- Detailed investigation of anticancer activity of sulfamoyl benz(sulfon)amides and 1H–pyrazol–4–yl benzamides: An experimental and computational study
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Cancer is the second leading cause of mortality worldwide. Therapeutic approach to cancer is a multi-faceted one, whereby many cellular/enzymatic pathways have been discovered as important drug targets for the treatment of cancer. A major disadvantage of most of the currently available anticancer drugs is their non-selective cytotoxicity towards cancerous as well as healthy cells. Another major hurdle in cancer therapy is the development of resistance to anticancer drugs. This necessitates the discovery of new molecules with potent and selective cytotoxic activity towards only cancerous cells, with minimum or no damage to the normal/healthy cells. Herein we report detailed investigation into the anticancer activity of sulfamoyl benz(sulfon)amides (1a-1g, 2a-2k) and 1H–pyrazol–4–yl benzamides (3a-3j) against three cancer cell lines, breast cancer cells (MCF–7), bone-marrow cancer cells (K–562) and cervical cancer cells (HeLa). For comparison, screening against healthy baby hamster kidney cells (BHK-21) was carried out. All compounds exhibited selective cytotoxicity towards cancerous cells. Cell cycle analysis was carried out using flow cytometry, followed by fluorescence microscopic analysis. DNA interaction and docking studies were also carried out.
- Iqbal, Jamshed,Ejaz, Syeda Abida,Saeed, Aamer,al-Rashida, Mariya
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- Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties
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DNA-encoded chemical libraries are increasingly used to identify leads for drug discovery or chemical biology. Despite the resurging interest in covalent inhibitors, libraries are typically designed with synthon filtered out for reactive functionalities that can engage a target through covalent interactions. Herein, we report the synthesis of two libraries containing Michael acceptors to identify cysteine reactive ligands. We developed a simple procedure to discriminate between covalent and high affinity non-covalent inhibitors using DNA display of the library in a microarray format. The methodology was validated with known covalent and high affinity non-covalent kinase inhibitors. Screening of the library revealed novel covalent inhibitors for MEK2 and ERBB2.
- Zambaldo,Daguer,Saarbach,Barluenga,Winssinger
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supporting information
p. 1340 - 1351
(2016/07/21)
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- Synthesis, characterization and biological evaluation of N-(2,3-dimethyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazol-4-yl)benzamides
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We report the synthesis of a series of different substituted N-(2,3-dimethyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazol-4-yl)benzamides by making use of a non-steroidal anti-inflammatory drug known as 4-aminophenazone also called as antipyrine, a compound of great interest in drug chemistry. These compounds possess potential biological applications and were screened against human recombinant alkaline phosphatase including human tissue-nonspecific alkaline phosphatase (h-TNAP), tissue specific human intestinal alkaline phosphatase (h-IAP), human placental alkaline phosphatase (h-PLAP) and human germ cell alkaline phosphatase (h-GCAP). These compounds were also tested for their inhibitory potential against recombinant human and rat ecto-5′-nucleotidases (h-e5-NT & r-e5-NT, respectively). All benzamide derivatives inhibited APs to a lesser degree than e5-NT. The reported compounds are of considerable interest for further applications in the field of medicinal chemistry as these compounds have potential to bind nucleotide protein targets.
- Saeed, Aamer,Ejaz, Syeda Abida,Khurshid, Asma,Hassan, Sidra,Al-Rashida, Mariya,Latif, Muhammad,Lecka, Joanna,Sévigny, Jean,Iqbal, Jamshed
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p. 86428 - 86439
(2015/11/03)
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- Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2
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Resveratrol (3,5,4′-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation.
- St. John, Sarah E.,Jensen, Katherine C.,Kang, Soosung,Chen, Yafang,Calamini, Barbara,Mesecar, Andrew D.,Lipton, Mark A.
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p. 6022 - 6037
(2013/09/23)
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- Synthesis and Biological Activities of 1,1′-Bis(p-substituted-benzoyloxy-substituted-phenyl)cyclohexane
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1,1′-Bis(p-substituted-benzoyloxy-substituted-phenyl)cyclohexane have been synthesized. Most of the compounds exhibit promising antibacterial activity and moderate anifungal activity.
- Rajkotia,Parsania
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p. 524 - 525
(2007/10/03)
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