Design, synthesis and evaluation of antiestrogen and histone deacetylase inhibitor molecular hybrids

Mendoza-Sanchez, Rodrigo; Cotnoir-White, David; Kulpa, Justyna; Jutras, Isabel; Pottel, Joshua; Moitessier, Nicolas; Mader, Sylvie; Gleason, James L.

doi:10.1016/j.bmc.2015.11.005

Cited by 34 publications

(14 citation statements)

References 73 publications

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“…Compound 1 was found to affect the cell cycle and promote apoptosis [5], induce polyploidy-dependent senescence [6], and inhibit epidermal growth factor receptor (EGFR) expression, thereby disrupting the associated downstream signaling [7]. The combination of 1 with other drugs in hybrid anti-cancer molecules has proven to be effective, e.g., as reported by Mendoza-Sanchez et al [8] who developed a bifunctional anti-proliferative 1 /estrogen receptor modulator ICI-164,384 compound active on both TNBC (MDA-MB-231) and estrogen receptor–positive (MCF-7) cells. VEGF is a renowned angiogenic growth factor that is recognized by a family of receptor tyrosine kinases, the VEGFRs, thereby promoting endothelial cell proliferation and migration [9].…”

Section: Introductionmentioning

confidence: 99%

Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells

Librizzi

Spencer

Luparello

2016

IJMS

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We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically synthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle analysis showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addition, the results suggest that the two distinct classes of compounds under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biological activities of target cells and also showing the hybrid compound as an additional promising drug-like molecule for the prevention or therapy of “aggressive” breast carcinoma.

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Section: Introductionmentioning

confidence: 99%

Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells

Librizzi

Spencer

Luparello

2016

IJMS

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“…These findings render hybrid 112 as interesting lead for further optimization to produce potent and safe therapeutic agent for breast cancer treatment. Also, Sanchez et al . developed antiestrogenic HDAC inhibitors based on the structure of ICI‐164,384 ( 113 ), which is an estradiol‐based pure antiestrogen that possesses a long alkyl chain attached to the core of estradiol.…”

Section: Design Of Dual Hdac/nuclear Receptors Targeting Agentsmentioning

confidence: 99%

“…These findings render hybrid 112 as interesting lead for further optimization to produce potent and safe therapeutic agent for breast cancer treatment. Also, Sanchez et al 104 developed antiestrogenic HDAC inhibitors based on the structure of ICI-164,384 (113), which is an estradiol-based pure antiestrogen that possesses a long alkyl chain attached to the core of estradiol. The work group used this (113) negative cell lines rendering it good idea that requires more SAR studies and more in vivo investigations to develop agents that are able to circumvent breast cancer resistance.…”

Section: Design Of Dual Estrogen Receptors/hdac Inhibitorsmentioning

confidence: 99%

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Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Hesham

Lasheen

Abouzid

2018

Medicinal Research Reviews

120

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Recently, molecular hybridization paradigm became an interesting and smart way to defeat the multifaceted cancer disease by a single molecular entity that acts via several mechanisms just like a magic bullet. Also, HDAC is an important epigenetic target in drug discovery, and the HDAC inhibitors showed successful pattern as cytotoxic agents. Because of their flexible structure activity relationship, it was easy to link them to other anticancer scaffolds. So, many dual action HDAC inhibitors have been developed and most of these hybrids have higher potency than the constituting parents in fighting of the cancer cells. This review describes potential applications of chimeric HDAC inhibitors, which simultaneously modulate not only HDAC but also multiple targets, in treatment of relapsing and drug-resistant cancers. We have nearly collected most of the reported dual action HDAC inhibitors yet to provide a comprehensive guide for the drug discovery process for developing more efficient anticancer agents.

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“…Mendoza-Sanchez et al 62 outlined the fusion of antiestrogens with known HDACIs to obtain more effective antiproliferative isoform compounds for the treatment of breast cancer. The fused compound 6 had antiestrogenic and HDACI activity.…”

Section: (5)mentioning

confidence: 99%

Histone Deacetylase Inhibitors: A Prospect in Drug Discovery

Yadav¹,

Mishra²,

Yadav³

2019

tjps

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Kanser tedavisi tüm toplum için büyük bir kışkırtıcıdır ve ilaç keşfi alanında bir araştırma hattını izlemektedir. Bu nedenle, işlemeyen ilaç hedeflerini iyileştirme yeterliliğine sahip, tıbbi aktif bir ajan keşfetmek için hayati bir gereklilik vardır. Artan pragmatik kanıtlar, histon deasetilazların (HDAC) kanserin ilerleme aşamasında deasetilasyonu arttırarak ve malignite değişikliklerini tetikleyerek kapana kısıldığını ifade etmektedir. HDAC inhibitörleri, ilaç keşfi bağlamında terapötik bir hedef olarak HDAC biyolojisiyle ilgili kimyasal varlığı araştırmak için, çığır açıcı iskele ve ulaşılabilir bir anahtar sağlarlar. HDAC inhibitörünün gen ekpresyonu yoluyla, kanserli hücrelere sitotoksisiteyi ihtiyatlı bir şekilde aktarmak için anti-kanser bir madde olarak geliştirilmesi yaklaşan bir gerekliliktir. Bu derlemede HDAC enziminin temelleri, inhibitörleri ve terapötik sonuçları üzerinde durulmuştur. Anahtar kelimeler: Histon deasetilaz inhibitörleri, apopitoz, çoklu tedavi yaklaşımı, kanser Cancer is a provocative issue across the globe and treatment of uncontrolled cell growth follows a deep investigation in the field of drug discovery. Therefore, there is a crucial requirement for discovering an ingenious medicinally active agent that can amend idle drug targets. Increasing pragmatic evidence implies that histone deacetylases (HDACs) are trapped during cancer progression, which increases deacetylation and triggers changes in malignancy. They provide a groundbreaking scaffold and an attainable key for investigating chemical entity pertinent to HDAC biology as a therapeutic target in the drug discovery context. Due to gene expression, an impending requirement to prudently transfer cytotoxicity to cancerous cells, HDAC inhibitors may be developed as anticancer agents. The present review focuses on the basics of HDAC enzymes, their inhibitors, and therapeutic outcomes.

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Design, synthesis and evaluation of antiestrogen and histone deacetylase inhibitor molecular hybrids

Cited by 34 publications

References 73 publications

Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells

Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

Histone Deacetylase Inhibitors: A Prospect in Drug Discovery

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