Abstract：
:The microtubule-binding taxanes, docetaxel and cabazitaxel, are administered intravenously for the treatment of castration-resistant prostate cancer (CRPC) as the oral administration of these drugs is largely hampered by their low and highly variable bioavailabilities. Using a simple, rapid, and environmentally friendly microwave-assisted protocol, we have synthesized a number of 3,5-bis(styryl)pyrazoles 2a-l, thus allowing for their screening for antiproliferative activity in the androgen-independent PC3 prostate cancer cell line. Surprisingly, two of these structurally simple 3,5-bis(styryl)pyrazoles (2a and 2l) had concentrations which gave 50% of the maximal inhibition of cell proliferation (GI50) in the low micromolar range in the PC3 cell line and were thus selected for extensive further biologic evaluation (apoptosis and cell cycle analysis, and effects on tubulin and microtubules). Our findings from these studies show that 3,5-bis[(1E)-2(2,6-dichlorophenyl)ethenyl]-1H-pyrazole 2l 1) caused significant effects on the cell cycle in PC3 cells, with the vast majority of treated cells in the G2/M phase (89%); 2) induces cell death in PC3 cells even after the removal of the compound; 3) binds to tubulin [dissociation constant (Kd) 0.4 ± 0.1 μM] and inhibits tubulin polymerization in vitro; 4) had no effect upon the polymerization of the bacterial cell division protein FtsZ (a homolog of tubulin); 5) is competitive with paclitaxel for binding to tubulin but not with vinblastine, crocin, or colchicine; and 6) leads to microtubule depolymerization in PC3 cells. Taken together, these results suggest that 3,5-bis(styryl)pyrazoles warrant further investigation as lead compounds for the treatment of CRPC. SIGNIFICANCE STATEMENT: The taxanes are important components of prostate cancer chemotherapy regimens, but their oral administration is hampered by very low and highly variable oral bioavailabilities resulting from their poor absorption, poor solubility, high first-pass metabolism, and efficient efflux by P-glycoprotein. New chemical entities for the treatment of prostate cancer are thus required, and we report here the synthesis and investigation of the mechanism of action of some bis(styryl)pyrazoles, demonstrating their potential as lead compounds for the treatment of prostate cancer.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Liao VWY,Kumari A,Narlawar R,Vignarajan S,Hibbs DE,Panda D,Groundwater PWdoi
10.1124/mol.119.118539subject
Has Abstractpub_date
2020-06-01 00:00:00pages
409-422issue
6eissn
0026-895Xissn
1521-0111pii
mol.119.118539journal_volume
97pub_type
杂志文章abstract：:Stromal cell-derived factor-1 (SDF-1/CXCL-12) and vascular endothelial growth factor (VEGF), which can be secreted by hypoxic tumors, promote the generation of new blood vessels. These potent angiogenic factors stimulate endothelial cell migration via the activation of Rho GTPases and the phosphatidylinositol 3-kinase...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.060400
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journal_title：Molecular pharmacology
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doi：10.1124/mol.107.042846
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-03-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-07-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.040014
更新日期：2008-03-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.110.068007
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journal_title：Molecular pharmacology
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doi：10.1124/mol.118.113530
更新日期：2018-12-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.66.1.97
更新日期：2004-07-01 00:00:00
abstract：:We describe here an approach to characterize various lesions induced in DNA by drug treatments, using three parameters: (a) release of single-stranded DNA fragments by cell lysis in dilute alkali, which result from enzymatic strand scission during DNA repair or chemical alterations of DNA; (b) the presence of high mol...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-07-01 00:00:00
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doi：10.1124/mol.64.3.721
更新日期：2003-09-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1999-10-01 00:00:00
abstract：:Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CY...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-10-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
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更新日期：2015-10-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.62.1.15
更新日期：2002-07-01 00:00:00
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pub_type： 杂志文章
doi：10.1124/mol.58.6.1326
更新日期：2000-12-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.116.104786
更新日期：2016-08-01 00:00:00
abstract：:Cell-penetrating peptides are amphipathic or cationic oligopeptides able to transport covalently attached cargoes across cell membranes. Peptide aptamers are polypeptide fragments of endogenous proteins that mimic and thus perturb interactions with other cellular proteins. Combining aptamer and CPP technology can gene...
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pub_type： 评论,杂志文章
doi：10.1124/mol.105.011429
更新日期：2005-04-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.56.6.1317
更新日期：1999-12-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1998-02-01 00:00:00
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journal_title：Molecular pharmacology
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doi：10.1124/mol.59.4.852
更新日期：2001-04-01 00:00:00
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.54.1.59
更新日期：1998-07-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.015750
更新日期：2005-11-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.4.906
更新日期：2004-04-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-07-01 00:00:00
abstract：:In the hippocampus, two distinct forms of GABAergic inhibition have been identified, phasic inhibitory postsynaptic currents that are the consequence of the vesicular release of GABA and a tonic conductance that is activated by low ambient concentrations of extracellular GABA. It is not known what accounts for the dis...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.63.1.2
更新日期：2003-01-01 00:00:00
abstract：:There is no approved means to prevent the toxic actions of cocaine. Cocaine esterase (CocE) is found in a rhodococcal strain of bacteria that grows in the rhizosphere soil around the coca plant and has been found to hydrolyze cocaine in vitro. The esteratic activity of CocE (0.1-1.0 mg, i.v.) was characterized and con...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.106.025999
更新日期：2006-12-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.62.3.638
更新日期：2002-09-01 00:00:00
abstract：:The gene encoding a human 5-hydroxytryptamine (5-HT)1 receptor subtype was isolated from a human placental genomic library by using oligonucleotide probes derived from transmembrane regions of the cloned human 5-HT1D beta receptor. The deduced amino acid sequence of the genomic clone hp75d is identical to that of the ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1992-08-01 00:00:00
abstract：:Iron is a biologically essential metal, but excess iron can cause damage to the cardiovascular and nervous systems. We examined the effects of extracellular Fe²⁺ on permeation and gating of Ca(V)3.1 channels stably transfected in HEK293 cells, by using whole-cell recording. Precautions were taken to maintain iron in t...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.080184
更新日期：2012-12-01 00:00:00
