Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells

Muniyan, Sakthivel; Chou, Yu Wei; Ingersoll, Matthew A.; Devine, Alexus; Morris, Marisha; Odero-Marah, Valerie; Khan, Shafiq A.; Chaney, William G.; Bu, Xiu R.; Lin, Ming Fong

doi:10.1016/j.canlet.2014.07.002

Cited by 25 publications

(19 citation statements)

References 46 publications

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“…Earlier researcher were synthesized many heterocyclic compounds and tested for their anticancer activity . The small heterocyclic frame works like Imidazopyridine derivatives are a category of new compounds which contain pyridine and aromatic aldehydes and possess significance activity . Among them, Imidazo[1,2‐ a ]pyridine is the most important in the area of pharmaceuticals and natural products.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Piperazine‐Linked Imidazo[1,2‐a]pyridine Derivatives as Potent Anticancer Agents

et al. 2019

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Designed, synthesized a series of novel imidazo[1,2-a]pyridine derivatives and evaluated for their in vitro cytotoxicity. Fluorine containing compounds, (2-fluorophenyl)(4-(2-(pyridin-2-yl)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methanone (7 e),(4-(2-(pyridin-2-yl)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)(2-(trifluoromethyl)phenyl)methanone (7 h) and (3-fluorophenyl) (4-(2-(pyridin-2-yl)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methanone (7 i) were found to have an effective cytotoxic profile against HepG2, HeLa and MDA-MB-231. Compounds 7 h (IC 50 = 5.8 μM) and 7 i (IC 50 = 3.5 μM) were found potent when compared with control Paclitaxel (IC 50 = 2.8 μM), against HeLa. Compound 7 h also found to be potent against HepG2 (IC 50 = 2.0 μM) and MDAMB-231(IC 50 = 6.9 μM) respectively, when compared with Paclitaxel (HepG2, IC 50 = 0.56 μM; MDAMB-231, IC 50 = 1.9 μM). Compound 7 e also found to be potent against HepG2 (IC 50 = 9.8 μM) cell lines. Synthesized piperazine linked imidazo[1,2-a]pyridine derivatives (7 i, IC 50 = 3.5 μM) and (7 h, IC 50 = 5.8 μM) showed 1.74 fold, 1.12 fold increase in antiproliferative activity than reported homopiperazine linked imidazo [1,2-a]pyrimidine derivatives (4-Fluorophenyl)(4-(2-(4fluorophenyl)imidazo[1,2-a]pyrimidin-7-yl)-1,4-diazepan-1-yl)methanone(10 f, IC 50 = 6.12 μM) and (4-(2-(4-Fluorophenyl)imidazo[1,2-a]pyrimidin-7-yl)-1,4-diazepan-1-yl)(3methoxyphenyl)methanone (12, IC 50 = 6.54 μM) against Hela cell lines. Molecular docking studies showed that designed compounds occupy at the active site of both colchicine and human estrogen receptor which demonstrated that the designed compounds were able to bind with multiple targets, the biological activity of these compounds hold promise to find application in considering for treatment protocol.[a] M.

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Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Piperazine‐Linked Imidazo[1,2‐a]pyridine Derivatives as Potent Anticancer Agents

et al. 2019

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“…Such inhibitors include a series of diphenyl quinoxalines [22], imidazopyridine [32], 2-pyrimidyl-5-amidothiophenes [33], prenylated flavonoids [34, 35], pyrimidines [36] and pyridines [37, 38]. Furthermore, ligand as well as structure-based modelling strategies, including the support vector classification (SVC) method [39], comparative molecular similarity indices analysis (CoMSIA), comparative molecular field analysis (CoMFA) [40–42] and molecular docking simulations [40, 43] have been used for the structural optimization of the identified lead compounds.…”

Section: Introductionmentioning

confidence: 99%

A 2D-QSAR and Grid-Independent Molecular Descriptor (GRIND) Analysis of Quinoline-Type Inhibitors of Akt2: Exploration of the Binding Mode in the Pleckstrin Homology (PH) Domain

