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      Design, Synthesis, and Structural Characterization of Novel Diazaphenothiazines with 1,2,3-Triazole Substituents as Promising Antiproliferative Agents

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          Abstract

          A series of novel 1,2,3-triazole-diazphenothiazine hybrids was designed, synthesized, and evaluated for anticancer activity against four selected human tumor cell lines (SNB-19, Caco-2, A549, and MDA-MB231). The majority of the synthesized compounds exhibited significant potent activity against the investigated cell lines. Among them, compounds 1d and 4c showed excellent broad spectrum anticancer activity, with IC 50 values ranging from 0.25 to 4.66 μM and 0.25 to 6.25 μM, respectively. The most promising compound 1d, possessing low cytotoxicity against normal human fibroblasts NHFF, was used for gene expression analysis using reverse transcription–quantitative real-time PCR (RT–qPCR). The expression of H3, TP53, CDKN1A, BCL-2, and BAX genes revealed that these compounds inhibited the proliferation in all cells ( H3) and activated mitochondrial events of apoptosis ( BAX/BCL-2).

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          Click chemistry for drug development and diverse chemical-biology applications.

          Prakasam Thirumurugan, Dariusz Matosiuk, Krzysztof Jozwiak (2013)
          Article 0 comments Cited 277 times – based on 0 reviews     Review now
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            Medicinal attributes of 1,2,3-triazoles: Current developments.

            Divya Dheer, Virender Singh, Ravi Pathiyil Shankar (2017)
            1,2,3-Triazoles are important five-membered heterocyclic scaffold due to their extensive biological activities. This framework can be readily obtained in good to excellent yields on the multigram scale through click chemistry via reaction of aryl/alkyl halides, alkynes and NaN3 under ambient conditions. It has been an emerging area of interest for many researchers throughout the globe owing to its immense pharmacological scope. The present work aims to summarize the current approaches adopted for the synthesis of the 1,2,3-triazole and medicinal significance of these architectures as a lead structure for the discovery of drug molecules such as COX-1/COX-2 inhibitors (celecoxib, pyrazofurin), HIV protease inhibitors, CB1 cannabinoid receptor antagonist and much more which are in the pipeline of clinical trials. The emphasis has been given on the major advancements in the medicinal prospectus of this pharmacophore for the period during 2008-2016.
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              Is Open Access

              Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms

              Mary Ann Quinn-Allen, Zdenek Andrysik, Veronica Dengler … (2014)
              The p53 transcription factor is a potent suppressor of tumor growth. We report here an analysis of its direct transcriptional program using Global Run-On sequencing (GRO-seq). Shortly after MDM2 inhibition by Nutlin-3, low levels of p53 rapidly activate ∼200 genes, most of them not previously established as direct targets. This immediate response involves all canonical p53 effector pathways, including apoptosis. Comparative global analysis of RNA synthesis vs steady state levels revealed that microarray profiling fails to identify low abundance transcripts directly activated by p53. Interestingly, p53 represses a subset of its activation targets before MDM2 inhibition. GRO-seq uncovered a plethora of gene-specific regulatory features affecting key survival and apoptotic genes within the p53 network. p53 regulates hundreds of enhancer-derived RNAs. Strikingly, direct p53 targets harbor pre-activated enhancers highly transcribed in p53 null cells. Altogether, these results enable the study of many uncharacterized p53 target genes and unexpected regulatory mechanisms. DOI: http://dx.doi.org/10.7554/eLife.02200.001
              Article 0 comments Cited 119 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 30 November 2019
                Publication date Collection: December 2019
                Volume: 24
                Issue: 23
                Electronic Location Identifier: 4388
                Affiliations
                [1 ]Department of Organic Chemistry, Faculty of Pharmaceutical Sciences, The Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland; pluta@ 123456sum.edu.pl (K.P.); manowak@ 123456sum.edu.pl (M.J.)
                [2 ]Department of Cell Biology, Faculty of Pharmaceutical Sciences, The Medical University of Silesia, Jedności 8, 41-200 Sosnowiec, Poland; mlatocha@ 123456sum.edu.pl (M.L.); dkusmierz@ 123456sum.edu.pl (D.K.)
                Author notes
                [* ]Correspondence: bmlodawska@ 123456sum.edu.pl ; Tel.: +48-32-364-16-04
                Author information
                https://orcid.org/0000-0001-5389-1079
                https://orcid.org/0000-0002-4144-990X
                Article
                Publisher ID: molecules-24-04388
                DOI: 10.3390/molecules24234388
                PMC ID: 6930555
                PubMed ID: 31801304
                SO-VID: 06e5829d-1f3f-49a1-bb86-ea9f7a5558a1
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 28 October 2019
                Date accepted : 27 November 2019
                Categories
                Subject: Article

                Keywords: diazaphenothiazines,1,2,3-triazole ring,antiproliferative activity,intracellular apoptosis pathway,h3,tp53,cdkn1a,bax/bcl-2 ratio
                Data availability:
                Keywords: diazaphenothiazines, 1,2,3-triazole ring, antiproliferative activity, intracellular apoptosis pathway, h3, tp53, cdkn1a, bax/bcl-2 ratio

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