Discovery of novel [1,2,4]triazolo[4,3- a ]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment

Imran, Ali; Lee, Joo Yun; Go, Areum; Choi, Gildon; Lee, Kwang-Ho

doi:10.1016/j.bmcl.2017.09.025

Cited by 28 publications

(19 citation statements)

References 22 publications

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“…Further pharmacokinetic study showed the great potential for further drug development. In 2017, Ali et al performed docking-based virtual screening with fragment-like database containing nearly 800,000 compounds from ZINC database in an effort to pursue BRD4 inhibitors (Ali et al, 2017 ). Finally, the authors unveiled the discovery of a novel scaffold (compound 86 in Figure 4 ) contained [1,2,4]triazolo[4,3-α]quinoxaline as BET inhibitors.…”

Section: Readermentioning

confidence: 99%

Computer-Aided Drug Design in Epigenetics

Zhang

Jiang

et al. 2018

Front. Chem.

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Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

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Section: Readermentioning

confidence: 99%

Computer-Aided Drug Design in Epigenetics

Zhang

Jiang

et al. 2018

Front. Chem.

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“…[6] Literature survey clarified that triazoloquinoxalines were known as anticancer agents. [7,8] In 2018, Mohamed Alswah et al reported that 1-(4-(1-ethyl- [1,2,4]triazolo [4,3-a]quinoxalin-4-ylamino)phenyl)-3-(substitutedphenyl) prop-2-en-1-one A had antiproliferative characteristics with EGFR kinase inhibition (IC 50 = 0.039 μM). [2] Noteworthy, pyrazoles were proved to possess potent anticancer activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel triazoloquinoxaline‐pyrazole hybrids as antiproliferatives, EGFR inhibitors, and apoptosis inducers

Saeed

Bayoumi

Sarg

et al. 2020

Journal of Heterocyclic Chem

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Novel triazoloquinoxaline-pyrazole hybrids have been developed and synthesized. All derivatives' anticancer activity has been evaluated using Sulforhodamine-B (SRB) assay for cancer cell lines MCF-7, HepG-2, and HCT-116. Compound 12b was 2-fold more cytotoxic than Doxorubicin, while 12a,c demonstrated comparable cytotoxicity to the reference Doxorubicin. Further investigations on the most active derivatives 12a-c were done to study their inhibitory activity on two EGFR subtypes wild EGFR and mutant EGFR (L858R) tyrosine kinases in MCF-7 cell lines. Compound 12b exhibited potent inhibitory activity toward wild EGFR (IC 50 : 0.98 μM) when compared to Gefitinib (IC 50 :18.07 μM). 12b also possessed a marked inhibition against mutant EGFR (L858R-TK) exhibiting (IC 50 :27.45 μM) in comparison to Lapatinib (IC 50 : 61.06 μM). Compound 12b improved the active Caspase-3 value and the BAX/Bcl-2 reference. Furthermore, 12b showed G2/M cell cycle arrest induced apoptosis in cell line MCF-7. In addition, the most active derivatives have been orally bioavailable as shown in the in silico determination of the ADME characters. The binding pattern of compound 12b was also studied by molecular docking.

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“…18 Compound 14 is a lead molecule (IC 50 <100 nM), that acts as an inhibitor of bromodomain and extra-terminal motif (BET) proteins for cancer treatment. 19 Compound 15 is patented as an N -methyl-d-aspartate subtype 2B (NM-DAR2B) receptor antagonist. 20 11 is an inhibitor of the UT-A1 transporter; 12 is a ROMK inhibitor; Sitagliptin (13) is an FDA approved antidiabetic drug; 14 is a BET inhibitor with potential in cancer treatment; 15 is an NM-DAR2B receptor antagonist.…”

Section: Introductionmentioning

confidence: 99%

Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials

Korsik

Tse²,

Smith³

et al. 2020

Preprint

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We have discovered and studied a telesubstitution reaction in a biologically important heterocyclic ring system. Conditions that favour the tele-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base, or the use of softer nucleophiles, less polar solvents and larger halogens on the electrophile. Using results from X-ray crystallography and isotope labelling experiments a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the in vivo active anti-plasmodium compounds of Series 4 of the Open Source Malaria consortium. Archive of the electronic laboratory notebook with the description of all conducted experiments and raw NMR data could be accessed via following link <a href="https://ses.library.usyd.edu.au/handle/2123/21890">https://ses.library.usyd.edu.au/handle/2123/21890</a> . For navigation between entries of laboratory notebook please use file "Strings for compounds in the article.pdf" that works as a reference between article codes and notebook codes, also this file contain SMILES for these compounds.

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Discovery of novel [1,2,4]triazolo[4,3- a ]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment

Cited by 28 publications

References 22 publications

Computer-Aided Drug Design in Epigenetics

Computer-Aided Drug Design in Epigenetics

Synthesis of novel triazoloquinoxaline‐pyrazole hybrids as antiproliferatives, EGFR inhibitors, and apoptosis inducers

Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials

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