Chemistry (Weinheim an der Bergstrasse, Germany), Jan 14, 2015
A highly efficient synthesis of phenanthridine/benzoxazine-fused quinazolinones by ligand-free pa... more A highly efficient synthesis of phenanthridine/benzoxazine-fused quinazolinones by ligand-free palladium-catalyzed intramolecular C-H bond activation under mild conditions has been developed. The C-C coupling provides the corresponding N-fused polycyclic heterocycles in good to excellent yields and with wide functional group tolerance.
DNA ligases are critical components for DNA metabolism in all organisms. NAD(+)-dependent DNA lig... more DNA ligases are critical components for DNA metabolism in all organisms. NAD(+)-dependent DNA ligases (LigA) found exclusively in bacteria and certain entomopoxviruses are drawing increasing attention as therapeutic targets as they differ in their cofactor requirement from ATP-dependent eukaryotic homologs. Due to the similarities in the cofactor binding sites of the two classes of DNA ligases, it is necessary to find determinants that can distinguish between them for the exploitation of LigA as an anti-bacterial target. In the present endeavour, we have synthesized and evaluated a series of tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives for their ability to distinguish between bacterial and human DNA ligases. The in vivo inhibition assays that employed LigA deficient E. coli GR501 and S. typhimurium LT2 bacterial strains, rescued by ATP-dependent T4 DNA ligase or Mycobacterium tuberculosis NAD(+)-dependent DNA ligase (Mtb LigA), respectively, showed that the compounds can specifically inhibit bacterial LigA. The in vitro enzyme inhibition assays using purified MtbLigA, human DNA ligase I & T4 DNA ligase showed specific inhibition of MtbLigA at low micromolar range. Our results demonstrate that tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives can distinguish between bacterial and human DNA ligases by ∼5-folds. In silico docking and enzyme inhibition assays identified that the compounds bind to the cofactor binding site and compete with the cofactor. Ethidium bromide displacement and gel-shift assays showed that the inhibitors do not exhibit any unwanted general interactions with the substrate DNA. These results set the stage for the detailed exploration of this compound class for development as antibacterials.
Facile Synthesis of 2-Arylbenzo[b]furans Through Unusual Acid Catalyzed 1,2-Elimination. ... For ... more Facile Synthesis of 2-Arylbenzo[b]furans Through Unusual Acid Catalyzed 1,2-Elimination. ... For Abstract see ChemInform Abstract in Full Text. ... Mechanistical aspects of the transformation of (III) to (IV) are discussed. The structure of compound (III) is determined by X-ray analysis.
ABSTRACT A metal-free one-pot approach to the diversity oriented synthesis of N-heterocycles, 1,2... more ABSTRACT A metal-free one-pot approach to the diversity oriented synthesis of N-heterocycles, 1,2,4- oxadiazoles and 2,6 disubstituted pyrimidin-4-ones is described via carboxamidation of amidines with aryl carboxylic acids and aryl propargylic acids. The reactions occur at room temperature forming N-acylamidines which undergo tandem nucleophilic addition / deamination / intramolecular cyclisation to give the corresponding heterocyclic compounds in good to excellent yields. This one pot approach has led to the successful synthesis of drug lead molecule, ataluren, (3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl) benzoic acid in two steps.
The present study was undertaken to explore the mechanism of anti-proliferative action of benzopy... more The present study was undertaken to explore the mechanism of anti-proliferative action of benzopyran compound D1 (2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzopyran) and its hydroxy-(D2) and methoxy-(D3) derivatives in Ishikawa and human primary endometrial adenocarcinoma cells.
