Browsing by Author "Joshi, G."

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Anticancer activity of dihydropyrazolo[1,5-c]quinazolines against rat C6 glioma cells via inhibition of topoisomerase II
(Wiley-VCH Verlag, 2018) Kaur, G.; Cholia, R.P.; Joshi, G.; Amrutkar, S.M.; Kalra, S.; Mantha, Anil K.; Banerjee, U.C.; Kumar, Raj
The design and synthesis of dihydropyrazolo[1,5-c]quinazolines (1a?h) as human topoisomerase II (TopoII) catalytic inhibitors are reported. The compounds were investigated for their antiproliferative activity against the C6 rat glial cell line. Two compounds, 1b and 1h, were found to be potent cytotoxic agents against glioma cells and exerted selective TopoII inhibitory activity. Furthermore, the compounds induced alterations in reactive oxygen species levels as measured by DCFDA assay and were found to induce cell cycle arrest at the G1 phase at lower concentrations and profound apoptosis at higher concentrations. The interaction of selected investigational molecules with TopoII was further corroborated by molecular modeling. ? 2018 Deutsche Pharmazeutische Gesellschaft
Cyclocondensation reactions of an electron deactivated 2-aminophenyl tethered imidazole with mono/1, 2-biselectrophiles: synthesis and DFT studies on the rationalisation of imidazo [1, 2-a] quinoxaline versus benzo [f] imidazo [1, 5-a][1, 3, 5] triazepine selectivity switches.
(Royal Society of Chemistry, 2018) Joshi, G.; Chauhan, M; Kumar, R; Thakur, A; Sharma, S; Singh, R.; Wani, A.A.; Sharon, A.; Bharatam, P.V; Kumar, R.
Microwave-promoted ring-closure reactions of 5-amino-1-(2-aminophenyl)-1H-imidazole-4-carbonitrile (7) with various mono/1,2-biselectrophiles are presented. The reaction of 7 with aldehydes, ketones and isocyanates produced the corresponding Pictet–Spengler (PS) products i.e. the imidazo[1,2-a]quinoxaline ring system via 6-endo-trig cyclisation. On the other hand, the reaction of 7 with CH(OEt)3, and CDI resulted in the formation of benzo[f]imidazo[1,5-a][1,3,5]triazepine scaffolds via a 7-exo-trig cyclisation process. The mechanistic aspects of these ring cyclisation processes have been analysed and studied to rationalise 6- versus 7-membered ring formation using density functional theory (DFT). DFT calculations revealed the involvement of N-Heterocyclic Carbene (NHC) in the PS reaction mechanism.
Interaction between topoisomerases and histone deacetylases: Role in cancer progression and therapeutic interventions
(Nova Science Publishers, Inc., 2017) Joshi, G.; Thakur, A.; Kaur, G.; Kalra, S.; Singh, S.; Kumar, R.
DNA topoisomerases are termed as the magicians of the DNA world, as they are involved in overcoming all the topological DNA problems. Histone Deacetylases are the collection of enzymes that assist in the regulation of DNA control. The overexpression of topoisomerases and histone deacetylases are found in various diseases including cancer. Till date, many therapies have been discovered to target topoisomerases and histone deacetylases individually. However, most of these treatments are associated with the toxicities and drug resistance. The drug resistance apart from known mechanism(s) could occur due to crosstalk(s) of topoisomerases with various proteins associated directly or indirectly with the cancer prognosis. Histone deacetylases that render topoisomerase inhibitors resistant also insensitize them toward binding to the receptor. The chapter overlays the discussion on the underlying mechanism(s) involved in topoisomerase and histone deacetylases interactions. The chapter also congregates the information suggested for the essential pharmacophore development for such hybrid drug discovery. The attempt has also been made to give a preliminary virtual background on the fundamental interaction of these two proteins along with the primary amino acids involved in such interaction. ? 2017 Nova Science Publishers, Inc.
A review on pharmacophoric designs of antiproliferative agents
(Birkhauser Boston, 2015) Rana, A.; Alex, J.M.; Chauhan, M.; Joshi, G.; Kumar, Raj
Past few decades have witnessed the dawn of new diseases in which cancer is a major problem and the race ensued to eradicate cancer by charting out various effective therapeutic regimens. Circumventing resistance issues and combating the toxicity and selectivity problems are matter-of-concern in cancer treatment. Persistent failure to ensure complete remission and eradication of cancer instigated the researchers to exploit the strategies of combining pharmacophores as targeted therapeutic agents. Momentous improvement in the pharmacokinetic as well as pharmacodynamic profile resulting in the enhancement of bioavailability was seen with the introduction of these pharmacophores. The scope of molecular hybridization can be clearly exemplified through the US-FDA approved estramustine and others such as CUDC-101, CBLC-137, PLX3397, E-3810, and CUDC-907 that are currently in different phases of clinical trials. This review seeks to highlight and discuss anti-proliferative activity of some important hybrid, dual, and multi-targeted pharmacophores reported to date along with their designs, structure activity relationships, scope, and limitations. Further, an emphasis has been made to summarize US-FDA approved as well as drugs currently undergoing clinical trials of anticancer drug development. ? 2014 Springer Science+Business Media New York.