Discovery of 4-Aryl-4<i>H</i>-chromenes as a New Series of Apoptosis Inducers Using a Cell- and Caspase-based High-Throughput Screening Assay. 1. Structure−Activity Relationships of the 4-Aryl Group

Kemnitzer, William; Drewe, John; Jiang, Songchun; Zhang, Hong; Wang, Yan; Zhao, Jianghong; Jia, Shaojuan; Herich, John; Labreque, Denis; Storer, Richard; Meerovitch, Karen; Bouffard, David Y.; Rej, Rabindra; Denis, Real; Blais, Charles; Lamothe, Serge; Attardo, Giorgio; Gourdeau, Henriette; Tseng, Ben; Kasibhatla, Shailaja; Cai, Sui Xiong

doi:10.1021/jm049640t

Cited by 263 publications

(142 citation statements)

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Section: Boyden Chamber Cell Assaymentioning

confidence: 99%

“…Finally, we used molecular hybridization to design a hybrid of piperlongumine and chromene (6), the latter of which is widely known for its cytotoxicity and induction of apoptosis. 33 The designed compounds are presented in Scheme 1.The synthesis of piperlongumine using different methods is described in the literature. 32,[34][35][36][37] One of the newest and simplest approaches for amide bond formation consists of the coupling of the NH-lactam (piperidonic group) with 3,4,5-trimethoxy cinnamoyl chloride in the presence of a base.…”

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confidence: 99%

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Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

Valli¹,

Altei²,

Santos³

et al. 2017

J. Braz. Chem. Soc.

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Piperlongumine is a natural amide alkaloid isolated from several species of Piper and is described in the literature as selectively cytotoxic to several cancer cell lines. Inhibiting cell migration has gained considerable interest as an approach for discovering antimetastatic agents because this process is fundamental to metastasis. Piperlongumine, selected from cell-based assay screening of NuBBE Database, inhibited the migration of MDA-MB-231 breast cancer cells with an EC 50 of 3.0 ± 1.0 µM by the Boyden chamber assay. A series of five analogous compounds based on the structure of piperlongumine were designed, synthesized and evaluated in cell migration and cytotoxicity assays. The analogue designed by molecular simplification ((E)-N-acryloyl-3-(3,4,5-trimethoxyphenyl)acrylamide) was the most active of the series, with an EC 50 of 1.5 ± 1 µM. Additionally, this compound was selectively cytotoxic, with a selectivity index (SI) of 4.4. Keywords: piperlongumine, piplartine, piperamide, cytotoxicity, cell migration inhibition IntroductionMetastasis is the process by which undifferentiated cancer cells migrate to other parts of the body.1,2 Suppression of metastasis is an urgent need in cancer treatment, as most existing drugs only inhibit cell proliferation.3 Traditionally, chemotherapy is based on cytotoxic therapeutic agents that inhibit proliferation and cause cell death. However, the strategy of inhibiting cell migration has recently gained considerable interest. 4 Several compounds that inhibit the process of metastasis have been described to date. 5,6 Paclitaxel, which was originally discovered as an antimitotic agent that disrupts the cell cycle in cancer cells by stabilizing microtubules, exhibits marked and selective inhibition of tumor cell migration. 7As extensively reviewed elsewhere, biodiversity in nature has provided unique chemical scaffolds that have been used as templates for medicinal chemistry and drug discovery. [8][9][10][11][12][13] The availability of natural compound libraries is of significant importance for integrating natural products and medicinal chemistry, especially for the identification of new bioactive agents and the rational design of compounds in drug discovery.14 Within this context, we selected the natural product piperlongumine (1), also known as piplartine, from cell-based assay screening of NuBBE Database (NuBBE DB ) 15 and evaluated its ability to inhibit Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration J. Braz. Chem. Soc. 476 cancer cell migration using biological and target-based experiments.Piperlongumine (1, Figure 1) is an alkamide isolated from several species of Piper (Piperaceae). 16 It is described as possessing antifungal properties, 17 cytotoxicity toward several cancer cell lines, 18,19 and trypanocidal effects, 20 as well as other biological activities. 21 Furthermore, piperlongumine selectively induces cell death in cancer cells but does not reduce viability in normal cells. 22This ...

