Abstract:
:The reductive conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase (RR) is a crucial and rate-controlling step in the pathway leading to the biosynthesis of DNA, since deoxyribonucleotides are present in extremely low levels in mammalian cells. Mammalian ribonucleotide reductase (RR) is composed of two dissimilar proteins, often referred to as R(1), which contains polythiols and R(2), which contains non-heme iron and a free tyrosyl radical. Both the R(1) and R(2) subunits contribute to the active site of the enzyme. Currently, there are two broad classes of RR inhibitors. The first class includes nucleoside analogs which bind to the R1 subunit of the enzyme, several of which are in development. Among those, Gemcitabine and MDL 101,731 have demonstrated impressive efficacy against various solid tumors. Gemcitabine has now been approved for the treatment of pancreatic cancer and non-small cell lung cancer. The most promising second class of inhibitors of RR includes HCTs [alpha--(N)-heterocyclic carboxaldehyde thiosemicarbazones, e.g., 3-AP and 3-AMP], which exert enzyme inhibitory effect through high affinity binding with non-heme iron. Based on the clinical success achieved by Gemcitabine, it seems reasonable that a strong inhibitor of RR, which is essential for cellular replication, would be a useful addition to the existing therapeutic agents against cancer. In this chapter, we wish to report several highly efficient syntheses for both 3-AP and 3-AMP based upon palladium mediated Stille/Suzuki/Heck coupling reactions. Based upon the in vivo efficacy profile observed with these two agents, 3-AP was chosen over 3-AMP as the candidate for further optimization with the intention to improve its biological and pharmaceutical properties. In this vein, we have completed the synthesis of two water soluble phosphate containing prodrugs and one disulfide-linked prodrug of 3-AP. As expected, bioconversion study using either alkaline phosphatase or glutathione showed that these prodrugs were indeed converted to the parent 3-AP. When evaluated against the murine M-109 lung carcinoma as well as the B16-F10 murine melanoma xenograft models, the newly prepared phosphate prodrugs displayed improved efficacy and safety profiles than that found with the parent. More significantly, the ortho-phosphate prodrug 21 demonstrated impressive antitumor effect using once-a-day dosing regimen. In summary, the results disclosed herein demonstrated that some of 3-AP prodrugs prepared indeed demonstrated improved pharmaceutical, biological and toxicity profiles over the parent 3-AP. Efforts directed towards further optimization of 3-AP prodrugs as novel anticancer agents is clearly warranted.
journal_name
Curr Med Chemjournal_title
Current medicinal chemistryauthors
Li J,Zheng LM,King I,Doyle TW,Chen SHdoi
10.2174/0929867013373741subject
Has Abstractpub_date
2001-02-01 00:00:00pages
121-33issue
2eissn
0929-8673issn
1875-533Xjournal_volume
8pub_type
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journal_title:Current medicinal chemistry
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journal_title:Current medicinal chemistry
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更新日期:2010-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2012-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2014-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2020-08-10 00:00:00
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journal_title:Current medicinal chemistry
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journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
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更新日期:2006-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2008-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2016-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2012-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2011-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2018-01-01 00:00:00
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journal_title:Current medicinal chemistry
pub_type: 杂志文章,评审
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更新日期:2009-01-01 00:00:00
abstract:BACKGROUND:Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, with an incidence of 3.19 cases per 100,000 person years and remarkably poor prognosis showing a 5-year survival rate of 4-5%, and only a 26-33% survival rate at 2 years in clinical trials. OBJECTIVE:In this paper, we review the...
journal_title:Current medicinal chemistry
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doi:10.2174/0929867324666170516123206
更新日期:2017-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2018-01-01 00:00:00
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更新日期:2001-04-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2010-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2016-01-01 00:00:00
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更新日期:2013-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:1999-02-01 00:00:00
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更新日期:2013-01-01 00:00:00
abstract::Pyoverdine is the generic name given to a vast family of fluorescent green-yellowish pigments produced by Pseudomonas species. Pseudomonas aeruginosa is an opportunistic pathogen, particularly infecting humans with compromised natural defenses. These infections result in significantly higher morbidity, longer hospital...
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更新日期:2015-01-01 00:00:00
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更新日期:2005-01-01 00:00:00
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journal_title:Current medicinal chemistry
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更新日期:2019-01-01 00:00:00
abstract:BACKGROUND:Cholesterol efflux as a key event in reverse cholesterol transport (RCT) is considered now as both diagnostic tool and a promising target for the treatment of atherosclerosis. Radioactive in vitro cholesterol efflux assay (CEA) is the gold standard for determination of efflux at cellular level. Fluorescent t...
journal_title:Current medicinal chemistry
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更新日期:2016-01-01 00:00:00