Document Detail

Rationally designed analogues of tamoxifen with improved calmodulin antagonism.
MedLine Citation:
PMID:  7830266     Owner:  NLM     Status:  MEDLINE    
Computerized molecular modeling studies on the interactions of the antiestrogen tamoxifen (1) and its analogues bound to the calcium-binding protein calmodulin have guided the rational design of more potent antagonists. Compounds with either three or four methylene units in the basic side chain or slim lipophilic 4-substituents were expected to be more potent. All compounds were tested for antagonism of the calmodulin-dependent activity of cAMP phosphodiesterase and for binding affinity to the estrogen receptor from rat uteri. Some compounds were assayed for cytotoxicity against MCF-7 breast tumor cells in vitro. Introduction of lipophilic 4-substituents was accomplished by using palladium(0)-catalyzed coupling reactions with a 4-iodinated precursor. Both the 4-ethynyl (16 and 17) and 4-butyl (18 and 19) compounds were more potent calmodulin antagonists than tamoxifen. Extension of the basic aminoethoxy side chain of 4-iodotamoxifen (3) and idoxifene (2) ((E)-1-[4-[2-(N-pyrrolidino)ethoxy]phenyl]-1-(4-iodophenyl)-2-phen yl-1- butene) by one or two methylene units resulted in modest gains in calmodulin antagonism (10-13). All the compounds assayed retained estrogen receptor binding characteristics. The compound possessing the optimal combination of calmodulin antagonism and estrogen receptor binding was 12 ((E)-1-[4-[3-(N-pyrrolidino)propoxy]phenyl]-1-(4-iodophenyl)-2-phe nyl-1 - butene) (IC50 = 1.1 microM, RBA = 23). Correlation between calmodulin antagonism and cytotoxicity was demonstrated for selected compounds.
I R Hardcastle; M G Rowlands; J Houghton; I B Parr; G A Potter; M Jarman; K J Edwards; C A Laughton; J O Trent; S Neidle
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  38     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1995 Jan 
Date Detail:
Created Date:  1995-02-23     Completed Date:  1995-02-23     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  241-8     Citation Subset:  IM    
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, U.K.
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MeSH Terms
3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
Calmodulin / antagonists & inhibitors*
Cyclic Nucleotide Phosphodiesterases, Type 1
Drug Design
Models, Molecular
Structure-Activity Relationship
Tamoxifen / analogs & derivatives*,  chemistry
Reg. No./Substance:
0/Calmodulin; 10540-29-1/Tamoxifen; EC',5'-Cyclic-AMP Phosphodiesterases; EC Nucleotide Phosphodiesterases, Type 1

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