Synthesis of 2,4-diaryl chromenopyridines and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship

Thapa, Uttam; Thapa, Pritam; Karki, Radha; Yun, Minho; Choi, Jae Hun; Jahng, Yurngdong; Lee, Eun-Young; Jeon, Kyung Hwa; Na, Younghwa; Ha, Eun Mi; Cho, Won Jea; Kwon, Young Joo; Lee, Eung Seok

doi:10.1016/j.ejmech.2011.04.029

Cited by 51 publications

(22 citation statements)

References 30 publications

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“…The 'chromenopyridine nucleus' carried by Amlexanoxhas several interesting pharmacological properties [110] and has in fact been determined to represent a heterocyclic privileged medicinal scaffold and thus is highly pharmacologically relevant [111]. Compounds with the chromenopyridine nucleus have been indicated to have anticancer [112] as well as dopamine receptor antagonist properties [113]. Further, this nucleus forms a structural part of glucocorticoid receptor modulators [114].…”

Section: Enter Amlexanoxmentioning

confidence: 99%

Repurposing Amlexanox as a Run the Red Light Cure-All with Readthrough a No-Nonsense Approach to Personalised Medicine

Loudon¹

2013

J Bioanal Biomed

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Catalogue of somatic mutations in cancerContinuing with the cancer theme, even a brief examination of COSMIC -Catalogue of somatic mutations in cancer [1] shows the weight PTC mutations carry in the causation of a whole range of cancers through TS inactivation. As such, COSMIC provides for an excellent AbstractThe burden of inherited diseases in terms of congenital defects and cancer predisposition in addition to a multitude of neurological, cardiovascular and other organ diseases arising sporadically during life is enormous on the individual, immediate family and society globally. I approach this major burden to human society by invoking the powerful technology behind read-through, whereby disease-causing substitution nonsense mutations, oftentimes at the root of human diseases, are rescued. Further, the importance of nonsense mutations in the realm of developmental factors linked to cancer stem cell maintenance is presented. The methodology behind the technique is given and proof of concept behind its use ex vivo and in clinical trials. The discovery of a novel read-through drug, Amlexanox, which has been in use for over twenty years in dentistry for oral ulcerations, represents a next generation read-through agent. This agent has been demonstrated in cell lines to correct functional loss in cystic fibrosis CFTR, dystrophin and the tumour suppressor, p53. Its novel ability to inhibit nonsense mediated decay is discussed. Amlexanox is therefore presently ready for testing in a wide variety of in vivo models of human diseases and also in clinical trials. Given the safety profile of Amlexanox and ex vivo efficacy in studies thus far it is envisaged that this accepted medication shall successfully debut as an all-purpose agent for the prevention and management of human diseases.

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Section: Enter Amlexanoxmentioning

confidence: 99%

Repurposing Amlexanox as a Run the Red Light Cure-All with Readthrough a No-Nonsense Approach to Personalised Medicine

Loudon¹

2013

J Bioanal Biomed

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“…Previously, our research group synthesized various rigid analogues of 2,4,6-trisubstituted pyridines and evaluated thse analogues for their topoisomerase inhibitory activity, as well as cytotoxicity, in order to determine the effects of rigid structure on anticancer activity (8)(9)(10). Rigid structures are commonly considered to have little conformational entropy compared to flexible structures, and can be more efficiently fitted into the active site of a receptor (11).…”

Section: Introductionmentioning

confidence: 99%

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

Park

Kim

et al. 2014

International Journal of Molecular Medicine

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Abstract. The inhibition of topoisomerase can suppress the growth of cancer cells and induce apoptosis. The aim of this study was to evaluate the anticancer effects and mechanisms of action of a novel topoisomerase inhibitor, 4-(furan-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-1,10-phenanthroline (FPDHP). FPDHP suppressed the growth of Caki, A549, HT29 and MDA-MB-231 cells, and induced caspase-dependent apoptosis in the Caki cells. In particular, FPDHP also induced caspase-dependent apoptosis and the downregulation of the protein expression levels of cellular FLICE-like inhibitory protein (cFLIP) and the phosphorylation of Akt in Caki cells. Notably, the overexpression of cFLIP, but not that of Akt, in part, blocked the FPDHP-mediated apoptosis in Caki cells. In addition, FPDHP was further shown to induce the caspase-independent detachment of Caki cells from the culture dish; higher populations of apoptotic cells were observed in the detached cells than in the attached cells. To the best of our knoweledge, these results collectively demonstrate for the first time that FPDHP has a killing effect on Caki cells, which is mediated through both caspase-dependent apoptosis and caspase-independent cell detachment.

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“…With similar synthetic procedures, several (E)-3-heteroarylidenechroman-4-ones were synthesized starting from chroman-4-ones and different heteroaryl aldehydes [13,[16][17][18][19][20]. As illustrated in Scheme 1, we conveniently obtained the designed (E)-3-heteroarylidenechroman-4-ones 1a-r using pyrrolidine as catalyst of the condensation.…”

Section: Chemistrymentioning

confidence: 99%

( E )-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors

Desideri

Monaco

Fioravanti

et al. 2016

European Journal of Medicinal Chemistry

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A series of (E)-3-heteroarylidenechroman-4-ones (1a-r) was designed, synthesized and investigated in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO) isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors showing IC50 values in the nanomolar or micromolar range. (E)-5,7-Dichloro-3-{[(2-(dimethylamino)pyrimidin-5-yl]methylene}chroman-4-one (1c) was the most interesting compound identified in this study, endowed with higher hMAO-B potency (IC50 = 10.58 nM) and selectivity (SI > 9452) with respect to the reference selective inhibitor selegiline (IC50 = 19.60 nM, IC50 > 3431). Molecular modelling studies were performed for rationalizing at molecular level the target selective inhibition of our compounds, revealing a remarkable contribution of hydrogen bond network and water solvent.

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Synthesis of 2,4-diaryl chromenopyridines and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship

Cited by 51 publications

References 30 publications

Repurposing Amlexanox as a Run the Red Light Cure-All with Readthrough a No-Nonsense Approach to Personalised Medicine

Repurposing Amlexanox as a Run the Red Light Cure-All with Readthrough a No-Nonsense Approach to Personalised Medicine

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

( E )-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors

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