A dihydro-pyrido-indole potently inhibits HSV-1 infection by interfering the viral immediate early transcriptional events

Bag, Paromita; Ojha, Durbadal; Mukherjee, Hemanta; Halder, Umesh Chandra; Mondal, Samiran; Biswas, Aruna; Sharon, Ashoke; Kaer, Luc Van; Chakrabarty, Sekhar; Das, Gobardhan; Mitra, Debashis; Chattopadhyay, Debprasad

doi:10.1016/j.antiviral.2014.02.007

Cited by 56 publications

(48 citation statements)

References 31 publications

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“…There is increasing evidence to support the hypothesis that analogues such as 6d could inhibit the function of LSD1 indirectly by disrupting the complex formed with HDAC 1 and 2, REST and CoREST. 28, 29 Along those lines, we are conducting pull-down experiments to determine which cellular factors are associated with the complex following application of these LSD1 inhibitors, and these results will be reported separately.…”

Section: Biological Evaluationmentioning

confidence: 99%

Structure–activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures

Nowotarski

Pachaiyappan

Holshouser

et al. 2015

Bioorganic & Medicinal Chemistry

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Methylation at specific histone lysine residues is a critical post-translational modification that alters chromatin architecture, and dysregulated lysine methylation/demethylation is associated with the silencing of tumor suppressor genes. The enzyme lysine-specific demethylase 1 (LSD1) complexed to specific transcription factors catalyzes the oxidative demethylation of mono- and dimethyllysine 4 of histone H3 (H3K4me and H3K4me2 respectively). We have previously reported potent (bis)urea and (bis)thiourea LSD1 inhibitors that increase cellular levels of H3K4me and H3K4me2, promote the re-expression of silenced tumor suppressor genes and suppress tumor growth in vitro. Here we report the design additional (bis)urea and (bis)thiourea LSD1 inhibitors that feature 3-5-3 or 3-6-3 carbon backbone architectures. Three of these compounds displayed single-digit IC50 values in a recombinant LSD1 assay. In addition, compound 6d exhibited an IC50 of 4.2 μM against the Calu-6 human lung adenocarcinoma line, and 4.8 μM against the MCF7 breast tumor cell line, in an MTS cell viability assay. Following treatment with 6b–6d, Calu-6 cells exhibited a significant increase in the mRNA expression for the silenced tumor suppressor genes SFRP2, HCAD and p16, and modest increases in GATA4 message. The compounds described in this paper represent the most potent epigenetic modulators in this series, and have potential for use as antitumor agents.

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Section: Biological Evaluationmentioning

confidence: 99%

Structure–activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures

Nowotarski

Pachaiyappan

Holshouser

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Additionally, the histone acetyl transferase, CLOCK, also appears to promote viral gene expression and may interact with HCF1 through the transcription factor BMAL1. 312 The dihydro‐pyrido‐indole natural product Harmaline reportedly represses α gene activation, possibly by disrupting this viral‐host hybrid protein complex . Gu and coworkers have also suggested that the viral α protein ICP0 interacts with CoREST and may compete HDAC1 away from the REST/CoREST complex to initiate the switch to β/γ genes .…”

Section: Functionally Important Interactions Of Kdm1a and Kdm1b Demetmentioning

confidence: 99%

KDM1 class flavin‐dependent protein lysine demethylases

et al. 2015

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Flavin-dependent, lysine-specific protein demethylases (KDM1s) are a subfamily of amine oxidases that catalyze the selective posttranslational oxidative demethylation of methyllysine side chains within protein and peptide substrates. KDM1s participate in the widespread epigenetic regulation of both normal and disease state transcriptional programs. Their activities are central to various cellular functions, such as hematopoietic and neuronal differentiation, cancer proliferation and metastasis, and viral lytic replication and establishment of latency. Interestingly, KDM1s function as catalytic subunits within complexes with coregulatory molecules that modulate enzymatic activity of the demethylases and coordinate their access to specific substrates at distinct sites within the cell and chromatin. Although several classes of KDM1 -selective small molecule inhibitors have been recently developed, these pan-active site inhibition strategies lack the ability to selectively discriminate between KDM1 activity in specific, and occasionally opposing, functional contexts within these complexes. Here we review the discovery of this class of demethylases, their structures, chemical mechanisms, and specificity. Additionally, we review inhibition of this class of enzymes as well as emerging interactions with coregulatory molecules that regulate demethylase activity in highly specific functional contexts of biological and potential therapeutic importance.

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“…The effective concentration of test drugs that reduced plaques' number by 50% (EC 50 ) was interpolated from the dose-response curves. 7 …”

Section: In Vitro Cytotoxicity and Anti-hsv Activity Studymentioning

confidence: 99%

“…The mixture was removed and added with fresh media. The PRA was carried out as described, 7,19 after incubation at 37 C in 5% CO 2 for 48 h. DMSO (0.1 %) and ACV (5.0 microg/ml) were used as control for all these experiment.…”

Section: Mode Of Action Time Of Addition Assaymentioning

confidence: 99%

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Synthesis of multi ring-fused imidazo [1,2-a]isoquinoline-based fluorescent scaffold as anti-Herpetic agent

Chakravarty

Ojha

Konreddy

et al. 2015

Antivir Chem Chemother

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Background: Natural product-inspired synthesis is a key incorporation in modern diversity-oriented synthesis to yield biologically novel scaffold. Inspired by b-carboline fused system, we have designed molecules with multi ring fused scaffold by modifying the tricyclic pyrido [3,4-b]indole ring with imidazo[1,2-a]isoquinoline. Methods: A highly convergent approach with new C-N and C-C bond formation to synthesize multiring fused complex scaffold imidazo[1,2-a]isoquinolinies as fluorophores. N-nucleophile-induced ring transformation of 2H-pyran-2-one followed by in situ cis-stilbene-type oxidative photocyclization yielded new C-C bond formation without additional oxidant. The cytotoxicity, effective concentrations, and the mode of action of the synthesized analogs were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),, plaque reduction, time of addition, and reverse transcriptase Polymerase Chain Reaction (PCR). Results: Novel imidazo[1,2-a]isoquinoline analogs were prepared, and the results revealed that trans isomer of cyclopropyl analog (EC 50 35 and 37.5 mg/ml) and trans isomer of citric acid salt of phenyl analog (EC 50 38.2 and 39.8 mg/ml) possess significant anti-Herpes Simplex Virus (HSV) activity with selectivity index of >10. The kinetic study demonstrated that both the analogs inhibited HSV-1F and HSV-2G at 2-4 h postinfection. Finally, western blot and reverse transcriptase PCR assays revealed that both the analogs suppressed viral immediate early transcription. Conclusion: Novel imidazo[1,2-a]isoquinoline analogs were synthesized from pyranone with appropriate amines. Two compounds showed better antiviral profile on HSV-infected Vero cells, compared to the standard drug acyclovir (ACV). Overall, we discovered a promising scaffold to develop a nonnucleoside lead targeting the viral immediate early transcription for the management of HSV infections.

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A dihydro-pyrido-indole potently inhibits HSV-1 infection by interfering the viral immediate early transcriptional events

Cited by 56 publications

References 31 publications

Structure–activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures

Structure–activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures

KDM1 class flavin‐dependent protein lysine demethylases

Synthesis of multi ring-fused imidazo [1,2-a]isoquinoline-based fluorescent scaffold as anti-Herpetic agent

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