154287-26-0Relevant academic research and scientific papers
Rationally designed analogues of tamoxifen with improved calmodulin antagonism
Hardcastle,Rowlands,Houghton,Parr,Potter,Jarman,Edwards,Laughton,Trent,Neidle
, p. 241 - 248 (1995)
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-phenyl-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-phenyl-1-butene)(IC50 = 1.1 μM, RBA= 23). Correlation between calmodulin antagonism and cytotoxicity was demonstrated for selected compounds.
Substituted 1,1,2-triphenylbutenes and their use in the treatment of cancer
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, (2008/06/13)
Compounds of the general formula (2) STR1 wherein n is an integer of from 3 to 10, the iodo substituent is in the 3- or 4-position and R 1 and R 2, which may be the same or different, represent C 1-3 alkyl, especially methyl or ethyl, groups or R l represents a hydrogen atom and R 2 a C 1-3 alkyl group or R 1 and R 2 together with the nitrogen atom to which they are attached represent a saturated heterocyclic group, especially a pyrrolidino group, in the form of their free bases or pharmaceutically acceptable acid addition salts are potent anti-oestrogenic compounds useful for treatment of oestrogen-dependent cancers, especially breast cancers. Compounds where the iodine atom is radioisotopic are useful in radiotherapy or gamma ray imaging of these cancers.