The aim of the present study was to investigate the effect of non-steroidal, pure antiestrogenic ... more The aim of the present study was to investigate the effect of non-steroidal, pure antiestrogenic benzopyran derivative i.e., 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran (K-1) on the growth of human endometrial cancer cells in vivo and in vitro and to elucidate its mechanism of action. Cell proliferation was assayed by measuring the incorporation of 5'-bromo-2'-deoxyuridine in Ishikawa and primary endometrial cancer cells. The expression of proliferation and apoptotic markers was analyzed by immunoblotting. The effect of K-1 on GPR30-regulated proteins was analyzed by ELISA and by immunoblotting. Nude mice bearing subcutaneous implanted-Ishikawa tumors, were treated for 14days with K-1 (200μg/kg body weight/day/orally). The proliferation markers, GPR30-regulated proteins and apoptotic markers were analyzed by immunoblotting in tumor xenograft. The apoptotic effect of compound K-1 was determined by TUNEL assay. Compound K-1 inhibited proliferation of endometrial adenocarcinoma cells and decreased the expression of proliferation markers. It caused apoptosis by increasing the expression of apoptotic markers (NOXA, PUMAα) and reducing the expression of p-CREB and BclxL. Compound interfered with GPR30-regulated-EGFR activation, decreased p-ERK, p-c-jun, c-fos, cyclinD1 and c-myc expression. Treatment of tumor-bearing mice with K-1 resulted in a significant decrease in tumor volume and weight. Decreased expression of p-ERK and its downstream molecules and increased expression of apoptotic markers were observed in tumor in K-1 treated animals. Findings suggest the potent inhibitory effect of compound K-1 on endometrial cancer cellular growth (in-vitro) and on tumor size (in-vivo) which is mediated at least, in part, by interference with GPR30-signaling.
1,2-Bis(4-substituted phenyl)-2-methyl ethanone (2,4-dinitrophenyl)hydrazones and 1-naphthyl-1-(4... more 1,2-Bis(4-substituted phenyl)-2-methyl ethanone (2,4-dinitrophenyl)hydrazones and 1-naphthyl-1-(4-substituted phenyl)-methanone (2,4-dinitrophenyl)hydrazones have been synthesized and evaluated for their anti-implantation, uterotrophic, antiuterotrophic, anticancer and antimicrobial activities. Diphenolic hydrazone (compound 6) showed maximum uterotrophic inhibition of 70%, whereas compound 20 exhibited cytotoxicity in the range of 50-70% against MCF-7 and ZR-75-1 human malignant breast cell lines.
... SS Dixit and SS Parmar, J. Pharm. Sci. 62,613 (1973). 6 AK Sen Gupta and HK Misra, Indian J. ... more ... SS Dixit and SS Parmar, J. Pharm. Sci. 62,613 (1973). 6 AK Sen Gupta and HK Misra, Indian J. Chem. 173, 185 (1979). 7 AK Sen Gupta and HK Misra, Indian J. Chem. 183, 381 (1979). 8 AK Sen Gupta and HK Misra, J. Pharm. Sci., 69, 1313 (1982). 9 PN Bhargava and MR ...
Chemistry (Weinheim an der Bergstrasse, Germany), Jan 14, 2015
A highly efficient synthesis of phenanthridine/benzoxazine-fused quinazolinones by ligand-free pa... more A highly efficient synthesis of phenanthridine/benzoxazine-fused quinazolinones by ligand-free palladium-catalyzed intramolecular C-H bond activation under mild conditions has been developed. The C-C coupling provides the corresponding N-fused polycyclic heterocycles in good to excellent yields and with wide functional group tolerance.
DNA ligases are critical components for DNA metabolism in all organisms. NAD(+)-dependent DNA lig... more DNA ligases are critical components for DNA metabolism in all organisms. NAD(+)-dependent DNA ligases (LigA) found exclusively in bacteria and certain entomopoxviruses are drawing increasing attention as therapeutic targets as they differ in their cofactor requirement from ATP-dependent eukaryotic homologs. Due to the similarities in the cofactor binding sites of the two classes of DNA ligases, it is necessary to find determinants that can distinguish between them for the exploitation of LigA as an anti-bacterial target. In the present endeavour, we have synthesized and evaluated a series of tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives for their ability to distinguish between bacterial and human DNA ligases. The in vivo inhibition assays that employed LigA deficient E. coli GR501 and S. typhimurium LT2 bacterial strains, rescued by ATP-dependent T4 DNA ligase or Mycobacterium tuberculosis NAD(+)-dependent DNA ligase (Mtb LigA), respectively, showed that the compounds can specifically inhibit bacterial LigA. The in vitro enzyme inhibition assays using purified MtbLigA, human DNA ligase I & T4 DNA ligase showed specific inhibition of MtbLigA at low micromolar range. Our results demonstrate that tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives can distinguish between bacterial and human DNA ligases by ∼5-folds. In silico docking and enzyme inhibition assays identified that the compounds bind to the cofactor binding site and compete with the cofactor. Ethidium bromide displacement and gel-shift assays showed that the inhibitors do not exhibit any unwanted general interactions with the substrate DNA. These results set the stage for the detailed exploration of this compound class for development as antibacterials.
