Document Detail

Meta-analysis of anticancer drug structures--significance of their polar allylic moieties.
MedLine Citation:
PMID:  17348828     Owner:  NLM     Status:  MEDLINE    
This meta-analysis examines a wide range of small molecule anticancer drugs to search for a structure common to all. Although they encompass a very wide range of structures, nearly all reveal the presence of an allylic O, N, or S atom. In some, the allylic oxygen is a carbonyl group, or an alcohol group, which can be substituted (ester, lactone, glycoside, ether) or replaced by an amino or imino nitrogen Some antineoplastic drugs do not exhibit this moiety but are converted in vivo to allylic derivatives. An allylic hydroxyl is also present in most sphingolipids, ubiquitous body components that control proliferative and anti-proliferative cell functions. Ceramide, the precursor of all the allylic sphingolipids, seems to be a general inducer of apoptosis in cancer cells. Further examination of sphingolipids and anticancer drugs shows the frequent occurrence of [i] double bonds conjugated to the allylic bond, (ii) two or more allylic moieties in each molecule, (iii) lipophilic features, especially linear chains, and (iv) attachment of an O, N, or S atom to a carbon atom of the allylic double bond, e.g., -CH(2)-C(OMe)=CH-CH(OH)-CH(2)-. Suggested mechanisms of action: (a) allylic ketone drugs undergo a Michael condensation with tumor thiols or other reactive groups; (b) allylic OH drugs undergo oxidation to an allylic ketone, generating reactive oxygen; (c) some interfere with mitochondrial ubiquinone, blocking ATP production; (d) some act as a ceramide mimic (inhibitor or agonist) in ceramide-controlled kinases, phosphatases, and proteases; (e) many antineoplastic drugs stimulate ceramide-forming processes.
Norman S Radin
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Publication Detail:
Type:  Journal Article; Meta-Analysis; Review    
Journal Detail:
Title:  Anti-cancer agents in medicinal chemistry     Volume:  7     ISSN:  1871-5206     ISO Abbreviation:  -     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-12     Completed Date:  2007-04-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101265649     Medline TA:  Anticancer Agents Med Chem     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  209-22     Citation Subset:  IM    
Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
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MeSH Terms
Antineoplastic Agents / chemistry*,  pharmacology*
Apoptosis / drug effects
Ceramides / chemical synthesis,  pharmacology
Structure-Activity Relationship
Reg. No./Substance:
0/Antineoplastic Agents; 0/Ceramides

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