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Section: Boyden Chamber Cell Assaymentioning

confidence: 99%

mentioning

confidence: 99%

Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

Valli¹,

Altei²,

Santos³

et al. 2017

J. Braz. Chem. Soc.

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“…Recently, two major classes of small molecular compounds inducing apoptosis have been developed as potential anticancer agents, including the caspase-inhibiting isatin derivatives [113][114][115] and the apoptosis-inducing 4-aryl-4H-chromens, which inhibit tubulin polymerization and bind at the colchicine binding site [115][116][117]. Several articles have reported the synthesis and biological evaluation of radiolabeled isatin derivatives for imaging of apoptosis using PET [114,[118][119][120][121][122][123].…”

Section: Apoptosis Pet Imaging For Cancer Therapy Responsementioning

confidence: 99%

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

Zhu

Shim

2011

Nucl Med Mol Imaging

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Molecular imaging is one of the fastest growing areas of medical imaging. Positron emission tomography (PET) has been widely used in the clinical management of patients with cancer. Nuclear imaging provides biological information at the cellular, subcellular, and molecular level in living subjects with noninvasive procedures. In particular, PET imaging takes advantage of traditional diagnostic imaging techniques and introduces positron-emitting probes to determine the expression of indicative molecular targets at different stages of cancer. 18 F-fluorodeoxyglucose ( 18 F-FDG), the only FDA approved oncological PET tracer, has been widely utilized in cancer diagnosis, staging, restaging, and even monitoring response to therapy; however, 18 F-FDG is not a tumor-specific PET tracer. Over the last decade, many promising tumor-specific PET tracers have been developed and evaluated in preclinical and clinical studies. This review provides an overview of the current non-18 F-FDG PET tracers in oncology that have been developed based on tumor characteristics such as increased metabolism, hyperproliferation, angiogenesis, hypoxia, apoptosis, and tumor-specific antigens and surface receptors.

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“…Since apoptosis induction effect of anti-cancer compounds has been proved, several researchers have attempted to synthesize various derivatives of chromene [10,11], although it has not been extensively studied for breast cancer.…”

mentioning

confidence: 99%

“…Right balance between apoptosis and inhibition of apoptosis plays an important role in maintaining the homeostasis of tissue and organ morphogenesis [10,12]. Cytological and biochemical changes happen in certain cells during apoptosis, including condensation of nucleoplasm and cytoplasm, DNA fragmentation, and formation of apoptotic bounded membrane bodies that are identified and eliminated by adjacent cells [13,14].…”

mentioning

confidence: 99%

Cytotoxicity and Apoptosis Inducing Activities of 2-Amino-4H-chromene-3-carbonitrile Derivatives Loaded on Gold Nanoparticles Against Human Breast Cancer Cell Line T47D

et al. 2014

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Chemotherapy drugs, used for prevention of uncontrolled cell proliferation in certain tissues as well as inducing apoptosis in tumor cells, are important candidates for treatment of cancer. The synthesized 2-amino-4H-chromene-3-carbonitrile derivatives effective on cancerous cells resistant to other drugs such as Paclitaxel were used due to their ability in induction of apoptosis. The growth inhibitory and inducing apoptosis activities were determined. In order to make it target-oriented, the best compound was conjugated with gold nanoparticles (NPs) by aspartic acid with chemical reduction method. Cytotoxicity effect of 2-amino-4H-chromene-3-carbonitrile derivatives against the T47D breast cancer cell line was determined by MTT assay. The synthesis of gold NPs was confirmed by transmission electron microscopy, UV-Vis and dynamic light scattering. To assess the effects of compounds on the process of apoptosis, staining methods with acridine orange-ethidium bromide and Hoechst staining by fluorescence microscopy and DNA fragmentation by the diphenylamine method were used. The synthesized compounds containing two NH 2 groups on benzene rings, demonstrated more cytotoxicity effect. The effect of conjugation with gold NPs and the induction of apoptosis were studied with the best compound. The cytotoxicity effects of the synthesized 2-amino-4H-chromene-3-carbonitrile compounds were changed by replacement of NO 2 group on thiol ring with different chemical groups on the benzene ring. Analyses of treated cell lines by conjugated and non-conjugated forms of compounds verified their ability in inducing apoptosis while conjugated form demonstrated higher apoptosis.

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Discovery of 4-Aryl-4H-chromenes as a New Series of Apoptosis Inducers Using a Cell- and Caspase-based High-Throughput Screening Assay. 1. Structure−Activity Relationships of the 4-Aryl Group

Cited by 263 publications

References 24 publications

Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

Cytotoxicity and Apoptosis Inducing Activities of 2-Amino-4H-chromene-3-carbonitrile Derivatives Loaded on Gold Nanoparticles Against Human Breast Cancer Cell Line T47D

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