pituitary adrenal (HPA) axis activity in underlying mechanism was also investigated by measuring serum corticosterone (CORT) level. The results revealed that TBI significantly altered cAMP, pCREB and BDNF levels. Moreover, a significant increase in oxidative-nitrosative stress markers levels, while, significant decreases in antioxidant enzymes markers level were observed. However, no significant change was observed in serum CORT level. Chronic ETZ (0.5 and 1mg/kg) treatment significantly attenuated TBI-induced behavioral deficits and restored the TBI induced derangements in molecular and biochemical markers. This study indicates that ETZ modulates cAMP signaling and oxidative/antioxidant markers in the TBI model suggesting its prospect as a potential candidate for the pharmacotherapy of depression.

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