Facile Synthesis of 2-Arylbenzo[b]furans Through Unusual Acid Catalyzed 1,2-Elimination. ... For ... more Facile Synthesis of 2-Arylbenzo[b]furans Through Unusual Acid Catalyzed 1,2-Elimination. ... For Abstract see ChemInform Abstract in Full Text. ... Mechanistical aspects of the transformation of (III) to (IV) are discussed. The structure of compound (III) is determined by X-ray analysis.
ABSTRACT A metal-free one-pot approach to the diversity oriented synthesis of N-heterocycles, 1,2... more ABSTRACT A metal-free one-pot approach to the diversity oriented synthesis of N-heterocycles, 1,2,4- oxadiazoles and 2,6 disubstituted pyrimidin-4-ones is described via carboxamidation of amidines with aryl carboxylic acids and aryl propargylic acids. The reactions occur at room temperature forming N-acylamidines which undergo tandem nucleophilic addition / deamination / intramolecular cyclisation to give the corresponding heterocyclic compounds in good to excellent yields. This one pot approach has led to the successful synthesis of drug lead molecule, ataluren, (3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl) benzoic acid in two steps.
The present study was undertaken to explore the mechanism of anti-proliferative action of benzopy... more The present study was undertaken to explore the mechanism of anti-proliferative action of benzopyran compound D1 (2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzopyran) and its hydroxy-(D2) and methoxy-(D3) derivatives in Ishikawa and human primary endometrial adenocarcinoma cells.
The aim of the present study was to investigate the effect of non-steroidal, pure antiestrogenic ... more The aim of the present study was to investigate the effect of non-steroidal, pure antiestrogenic benzopyran derivative i.e., 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran (K-1) on the growth of human endometrial cancer cells in vivo and in vitro and to elucidate its mechanism of action. Cell proliferation was assayed by measuring the incorporation of 5'-bromo-2'-deoxyuridine in Ishikawa and primary endometrial cancer cells. The expression of proliferation and apoptotic markers was analyzed by immunoblotting. The effect of K-1 on GPR30-regulated proteins was analyzed by ELISA and by immunoblotting. Nude mice bearing subcutaneous implanted-Ishikawa tumors, were treated for 14days with K-1 (200μg/kg body weight/day/orally). The proliferation markers, GPR30-regulated proteins and apoptotic markers were analyzed by immunoblotting in tumor xenograft. The apoptotic effect of compound K-1 was determined by TUNEL assay. Compound K-1 inhibited proliferation of endometrial adenocarcinoma cells and decreased the expression of proliferation markers. It caused apoptosis by increasing the expression of apoptotic markers (NOXA, PUMAα) and reducing the expression of p-CREB and BclxL. Compound interfered with GPR30-regulated-EGFR activation, decreased p-ERK, p-c-jun, c-fos, cyclinD1 and c-myc expression. Treatment of tumor-bearing mice with K-1 resulted in a significant decrease in tumor volume and weight. Decreased expression of p-ERK and its downstream molecules and increased expression of apoptotic markers were observed in tumor in K-1 treated animals. Findings suggest the potent inhibitory effect of compound K-1 on endometrial cancer cellular growth (in-vitro) and on tumor size (in-vivo) which is mediated at least, in part, by interference with GPR30-signaling.
1,2-Bis(4-substituted phenyl)-2-methyl ethanone (2,4-dinitrophenyl)hydrazones and 1-naphthyl-1-(4... more 1,2-Bis(4-substituted phenyl)-2-methyl ethanone (2,4-dinitrophenyl)hydrazones and 1-naphthyl-1-(4-substituted phenyl)-methanone (2,4-dinitrophenyl)hydrazones have been synthesized and evaluated for their anti-implantation, uterotrophic, antiuterotrophic, anticancer and antimicrobial activities. Diphenolic hydrazone (compound 6) showed maximum uterotrophic inhibition of 70%, whereas compound 20 exhibited cytotoxicity in the range of 50-70% against MCF-7 and ZR-75-1 human malignant breast cell lines.
... SS Dixit and SS Parmar, J. Pharm. Sci. 62,613 (1973). 6 AK Sen Gupta and HK Misra, Indian J. ... more ... SS Dixit and SS Parmar, J. Pharm. Sci. 62,613 (1973). 6 AK Sen Gupta and HK Misra, Indian J. Chem. 173, 185 (1979). 7 AK Sen Gupta and HK Misra, Indian J. Chem. 183, 381 (1979). 8 AK Sen Gupta and HK Misra, J. Pharm. Sci., 69, 1313 (1982). 9 PN Bhargava and MR ...
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