2,3-Diaryl-3 H -imidazo[4,5- b ]pyridine derivatives as potential anticancer and anti-inflammatory agents

Kirwen, Erin Marie; Batra, Tarun; Karthikeyan, Chandrabose; Deora, Girdhar Singh; Rathore, Vandana; Mulakayala, Chaitanya; Mulakayala, Naveen; Nusbaum, Amy Catherine; Chen, Joel; Amawi, Haneen; McIntosh, Kyle; Sahabjada,; Shivnath, Neelam; Chowarsia, Deepak; Sharma, Nisha; Ali, Arshad; Trivedi, Piyush; Tiwari, Amit K.

doi:10.1016/j.apsb.2016.05.003

Cited by 21 publications

(10 citation statements)

References 15 publications

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“…Generally, the crystal structures of HPA (PDB code 3OLD), human NtMGAM (PDB code 3L4W), CtMGAM (PDB code 3TOP), and NtSI (PDB code 3LPP) were obtained from the RCSB Protein Data Bank. The proteins were automatically cleaned up by the preparation tools for some common problems, such as incomplete residues, the lack of hydrogens and the existence of crystallographic water [34]. The active site of each protein for docking was determined based on the position of the co-crystalized ligand within the binding pocket.…”

Section: Methodsmentioning

confidence: 99%

Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking

et al. 2019

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α-glucosidase inhibitors (AGIs) have been an important category of oral antidiabetic drugs being widely exploited for the effective management of type 2 diabetes mellitus. However, the marketed AGIs not only inhibited the disaccharidases, but also exhibited an excessive inhibitory effect on α-amylase, resulting in undesirable gastrointestinal side effects. Compared to these agents, Ramulus Mori alkaloids (SZ-A), was a group of effective alkaloids from natural Morus alba L., and showed excellent hypoglycemic effect and fewer side effects in the Phase II/III clinical trials. Thus, this paper aims to investigate the selective inhibitory effect and mechanism of SZ-A and its major active ingredients (1-DNJ, FA and DAB) on different α-glucosidases (α-amylase and disaccharidases) by using a combination of kinetic analysis and molecular docking approaches. From the results, SZ-A displayed a strong inhibitory effect on maltase and sucrase with an IC50 of 0.06 μg/mL and 0.03 μg/mL, respectively, which was similar to the positive control of acarbose with an IC50 of 0.07 μg/mL and 0.68 μg/mL. With regard to α-amylase, SZ-A exhibited no inhibitory activity at 100 μg/mL, while acarbose showed an obvious inhibitory effect with an IC50 of 1.74 μg/mL. The above analysis demonstrated that SZ-A could selectively inhibit disaccharidase to reduce hyperglycemia with a reversible competitive inhibition, which was primarily attributed to the three major active ingredients of SZ-A, especially 1-DNJ molecule. In the light of these findings, molecular docking study was utilized to analyze their inhibition mechanisms at molecular level. It pointed out that acarbose with a four-ring structure could perform desirable interactions with various α-glucosidases, while the three active ingredients of SZ-A, belonging to monocyclic compounds, had a high affinity to the active site of disaccharidases through forming a wide range of hydrogen bonds, whose affinity and consensus score with α-amylase was significantly lower than that of acarbose. Our study illustrates the selective inhibition mechanism of SZ-A on α-glucosidase for the first time, which is of great importance for the treatment of type 2 diabetes mellitus.

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Section: Methodsmentioning

confidence: 99%

Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking

et al. 2019

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“…It is reported that 1,25(OH) 2 D 3 may restrain inflammatory progression through downregulation of MMP-3, INOS and COX-2 levels and upregulation of inflammatory mediators including IL-1 β , IL-6, IL-8, and prostaglandins (PGs) in macrophage190, 191. COX-2 is involved in pathogenesis of many inflammatory diseases 192 , and 1,25(OH) 2 D 3 is able to decrease COX-2 expression in many kinds of cancers such as breast cancer, colon cancer, ovarian cancer and prostate cancer, thereby suppressing cancer growth193, 194, 195, 196. In a clinical trial, higher levels of vitamin D were correlated with lower COX-2 level in prostate cancer cells and stroma cells 197 .…”

Section: Mechanisms Of Action Of Vitamin D Within the Tumor Microenvimentioning

confidence: 99%

Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment

Lü

et al. 2019

Acta Pharmaceutica Sinica B

103

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Tumor cells along with a small proportion of cancer stem cells exist in a stromal microenvironment consisting of vasculature, cancer-associated fibroblasts, immune cells and extracellular components. Recent epidemiological and clinical studies strongly support that vitamin D supplementation is associated with reduced cancer risk and favorable prognosis. Experimental results suggest that vitamin D not only suppresses cancer cells, but also regulates tumor microenvironment to facilitate tumor repression. In this review, we have outlined the current knowledge on epidemiological studies and clinical trials of vitamin D. Notably, we summarized and discussed the anticancer action of vitamin D in cancer cells, cancer stem cells and stroma cells in tumor microenvironment, providing a better understanding of the role of vitamin D in cancer. We presently re-propose vitamin D to be a novel and economical anticancer agent.

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“…The effect of the compounds on the cell survival was determined in different cancer and normal cell lines using the MTT assay. The MTT assay was conducted as previously as described [24,25]. The seeded cells in 96 well plates were incubated with different analogs at different concentrations for 72 hrs.…”

Section: Methodsmentioning

confidence: 99%

Novel 3-((2-chloroquinolin-3-yl)methylene)indolin-2-one derivatives produce anticancer efficacy in ovarian cancer in vitro

Karthikeyan

Amawi

Ashby

et al. 2019

Heliyon

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A novel series of 3-((2-chloroquinolin-3-yl)methylene)indolin-2-ones were synthesized, using the ‘molecular hybridization approach’ and evaluated for anticancer efficacy. Eleven 3-((2-chloroquinolin-3-yl)methylene)indolin-2-ones ( LM01 to LM11 ) were synthesized and evaluated for in vitro cytotoxic efficacy in cancer (ovarian, prostate and colon) and two non-cancerous cell lines. Among the 3-((2-chloroquinolin-3-yl)methylene)indolin-2-one derivatives, LM08, with a 6-Cl substitution in the 3-quinolinyl moiety, had selective and potent cytotoxic efficacy in the ovarian cancer cell line A2780. Further mechanistic investigations indicated that LM08 significantly inhibited the clonogenic survival of A2780 cancer cells, which was mediated by inducing apoptosis.

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2,3-Diaryl-3 H -imidazo[4,5- b ]pyridine derivatives as potential anticancer and anti-inflammatory agents

Cited by 21 publications

References 15 publications

Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking

Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking

Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment

Novel 3-((2-chloroquinolin-3-yl)methylene)indolin-2-one derivatives produce anticancer efficacy in ovarian cancer in vitro

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