A5042775164- Estrogen and related hormone effects
- Prostate Cancer Treatment and Research
- Hormonal and reproductive studies
- Retinoids in leukemia and cellular processes
- Steroid Chemistry and Biochemistry
- Cytokine Signaling Pathways and Interactions
- Pharmacogenetics and Drug Metabolism
- Cancer-related gene regulation
- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Cancer, Lipids, and Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Sexual Differentiation and Disorders
- Inflammatory mediators and NSAID effects
- Adenosine and Purinergic Signaling
- Nuclear Receptors and Signaling
- Synthesis and Catalytic Reactions
- Antioxidant Activity and Oxidative Stress
- Computational Drug Discovery Methods
- Plant biochemistry and biosynthesis
- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- Cancer therapeutics and mechanisms
University of Maryland, Baltimore
2015-2025
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
2015-2025
University of Maryland, Baltimore County
2025
Sidney Kimmel Comprehensive Cancer Center
2020-2025
U-M Rogel Cancer Center
2008-2018
University of Baltimore
2007-2016
University of Mary
2007-2016
Thomas Jefferson University
2009-2015
Sidney Kimmel Cancer Center
2010-2015
Jefferson College
2010
In our effort to discover potent and specific inhibitors of 17α-hydroxylase/17,20-lyase (CYP17), the key enzyme which catalyzes biosynthesis androgens from progestins, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Galeterone or TOK-001, formerly called VN/124-1) was identified as a selective development candidate modulates multiple targets in androgen receptor (AR) signaling pathway. This drug annotation summarizes mechanisms action, scientific rationale, medicinal chemistry,...
New chemical entities, steroidal C-17 benzoazoles (5, 6, 9 and 10) pyrazines (14 15) were rationally designed synthesized. The key reaction for synthesis of the involved nucleophilic vinylic "addition−elimination" substitution 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) benzoazole nucleophiles, while that palladium-catalyzed cross-coupling 17-iodoandrosta-5,16-dien-3β-ol (13) with tributylstannyl diazines. Some compounds shown to be potent inhibitors human CYP17 enzyme as well...
Because cancer is a complex disease, it unlikely that single mono functional 'targeted' drug will be effective for treating this most advanced disease. Combined drugs impact multiple targets simultaneously are better at controlling disease systems, less prone to resistance and the standard of care in treatment. In order improve efficiency using two-drug cocktail, one approach involves use so-called hybrid drugs, which comprises incorporation two molecule with intention exerting dual...
// Andrew K. Kwegyir-Afful 1, 2 , Senthilmurugan Ramalingam Puranik Purushottamachar Vidya P. Ramamurthy Vincent C.O. Njar 2, 3 1 Department of Pharmacology, University Maryland School Medicine, Baltimore, MD 21201-1559, USA Center for Biomolecular Therapeutics, Marlene Stewart Greenebaum Cancer Center, Correspondence to: Njar, e-mail: vnjar@som.umaryland.edu Keywords: prostate cancer, androgen receptors (AR/AR-V7), galeterone (gal), gal’s analog VNPT55, mechanisms AR/AR-V7 degradation...
Abstract We previously reported that our novel compound 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17α-hydroxylase/17,20-lyase (CYP17) inhibitor/antiandrogen and strongly inhibits the formation proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice. In this study, we report VN/124-1 other CYP17 inhibitors also cause down-regulation androgen receptor (AR) protein expression vitro vivo. This mechanism action...
As part of our program to explore the influence small structural modifications drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on modulation androgen receptor (AR), we have prepared and evaluated a series novel C-3, C-16, C-17 analogues. Using structure activity analysis, established that benzimidazole moiety at is essential optimal also hydrophilic heteroaromatic groups C-3 enhance both antiproliferative (AP) AR degrading (ARD) activities. The most...
Abstract Cancer stem cells (CSCs) virtually present in all tumors albeit small numbers are primarily responsible for driving cancer progression, metastasis, drug resistance, and recurrence. Prostate (PCa) is the second most frequent men worldwide, castration resistant prostate (CRPC) remains a major challenge despite tremendous advancements medicine. Currently, none of available treatment options effective treating CRPC. We earlier reported that VNPP433‐3β, lead next‐generation galeterone...
A new synthetic route to a variety of novel delta 16-17-azolyl steroids is described: it involves the nucleophilic vinylic "addition-elimination" substitution reaction 3 beta-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and azolyl nucleophiles. Some these steroids, 6, 17, 19, 27-29, prepared in good overall yields, are very potent inhibitors human rat testicular P450(17) alpha. They shown be noncompetitive appear slow-binding The most compounds...
We have developed a procedure for the synthesis of N-hydroxy-N1-phenyloctanediamide (suberoylanilide hydroxamic acid (SAHA)), providing product in 79.8% yield. SAHA is potent inhibitor histone deacetylase, induces differentiation and/or apoptosis certain transformed cells culture, and suppressed growth human prostate cancer LNCaP PC-3 cell lines. The combination with other compounds inhibited proliferation additive fashion resulted synergistic inhibition.
Galantamine, a drug used to treat Alzheimer9s disease, is nicotinic allosteric potentiating ligand, and kynurenic acid (KYNA), neuroactive metabolite of the kynurenine pathway, an endogenous noncompetitive inhibitor α7* receptors (nAChRs) [the asterisk next nAChR subunit intended indicate that exact composition receptor not known (<i>Pharmacol Rev</i><b>51:</b>397–401, 1999)]. Here, possible interactions between KYNA galantamine at nAChRs were examined in vitro vivo. In presence tetrodotoxin...
// Senthilmurugan Ramalingam 1,2 , Lalji Gediya Andrew K. Kwegyir-Afful Vidya P. Ramamurthy Puranik Purushottamachar Hannah Mbatia and Vincent C. O. Njar 1,2,3 1 Department of Pharmacology, University Maryland School Medicine, Baltimore, MD, USA 2 Center for Biomolecular Therapeutics, 3 Marlene Stewart Greenebaum Cancer Center, Correspondence: C.O. Njar, email: Keywords : Breast cancer, RAMBA retinamides, eukaryotic initiation factor 4E, Mnk1/2. Received October 21, 2013 Accepted January 23,...
744 Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with limited treatment options. Dysregulated MAPK and PI3K signaling in PDAC activates the eukaryotic translational initiation complex, promoting cell growth, chemoresistance metastatic spread (PMID 25593033). Galeterone, novel steroidal anti-androgen, downregulates critical mediators of this complex including Mnk1/2 phosphorylated eIF4E, thereby blocking epithelial-to-mesenchymal transition NF-kB...
Cholesterol (CHOL) homeostasis is significantly modulated in prostate cancer (PCa) suggesting an active role PCa development and progression. Several studies indicate a strong correlation between elevated CHOL levels increased risk severity. Inhibition of biosynthesis at different steps, including lanosterol synthase (LSS), has shown significant efficacy against both hormone-dependent castration-resistant PCa. Earlier, we reported proteasomal degradation androgen receptor (AR)/AR-Vs Mnk1/2...
We report here a molecular modeling investigation of steroidal and nonsteroidal inhibitors human cytochrome P450 17alpha-hydroxylase-17,20-lyase (CYP17). Using the pharmacophore perception technique, we have generated common-feature model(s) to explain putative binding requirements for two classes CYP17 inhibitors. Common chemical features in steroid nonsteroid enzyme inhibitors, as deduced by Catalyst/HipHop program, are one hydrogen bond acceptors (HBAs) three hydrophobic groups. For...