Akhtar¹,

Jabeen²

2016

PLoS ONE

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Protein kinase B-β (PKBβ/Akt2) is a serine/threonine-specific protein kinase that has emerged as one of the most important regulators of cell growth, differentiation, and division. Upregulation of Akt2 in various human carcinomas, including ovarian, breast, and pancreatic, is a well-known tumorigenesis phenomenon. Early on, the concept of the simultaneous administration of anticancer drugs with inhibitors of Akt2 was advocated to overcome cell proliferation in the chemotherapeutic treatment of cancer. However, clinical studies have not lived up to the high expectations, and several phase II and phase III clinical studies have been terminated prematurely because of severe side effects related to the non-selective isomeric inhibition of Akt2. The notion that the sequence identity of pleckstrin homology (PH) domains within Akt-isoforms is less than 30% might indicate the possibility of the development of selective antagonists against the Akt2 PH domain. Therefore, in this study, various in silico tools were utilized to explore the hypothesis that quinoline-type inhibitors bind in the Akt2 PH domain. A Grid-Independent Molecular Descriptor (GRIND) analysis indicated that two hydrogen bond acceptors, two hydrogen bond donors and one hydrophobic feature at a certain distance from each other were important for the selective inhibition of Akt2. Our docking results delineated the importance of Lys30 as an anchor point for mapping the distances of important amino acid residues in the binding pocket, including Lys14, Glu17, Arg25, Asn53, Asn54 and Arg86. The binding regions identified complement the GRIND-based pharmacophoric features.

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“…The anchorage-independent growth of cells was determined by soft agar analysis as described previously [40, 41]. Briefly, 5×10 3 cells were seeded in 0.25% agarose on the top of a base layer containing 0.3% agarose.…”

Section: Methodsmentioning

confidence: 99%

ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells

Muniyan

Chen

Lin

et al. 2015

Cellular Signalling

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While androgen deprivation therapy (ADT) reduces tumor burden, autocrine growth factor loops such as human epidermal growth factor receptor 2 (HER2/ErbB-2/neu) have been proposed to contribute to prostate cancer (PCa) survival and relapse. However, the role of ErbB-2 in regulating androgen-sensitive (AS) and castration-resistant (CR) cell proliferation remains unclear. Here, we determined the role of ErbB-2 in PCa progression and survival under steroid-reduced conditions using two independent PCa cell progression models. In AR-positive androgen-independent (AI) PCa cells that exhibit the CR phenotype, ErbB-2 was constitutively activated, compared to corresponding AS PCa cells. In AS LNCaP C-33 cells, androgen-induced ErbB-2 activation through ERK1/2 mediates PCa cell proliferation. Further, the ErbB-2-specific but not EGFR-specific inhibitor suppresses basal and androgen-stimulated cell proliferation and also blocks ERK1/2 activation. ErbB-2 ectopic expression and cPAcP siRNA transfection of LNCaP C-33 cells each increases ErbB-2 tyrosine phosphorylation, correlating with increased AI PSA secretion and cell proliferation. Conversely, trapping ErbB-2 by transfected endoplasmic reticulum-targeting ScFv5R expression vector abolished DHT-induced LNCaP C-33 cell growth. Moreover, inhibition of ErbB-2 but not EGFR in AI LNCaP C-81 and MDA PCa2b-AI PCa cells significantly abolished AI cell growth. In contrast to androgens via ErbB-2/ERK1/2 signaling in AS PCa cells, the inhibition of ErbB-2 abrogated AI cell proliferation by inhibiting the cell survival protein Akt in those AI cells. These results suggest that ErbB-2 is a prominent player in mediating the ligand-dependent and -independent activation of AR in AS and AI/CR PCa cells respectively for PCa progression and survival.

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Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells

Cited by 25 publications

References 46 publications

Design and Synthesis of Piperazine‐Linked Imidazo[1,2‐a]pyridine Derivatives as Potent Anticancer Agents

Design and Synthesis of Piperazine‐Linked Imidazo[1,2‐a]pyridine Derivatives as Potent Anticancer Agents

A 2D-QSAR and Grid-Independent Molecular Descriptor (GRIND) Analysis of Quinoline-Type Inhibitors of Akt2: Exploration of the Binding Mode in the Pleckstrin Homology (PH) Domain

ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells

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