MOLPRINT 2D-based identification and synthesis of novel chromene based small molecules that target PLA2: validation through chemo- and bioinformatics approaches

Keerthy, Hosadurga K.; Vivek, H. K.; Bharathkumar, Hanumantharayappa; Rangappa, Shobith; Bulusu, Krishna C.; Mervin, Lewis; Fuchs, Julian E.; Priya, B. S.; Basappa, Basappa; S, Nanjuda Swamy; Bender, Andreas; Rangappa, Kanchugarakoppal S.

doi:10.1039/c5ra13085a

Cited by 7 publications

(4 citation statements)

References 33 publications

(56 reference statements)

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“…We reported the synthetic methodologies for the preparation of various bioactive heterocyclic moieties . In the present study, the green procedure for the synthesis of triazolo‐pyridine dicarbonitriles and dihydropyridine dicarbonitriles catalyzed by TBAB in water has been reported.…”

Section: Resultsmentioning

confidence: 96%

Triazole‐Pyridine Dicarbonitrile Targets Phosphodiesterase 4 to Induce Cytotoxicity in Lung Carcinoma Cells

Keerthy

Srinivasan

Basappa

et al. 2019

Chemistry & Biodiversity

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Phosphodiesterase 4 (PDE4) is a key enzyme involved in the hydrolysis of cyclic adenosine monophosphate (cAMP) and widely expressed in several types of cancers. The inhibition of PDE4 results in an increased concentration of intracellular cAMP levels that imparts the anti‐inflammatory response in the target cells. In the present report, two series of triazolo‐pyridine dicarbonitriles and substituted dihydropyridine dicarbonitriles were synthesized using green protocol (TBAB in refluxed water). We next evaluated the title compounds for their cytotoxicity towards lung cancer (A549) cells and identified 7′‐[4‐(methylsulfonyl)phenyl]‐5′‐oxo‐1′,5′‐dihydrospiro[cyclohexane‐1,2′‐[1,2,4]triazolo[1,5‐a]pyridine]‐6′,8′‐dicarbonitrile (5h) and 7′‐(1‐methyl‐1H‐imidazol‐2‐yl)‐5′‐oxo‐1′,5′‐dihydrospiro[cyclohexane‐1,2′‐[1,2,4]triazolo[1,5‐a]pyridine]‐6′,8′‐dicarbonitrile (5j) as lead analogs with the IC50 values of 15.2 and 24.1 μm, respectively. Furthermore, all the new compounds were tested for PDE4 inhibitory activity and 5j showed relatively good inhibitory activity towards PDE4 with inhibition of 50.9 % at 10 μm. In silico analysis demonstrated the favorable interaction of the title compounds with the target enzyme. Taken together, the present study introduces a new scaffold for the development of novel PDE4 inhibitors to fight against inflammatory diseases.

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Section: Resultsmentioning

confidence: 96%

Triazole‐Pyridine Dicarbonitrile Targets Phosphodiesterase 4 to Induce Cytotoxicity in Lung Carcinoma Cells

Keerthy

Srinivasan

Basappa

et al. 2019

Chemistry & Biodiversity

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“…In this regard, previously reported chromene-based organonitriles 53 were utilized as templates, using both ligand (MOLPRINT-2D) and structural bioinformatic methods 53 to design potential compounds. Hence, a library of compounds potentially targeting the dimeric form of TFF3 was generated (Figure S1C).…”

Section: ■ Resultsmentioning

confidence: 99%

Monomerization of Homodimeric Trefoil Factor 3 (TFF3) by an Aminonitrile Compound Inhibits TFF3-Dependent Cancer Cell Survival

Pandey

Poh

et al. 2022

ACS Pharmacol. Transl. Sci.

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Trefoil factor 3 (TFF3) is a secreted protein with an established oncogenic function and a highly significant association with clinical progression of various human malignancies. Herein, a novel small molecule that specifically targets TFF3 homodimeric functions was identified. Utilizing the concept of reversible covalent interaction, 2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) was identified as a molecule that interacted with TFF3. AMPC monomerized the cellular and secreted TFF3 homodimer at the cysteine (Cys)57-Cys57 residue with subsequent more rapid degradation of the generated TFF3 monomers. Hence, AMPC treatment also resulted in cellular depletion of TFF3 with consequent decreased cell viability in various human carcinoma-derived TFF3 expressing cell lines, including estrogen receptor positive (ER+) mammary carcinoma (MC). AMPC treatment of TFF3 expressing ER+ MC cells significantly suppressed total cell number in a dose-dependent manner. Consistently, exposure of TFF3 expressing ER+ MC cells to AMPC decreased soft agar colony formation, foci formation, and growth in suspension culture and inhibited growth of preformed colonies in 3D Matrigel. AMPC increased apoptosis in TFF3 expressing ER+ MC cells associated with decreased activity of EGFR, p38, STAT3, AKT, and ERK, decreased protein levels of CCND1, CCNE1, BCL2, and BCL-XL, and increased protein levels of TP53, CDKN1A, CASP7, and CASP9. siRNA-mediated depletion of TFF3 expression in ER+ MC cells efficiently abrogated AMPC-stimulated loss of cell viability and CASPASE 3/7 activities. Furthermore, in mice bearing ER+ MC cell-generated xenografts, AMPC treatment significantly impeded xenograft growth. Hence, AMPC exemplifies a novel mechanism by which small molecule drugs may inhibit a dimeric oncogenic protein and provides a strategy to impede TFF3-dependent cancer progression.

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“…In the past few decades, computational chemistry has seen significant advancements in developing novel therapeutics [ [31] , [32] , [33] , [34] ]. The molecular docking procedure was carried out by Prabhudeva et al [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

Structural and theoretical exploration of a multi-methoxy chalcone: Synthesis, quantum theory, electrostatics, molecular packing, DFT analysis, and in-silico anti-cancer evaluation

Al-Ostoot,

Akhileshwari,

Kameshwar

et al. 2024

Heliyon

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MOLPRINT 2D-based identification and synthesis of novel chromene based small molecules that target PLA2: validation through chemo- and bioinformatics approaches

Abstract: A chemoinformatics approach identified 2-Amino-4-(2′-methyl-[1,1′-biphenyl]-4-yl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile as a snake venom PLA2 inhibitor, this was confirmed with an IC50 = 12.5 μM.

Cited by 7 publications

References 33 publications

Triazole‐Pyridine Dicarbonitrile Targets Phosphodiesterase 4 to Induce Cytotoxicity in Lung Carcinoma Cells

Triazole‐Pyridine Dicarbonitrile Targets Phosphodiesterase 4 to Induce Cytotoxicity in Lung Carcinoma Cells

Monomerization of Homodimeric Trefoil Factor 3 (TFF3) by an Aminonitrile Compound Inhibits TFF3-Dependent Cancer Cell Survival

Structural and theoretical exploration of a multi-methoxy chalcone: Synthesis, quantum theory, electrostatics, molecular packing, DFT analysis, and in-silico anti-cancer evaluation

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