Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer

Yadav, Mange Ram; Barmade, Mahesh A.; Tamboli, Riyaj S.; Murumkar, Prashant R.

doi:10.1016/j.ejmech.2015.09.038

Cited by 60 publications

(31 citation statements)

References 231 publications

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“…[1] Breast cancer is at ype of malignant tumor that affects, with overwhelming incidence, young women.Its high mortality rate is due in large part to the development of resistance against chemotherapeutics. [2] In fact, breast cancer in younger women is often characterized by aggressive tumor subtypes that are less likely to be amenable to treatment at the time of diagnosis, resulting in poorer survival outcomes than for older women. [3,4] Therefore, the poor response to chemotherapy and the adverse effects of treatments in current use is driving the search forn ew chemopreventive agents that are able to eradicate the cancer, with fewer undesirable side effects.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Human Topoisomerase II by N,N,N‐Trimethylethanammonium Iodide Alkylcarbazole Derivatives

et al. 2018

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Chemotherapy is used for the treatment of all stages of breast cancer, including the metastatic stage of the disease. Treatment regimens are generally tailored for each patient′s particular situation. However, chemotherapeutic agents are the leading cause of serious drug‐related adverse effects; moreover, drug resistance often occurs. In this study, we designed and synthesized a new series of N‐alkylcarbazoles derived from ellipticine, an alkaloid with a carbazole skeleton initially used in the treatment of metastatic breast cancer and later dismissed because of poor aqueous solubility and severe side effects. After evaluating the binding modes of our class of newly synthesized compounds with human topoisomerase II (hTopo II), we performed hTopo II decatenation assays, identifying compound 4 f (2‐(4‐((3‐chloro‐9H‐carbazol‐9‐yl)pentyl)piperazin‐1‐yl)‐N,N,N‐trimethylethanammonium iodide) as a good inhibitor. Moreover, 4 f and 4 g (2‐(4‐((3‐chloro‐9H‐carbazol‐9‐yl)hexyl)piperazin‐1‐yl)‐N,N,N‐trimethylethanammonium iodide) showed a good anti‐proliferative activity toward breast cancer cells, causing apoptosis by activation of the caspase pathway. Interestingly, the activity of these two compounds on triple‐negative MDA‐MB‐231 cells, which tend to be highly metastatic and aggressive, is strictly connected to the observed inhibition of hTopo II.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Human Topoisomerase II by N,N,N‐Trimethylethanammonium Iodide Alkylcarbazole Derivatives

et al. 2018

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“…medicinal chemistry and QSAR work) in the quest of novel and potent aromatase inhibitors, there has been only a few review articles on the topic (Adhikari et al 2017[2]; Yadav et al 2015[106]). Briefly, Yadav et al (2015[106]) carried out a review focusing on molecular modeling as well as QSAR of steroidal AIs whereas Adhikari et al (2017[2]) based their review on QSAR studies of non-steroidal AIs. Herein, we have performed an extensive review on the mechanistic insights of pertinent features as derived from all previous QSAR models of both steroidal and non-steroidal AIs.…”

Section: Resultsmentioning

confidence: 99%

Towards understanding aromatase inhibitory activity via QSAR modeling

Shoombuatong

Schaduangrat

Nantasenamat

2018

EXCLI Journal; 17:Doc688; ISSN 1611-2156

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“…CYP19A1 is involved in GC biosynthesis and catalyzes the conversion of androgen to estrogen in mammalian tissues (Yadav et al , ). Anastrozole, letrozole exemestane and some others are known inhibitors of CYP19A1 (Ronny et al , ).…”

Section: Discussionmentioning

confidence: 99%

“…Anastrozole, letrozole exemestane and some others are known inhibitors of CYP19A1 (Ronny et al , ). These inhibitors are used in the treatment of breast cancer and ovarian cancer in postmenopausal women and gynecomastia in men as aromatase inhibitors (Shulman et al , ; Ronny et al , ; Yadav et al , ). Besides, many other xenobiotics are shown to inhibit the CYP19A1 such as phytoestrogens (Lephart, ) and other natural as well as synthetic chemicals to cause altered GC biosynthesis (Odermatt et al , ).…”

Section: Discussionmentioning

confidence: 99%

Molecular docking reveals the potential of phthalate esters to inhibit the enzymes of the glucocorticoid biosynthesis pathway

et al. 2016

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Glucocorticoids (GCs) are well known to exert broad-based effects on metabolism, behavior and immunity. Their impaired synthesis and production lead to adverse health effects. Some environmental toxicants, including phthalate esters (PAEs), are associated with endocrine disruption. These endocrine-disrupting chemicals (EDCs) also cause adrenal toxicity and alteration of GC biosynthesis and their functions. Using in silico tools of Schrodinger Maestro 9.4, we performed a molecular docking study of 32 ligands including PAEs of a known endocrine-disrupting potential with the selected enzymes of the GC biosynthesis pathway (GBP) such as CYP11A1, CYP11B2, CYP19A1, CYP17A1, CYP21A2 and 3α/20β-HSD. Binding affinities of the PAEs were compared with known inhibitors of these enzymes. Amongst PAEs, diphenyl benzene-1, 2 - dicarboxylate (DPhP) showed the lowest docking score of -8.95616 kcal mol against CYP21A1. Besides, benzyl butyl benzene-1,2-dicarboxylate (BBzP), bis(7-methylnonyl) benzene-1,2 dicarboxylate (DIDP) and bis(2-ethylhexyl) benzene-1,2-dicarboxylate (DEHP) also showed comparable molecular interaction with enzymes of GBP. DPhP showed a significant molecular interaction with different enzymes of GBP such as CYP21A1, CYP11A1 and CYP11B2. These interactions mainly included H-bonding, hydrophobic, polar and van dar Waals' interactions. Interestingly, this in silico study revealed that certain PAEs have more inhibitory potential against enzymes of GBP than their respective known inhibitors. Such studies become more relevant in the risk assessment of exposure to mixtures of phthalate eaters. Copyright © 2016 John Wiley & Sons, Ltd.

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Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer

Cited by 60 publications

References 231 publications

Inhibition of Human Topoisomerase II by N,N,N‐Trimethylethanammonium Iodide Alkylcarbazole Derivatives

Inhibition of Human Topoisomerase II by N,N,N‐Trimethylethanammonium Iodide Alkylcarbazole Derivatives

Towards understanding aromatase inhibitory activity via QSAR modeling

Molecular docking reveals the potential of phthalate esters to inhibit the enzymes of the glucocorticoid biosynthesis pathway

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