title: Rationally designed analogues of tamoxifen with improved calmodulin antagonism.
abstract: 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.
authors: CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, U.K.
authors: I R
authors: IR
authors: Hardcastle
authors: M G
authors: MG
authors: Rowlands
authors: J
authors: J
authors: Houghton
authors: I B
authors: IB
authors: Parr
authors: G A
authors: GA
authors: Potter
authors: M
authors: M
authors: Jarman
authors: K J
authors: KJ
authors: Edwards
authors: C A
authors: CA
authors: Laughton
authors: J O
authors: JO
authors: Trent
authors: S
authors: S
authors: Neidle
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D015195:Drug Design; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D002147:Calmodulin; D013629:Tamoxifen; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1