Computer‐Aided Design, Synthesis and Validation of 2‐Phenylquinazolinone Fragments as CDK9 Inhibitors with Anti‐HIV‐1 Tat‐Mediated Transcription Activity

Sancineto, Luca; Iraci, Nunzio; Massari, Serena; Attanasio, Vanessa; Corazza, Gianmarco; Barreca, Maria Letizia; Sabatini, Stefano; Manfroni, Giuseppe; Avanzi, Nilla; Cecchetti, Violetta; Pannecouque, Christophe; Marcello, Alessandro; Tabarrini, Oriana

doi:10.1002/cmdc.201300287

Cited by 34 publications

(22 citation statements)

References 67 publications

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“…All synthesized compounds were subsequently evaluated in vitro for antiproliferative activity against three human cancer cell lines (HeLa, HepG2, and A549) and HIV‐1 inhibition activity used as a readout of cellular activity. Then, compounds 2c and 3b with good antiproliferative activity against cancer cells and excellent HIV‐1 inhibition activity were selected for further cellular mechanism studies which included testing the induction of cell apoptosis, and checking the level of cleaved PARP (the mark of apoptosis), the phosphorylation level at Ser2 of RNAPII CTD, and the expression level of CDK9 …”

Section: Methodsmentioning

confidence: 99%

Synthesis, structure–activity relationship studies and biological evaluation of novel 2,5‐disubstituted indole derivatives as anticancer agents

et al. 2016

Chem Biol Drug Des

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Three novel series of 2,5-disubstituted indole derivatives were synthesized and evaluated in vitro for their antiproliferative activity against human cancer cells and HIV-1 inhibition activity used as a readout of cellular activity. Most compounds were found to have potent anticancer activity. In particular, 2c and 3b which showed effectively to repress HIV-1 transcription had a pan antiproliferative activity in cervical cancer cells (HeLa), breast cancer cells (MCF-7), liver cancer cells (HepG2), and lung cancer cells (H460 and A549). While 3b exhibited high sensitivity to A549 cells with the IC value 0.48 ± 0.15 μm, 2c showed high selectivity toward HepG2 cells with the IC value 13.21 ± 0.30 μm. With respect to the cellular mechanism of action, HepG2 cells treated with 2c and A549 cells treated with 3b for 24 h were studied by annexin V/PI staining and Western blot analysis, and results revealed that 2c and 3b may induce cancer cells apoptosis through inhibiting the phosphorylation at Ser2 of RNAPII CTD which can be phosphorylated by cyclin-dependent kinase 9. These studies indicated that 2c and 3b may develop as potent lead compounds in the therapy of cancer. However, determining their roles in preventing HIV-1 still requires further intensive study.

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Section: Methodsmentioning

confidence: 99%

Synthesis, structure–activity relationship studies and biological evaluation of novel 2,5‐disubstituted indole derivatives as anticancer agents

et al. 2016

Chem Biol Drug Des

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“…CDK 9 is a cyclin-dependent kinase that has been linked to HIV-1 pathogenesis in numerous studies—the CDK9/cyclin T1 enzyme, especially, has been shown to play an important role in HIV-1 transcription [ 54 – 56 ]. Due to the central nature of CDK9/cyclin T1 in HIV-1 transcription, several studies have investigated CDK 9 as a potential drug target [ 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Evolutionary Distance of Amino Acid Sequence Orthologs across Macaque Subspecies: Identifying Candidate Genes for SIV Resistance in Chinese Rhesus Macaques

2015

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We use the Reciprocal Smallest Distance (RSD) algorithm to identify amino acid sequence orthologs in the Chinese and Indian rhesus macaque draft sequences and estimate the evolutionary distance between such orthologs. We then use GOanna to map gene function annotations and human gene identifiers to the rhesus macaque amino acid sequences. We conclude methodologically by cross-tabulating a list of amino acid orthologs with large divergence scores with a list of genes known to be involved in SIV or HIV pathogenesis. We find that many of the amino acid sequences with large evolutionary divergence scores, as calculated by the RSD algorithm, have been shown to be related to HIV pathogenesis in previous laboratory studies. Four of the strongest candidate genes for SIVmac resistance in Chinese rhesus macaques identified in this study are CDK9, CXCL12, TRIM21, and TRIM32. Additionally, ANKRD30A, CTSZ, GORASP2, GTF2H1, IL13RA1, MUC16, NMDAR1, Notch1, NT5M, PDCD5, RAD50, and TM9SF2 were identified as possible candidates, among others. We failed to find many laboratory experiments contrasting the effects of Indian and Chinese orthologs at these sites on SIVmac pathogenesis, but future comparative studies might hold fertile ground for research into the biological mechanisms underlying innate resistance to SIVmac in Chinese rhesus macaques.

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“…67 Metal-catalyzed multi-component synthesis of DHQ derivatives was also reported. [68][69][70][71][72][73] Generally, the use of metals or Lewis acids as catalysts did not lead to great yields (<90%), except when I 2 is used under solvent-free conditions at 115 C 69 ( Table 3).…”

Section: Conventional Reaction Conditionsmentioning

confidence: 99%

2,3-Dihydroquinazolin-4(1H)-one as a privileged scaffold in drug design

2018

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Computer‐Aided Design, Synthesis and Validation of 2‐Phenylquinazolinone Fragments as CDK9 Inhibitors with Anti‐HIV‐1 Tat‐Mediated Transcription Activity

Cited by 34 publications

References 67 publications

Synthesis, structure–activity relationship studies and biological evaluation of novel 2,5‐disubstituted indole derivatives as anticancer agents

Synthesis, structure–activity relationship studies and biological evaluation of novel 2,5‐disubstituted indole derivatives as anticancer agents

Evolutionary Distance of Amino Acid Sequence Orthologs across Macaque Subspecies: Identifying Candidate Genes for SIV Resistance in Chinese Rhesus Macaques

2,3-Dihydroquinazolin-4(1H)-one as a privileged scaffold in drug design

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