Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis

Bharathkumar, Hanumantharayappa; Mohan, Chakrabhavi Dhananjaya; Rangappa, Shobith; Kang, Taehee; Keerthy, Hosadurga K.; Fuchs, Julian E.; Kwon, Nam Hoon; Bender, Andreas; Kim, Sung Hoon; Basappa, Basappa; Rangappa, Kanchugarakoppal S.

doi:10.1039/c5ob00791g

Cited by 39 publications

(24 citation statements)

References 25 publications

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“…K252a has also been reported to block leukemia inhibitory factor-induced STAT3 activation in olfactory receptor neurons (21). We have recently reported the synthesis and anticancer effect of various azaspirane derivatives and demonstrated their mechanism of action in several types of cancers (7,22,23). In our previous study, we reported the development of azaspirane based small molecule, 2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5)undecane (CIMO) and demonstrated inhibition of the JAK-STAT pathway in hepatocellular carcinoma (7).…”

Section: An Azaspirane Derivative Suppresses Growth and Induces Apoptmentioning

confidence: 99%

An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway

Sulaiman

Mohan

Basappa

et al. 2016

International Journal of Oncology

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Persistent activation of signal transducer and activator of transcription 3 (STAT3) is associated with the progression of a range of tumors. In this report, we present the anticancer activity of 2-(1-(4-(2-cyanophenyl)1-benzyl‑1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5)undecane (CIMO) against breast cancer cells. We observed that CIMO suppresses the proliferation of both estrogen receptor-negative (ER-) (BT-549, MDA-MB‑231) and estrogen receptor-positive (ER+) (MCF-7, and BT-474) breast cancer (BC) cells with IC50 of 3.05, 3.41, 4.12 and 4.19 µM, respectively, and without significantly affecting the viability of normal cells. CIMO was observed to mediate its anti-proliferative effect in ER- BC cells by inhibiting the phosphorylation of JAK2 and STAT3 proteins. Quantitative PCR analysis demonstrated that CIMO decreases the relative mRNA expression of genes that are involved in cell cycle progression (CCND1) and cell survival (BCL2, BCL-xL, BAD, CASP 3/7/9, and TP53). In addition, CIMO was observed to arrest BC cells at G0/G1 phase and of the cell cycle. Furthermore, CIMO suppressed BC cell migration and invasion with concordant regulation of genes involved in epithelial to mesechymal transition (CDH1, CDH2, OCLN and VIM). Thus, we report the utility of a synthetic azaspirane which targets the JAK-STAT pathway in ER- BC.

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Section: An Azaspirane Derivative Suppresses Growth and Induces Apoptmentioning

confidence: 99%

An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway

Sulaiman

Mohan

Basappa

et al. 2016

International Journal of Oncology

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“… [a] Paclitaxel represents the positive control and the IC 50 value of paclitaxel is taken from our previous report …”

Section: Resultsmentioning

confidence: 99%

“…The antiproliferative effect of triazolo-pyridines towards lung cancer cells were investigated by the MTT dye uptake method as described earlier. [41,42] Briefly, A549 cells (2.5 × 10 4 /ml) were incubated in triplicate in a 96-well plate in the presence or absence of the indicated concentrations of compounds in a final volume of 0.2 ml for different time intervals at 37°C. Thereafter, 20 μl of MTT solution (5 mg/ml in PBS) was added to each well.…”

Section: Mtt Assaymentioning

confidence: 99%

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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“…18,19,29,30 In addition, deletion or over-expression of FtsK can result in the inhibition of cell division. 20 The docking scores (DS) of the docked compounds with the FtsK motor domain are summarized in Table 7.…”

Section: Rationalization Of Putative Target Of the Bioactive Thiazolimentioning

confidence: 99%

“…Expansion of this chemotype enabled us to define the essential pharmacophore for Type III secretion inhibition by this structural class. 11,12 In a continuation of our work to synthesize and explore the pharmacological properties of various classes of heterocycles, [13][14][15][16][17][18][19][20] we report here the application of MoO 3 nanoparticles in the synthesis of novel thizolidin-4-ones, followed by their use as anti-bacterial agents against S. typhi and K. pneumoniae. Furthermore, we used chemogenomics approaches to predict protein targets in silico and rationalized the mode of action of the bioactive thiazolidin-4-one.…”

Section: Introductionmentioning

confidence: 99%

Nano-MoO₃-mediated synthesis of bioactive thiazolidin-4-ones acting as anti-bacterial agents and their mode-of-action analysis using in silico target prediction, docking and similarity searching

et al. 2016

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The efficacy of thiazolidin-4-ones as synthons for diverse biological small molecules has given impetus to anti-bacterial studies. Our work aims to synthesize novel bioactive thiazolidin-4-ones using nano-MoO 3 for the first time. The compelling advantage of using nano-MoO 3 is that the recovered nano-MoO 3 can be reused thrice without considerable loss of its catalytic activity. The synthesized thiazolidin-4-ones were tested for anti-bacterial activity against two strains of pathogenic bacteria, namely, Salmonella typhi and Klebsiella pneumoniae. Our results indicated that 3-(benzo [d]isoxazol-3-yl)-2-(3-methoxyphenyl)thiazolidine-4-one (compound 3b) showed significant inhibitory activity towards Salmonella typhi, in comparison with gentamicin.Furthermore, in silico target prediction presented the target of compound 3b as the FtsK motor domain of DNA translocase of Salmonella typhi. Hence, our hypothesis is that compound 3b may disrupt chromosomal segregation and thereby inhibit the division of Salmonella typhi. In addition, similarity searching showed that 34 compounds with a chemical similarity of 70% or higher to compound 3b, which were retrieved from ChEMBL, bound to targets associated with biological processes related to cell development in 36% of the cases. In summary, our work details novel usage of nano-MoO 3 for the synthesis of novel thiazolidin-4-ones possessing anti-bacterial activity, and presents a mode-of-action hypothesis.

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Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis

Abstract: Elevated activity of methionyl-tRNA synthetase (MRS) in many cancers renders it a possible drug target in this disease area, as well as in a series of parasitic diseases.

Cited by 39 publications

References 25 publications

An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway

An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway

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

Nano-MoO₃-mediated synthesis of bioactive thiazolidin-4-ones acting as anti-bacterial agents and their mode-of-action analysis using in silico target prediction, docking and similarity searching

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Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis

Abstract: Elevated activity of methionyl-tRNA synthetase (MRS) in many cancers renders it a possible drug target in this disease area, as well as in a series of parasitic diseases.

Cited by 39 publications

References 25 publications

An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway

An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway

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

Nano-MoO3-mediated synthesis of bioactive thiazolidin-4-ones acting as anti-bacterial agents and their mode-of-action analysis using in silico target prediction, docking and similarity searching

Contact Info

Product

Resources

About

Nano-MoO₃-mediated synthesis of bioactive thiazolidin-4-ones acting as anti-bacterial agents and their mode-of-action analysis using in silico target prediction, docking and similarity searching