Abstract：
:In an attempt to better understand the role of the cyclohexene ring (ring A) in the biochemical and pharmacological properties of anthracyclines related to doxorubicin and daunorubicin, we investigated the effects of introduction of a fluorine atom at position 8 of idarubicin (4-demethoxydaunorubicin) on drug molecular conformation and biochemical and pharmacological activities. The study showed that the stereochemistry of the substituent at position 8 influenced the "half-chair" conformation, so that in the (8R)-fluoroepimer the A ring retained the alpha half-chair conformation, which is the most stable for natural compounds (i.e., daunorubicin and doxorubicin), and the (8S)-fluoroepimers preferred the beta half-chair conformation. The (8R)-fluoroepimer was more effective than the (8S)-fluoroepimer and idarubicin in stimulating topoisomerase II-mediated DNA cleavage. Similarly, the epimer with the alpha conformation was markedly more potent than the (8S)-epimer as a cytotoxic agent in a variety of human tumor cell lines and was more effective as an antitumor agent in the treatment of an ovarian carcinoma xenograft. In addition, 8-fluoro derivatives were able to overcome the resistance to doxorubicin in a number of human tumor cell lines expressing different mechanisms of resistance. In conclusion, these findings provide evidence that drug interactions involving the external (nonintercalating) moiety of the anthracycline chromophore play an important role in determining pharmacological properties, including drug ability to induce DNA cleavage, and therefore their antitumor efficacy.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Animati F,Arcamone F,Bigioni M,Capranico G,Caserini C,De Cesare M,Lombardi P,Pratesi G,Salvatore C,Supino R,Zunino Fsubject
Has Abstractpub_date
1996-09-01 00:00:00pages
603-9issue
3eissn
0026-895Xissn
1521-0111journal_volume
50pub_type
杂志文章abstract：:Although ATP-sensitive K+ channels continue to be explored for their therapeutic potential, developments in high-affinity radioligands to investigate native and recombinant KATP channels have been less forthcoming. This study reports the identification and pharmacological characterization of a novel iodinated 1,4-dihy...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.64.1.143
更新日期：2003-07-01 00:00:00
abstract：:Fusion proteins were generated between the human 5-hydroxytryptamine (5-HT)(1A) receptor and both wild-type (Cys(351)) and pertussis toxin-resistant (Gly(351) and Ile(351)) forms of G(i1). These were expressed stably. Pertussis toxin treatment substantially reduced basal high-affinity GTPase activity in clones express...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1999-10-01 00:00:00
abstract：:The tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a vascular endothelial growth factor (VEGF) receptor-2 antagonist, has been used previously either alone or in combination with chemotherapeutic drugs for treating colorectal cancer in a mouse model. We analyzed the half-life of the peptide and found that because of degradation...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.119.117234
更新日期：2019-12-01 00:00:00
abstract：:The insecticide imidacloprid and structurally related neonicotinoids act selectively on insect nicotinic acetylcholine receptors (nAChRs). To investigate the mechanism of neonicotinoid selectivity, we have examined the effects of mutations to basic amino acid residues in loop D of the nAChR acetylcholine (ACh) binding...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.106.026815
更新日期：2006-10-01 00:00:00
abstract：:Studies of the biochemical mechanisms evoked by conventional treatments for neoplastic diseases point to apoptosis as a key process for elimination of unwanted cells. Although the pathways through which chemotherapeutics promote cell death remain largely unknown, caspase proteases play a central role in the induction ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.53.3.446
更新日期：1998-03-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.59.5.1249
更新日期：2001-05-01 00:00:00
abstract：:The liver is the only solid organ that can respond to major tissue loss or damage by regeneration to restore liver biomass. The aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt the regenerative process, as evidenced by suppression of DNA synthesis in rat primary hepatocyte...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.002410
更新日期：2005-01-01 00:00:00
abstract：:Cultured murine hepatoma 1c1c7 cells were treated with either the actin filament-disrupting drug cytochalasin D or the microtubule inhibitors colchicine and nocadazole (NOC) to assess the role of the cytoskeleton in the process of cytochrome P450 Cyp1a-1 induction. Indirect fluorescence analyses demonstrated that micr...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-05-01 00:00:00
abstract：:Histone deacetylase inhibitors (HDACi), which have emerged as a new class of anticancer agents, act by modulating expression of genes controlling apoptosis or cell proliferation. Here, we compared the effect of HDACi on transcriptional activation by estrogen or glucocorticoid receptors (ER and GR, respectively), two m...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.014514
更新日期：2005-12-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-10-01 00:00:00
abstract：:Allosteric modulators of G-protein-coupled receptors can regulate conformational states involved in receptor activation ( Mol Pharmacol 58: 1412-1423, 2000 ). This hypothesis was investigated for the corticotropin-releasing factor type 1 (CRF(1)) receptor using a novel series of ligands with varying allosteric effect ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.042978
更新日期：2008-05-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-07-01 00:00:00
abstract：:Cytosolic liver acetyl-CoA:arylamine N-acetyltransferase (EC 2.3.1.5) from homozygous rapid acetylator rabbits (strain III/J) was purified to homogeneity as judged by gel filtration sodium dodecyl sulfate-polyacrylamide disc gel electrophoresis and isoelectrofocusing. The isoelectric point was estimated to be 5.2. The...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-04-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.58.3.649
更新日期：2000-09-01 00:00:00
abstract：:Thapsigargin is a specific inhibitor of the sarco/endoplasmic reticulum Ca(2+) ATPase of the endoplasmic reticulum. Here, we show that stimulation of human HaCaT keratinocytes with nanomolar concentrations of thapsigargin triggers expression of activating transcription factor (ATF) 3, a basic-region leucin zipper tran...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.110.067637
更新日期：2010-11-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.118.113977
更新日期：2019-08-01 00:00:00
abstract：:The antiherpetic agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was found to be an efficient substrate for recombinant Drosophila melanogaster-deoxyribonucleoside kinase with a K(m) of 4.5 microM and a V(max) of 400 nmol/microg protein/h compared with 1.3 microM and 62.5 nmol/microg protein/h, respectively, for the...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.57.4.811
更新日期：2000-04-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.005355
更新日期：2005-01-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.043273
更新日期：2008-06-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-02-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
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更新日期：2012-10-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：2001-10-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
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更新日期：2009-09-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-12-01 00:00:00
abstract：:Poly(A)+ RNA from mammalian retina expresses bicuculline/baclofen-insensitive gamma-aminobutyric acid (GABA) receptors in Xenopus oocytes with properties similar to those of homooligomeric GABA rho 1 receptors. The pharmacological profile of these rho-like receptors was extended by measuring sensitivities to various G...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-04-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.113.088096
更新日期：2013-11-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-11-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.001586
更新日期：2004-11-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.64.6.1309
更新日期：2003-12-01 00:00:00
abstract：:Two human ovarian cancer cell lines were established from a patient before (PEO1) and after (PEO4) the onset of resistance to 5-fluorouracil (5-FU)/cisplatin-based chemotherapy. Using growth inhibition assays, we determined that the PEO4 line was almost 5-fold more resistant to 5-FU than the PEO1 line. The addition of...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-09-01 00:00:00
