RESUMO
Treatment of (ortho-trimethysilyl)aryl phenylsulfonates with a soluble fluoride source initiates a Truce-Smiles rearrangement leading to the formation of functionalized bi-aryls. This new carbon-carbon bond-forming reaction proceeds without recourse to transition metal catalysis, under mild reaction conditions and with good functional group compatibility.
RESUMO
Idoxifene is a novel selective estrogen (E2) receptor (ER) modulator that is currently in clinical development for the treatment of breast cancer. Compared to tamoxifen, idoxifene is metabolically more stable, with a higher relative binding affinity for the ER and reduced agonist activity on breast and uterine cells. Idoxifene also inhibits calmodulin, a calcium-binding protein that is involved in cell signal transduction pathways. In this study, the abilities of idoxifene and tamoxifen to antagonize E2-dependent MCF-7 xenograft growth in oophorectomized athymic mice were compared. The basis for idoxifene's antitumor activity was examined by comparing the effectiveness of the clinically used transisomer (referred to here as idoxifene) with its cis-isomer, which has a 50-fold lower relative binding affinity for ER than idoxifene but similar calmodulin-inhibitory activity. Changes in tumor cell proliferation, apoptosis, and ER-dependent protein expression were studied. Both idoxifene and tamoxifen significantly inhibited E2-dependent tumor growth, whereas cis-idoxifene had little effect. Withdrawal of E2 support induced significant tumor regression due to impaired cell proliferation (Ki-67 score, 9 versus 51% compared to E2 controls) and induction of apoptosis (3.6 versus 0.9% compared to E2 controls). Both anti-E2s inhibited cell proliferation and caused a significant 3-fold induction of apoptosis in E2 supported tumors after 1 week, which was maintained for 3 months with idoxifene (3.1 versus 0.48% compared to E2 controls) but decreased back to baseline in tumors treated with tamoxifen (0.69%). In contrast, cis-idoxifene had no effect on either cell proliferation or apoptosis. Both tamoxifen and idoxifene initially induced ER expression, whereas prolonged therapy with tamoxifen significantly reduced progesterone receptor levels. In conclusion, idoxifene resulted in similar inhibition of E2-dependent MCF-7 xenograft growth compared with tamoxifen, an effect that is mediated via ER rather than through calmodulin. Sustained induction of apoptosis may contribute to prolonged antagonism of E2-dependent growth, and it occurred to a greater extent following 3 months of idoxifene, compared to tamoxifen.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Hormonais/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Estradiol , Antagonistas de Estrogênios/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Receptores de Estrogênio/antagonistas & inibidores , Tamoxifeno/análogos & derivados , Adenocarcinoma/patologia , Animais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Antígeno Ki-67/análise , Camundongos , Camundongos Nus , Proteínas de Neoplasias/análise , Transplante de Neoplasias , Neoplasias Hormônio-Dependentes/patologia , Ovariectomia , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêuticoRESUMO
A novel diphosphate mimic, the 2,3,6-trifluoro-5-hydroxy-4-nitrophenoxy group (1), has been employed as the template in the solid-phase synthesis of novel farnesyl transferase inhibitors using the Mitsunobu reaction. The most potent inhibitor (farnesyloxy-5-hydroxy-2,3,6-trifluoro-4-nitrobenzene) displayed an IC50 of 6.3 microM versus farnesyl transferase.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , FarnesiltranstransferaseRESUMO
The drug tamoxifen shows evidence of genotoxicity, and induces liver tumours in rats. Covalent DNA adducts have been detected in the liver of rats treated with tamoxifen, and these arise through metabolism at the alpha-position to give an ester which reacts with DNA. (E)-1-(4-iodophenyl)-2-phenyl-1-[4-(2-pyrrolidinoethoxy)phenyl]-but-1-en e (idoxifene) is an analogue of tamoxifen in which formation of DNA adducts is greatly reduced; we could not detect any adducts in the DNA of cultured rat hepatocytes treated with 10 microM idoxifene, after analysis by the 32P-post-labelling method. The metabolite (Z)-4-(4-iodophenyl)-4-[4-(2-pyrrolidinoethoxy)phenyl]-3-phenyl-3-but en-2-ol (alpha-hydroxyidoxifene) gave adducts in rat hepatocytes, but far fewer than the corresponding tamoxifen metabolite. In human hepatocytes, neither idoxifene nor tamoxifen induced detectable levels of DNA adducts. We prepared the alpha-acetoxy ester of idoxifene as a model for the ultimate reactive metabolite formed in rat liver. It was less reactive than alpha-acetoxytamoxifen, as might be expected on mechanistic grounds. It reacted with DNA in the same way, to give adducts which were probably N2-alkyldeoxyguanosines, but to a lower extent. All these results indicate that idoxifene is much less genotoxic than tamoxifen, and should therefore be a safer drug.
Assuntos
Adutos de DNA/metabolismo , Antagonistas de Estrogênios/metabolismo , Fígado/metabolismo , Tamoxifeno/análogos & derivados , Animais , Feminino , Humanos , Ratos , Ratos Endogâmicos F344 , Tamoxifeno/metabolismoRESUMO
The monoterpenes limonene and perillyl alcohol are undergoing clinical evaluation in cancer patients. In this paper, we report the chemical synthesis, characterisation, and quantitation in patients' plasma of a novel human metabolite of limonene, which is identified as an isomer of perillic acid. The synthesis of R-perillic acid is also described, because previous reports on the activity of perillic acid against isoprenylation enzymes refer to the S-enantiomer, although it is the R-enantiomer which is the metabolite of R-limonene. The above monoterpenes, with several related compounds, were assayed for inhibitory activity towards the isoprenylation enzymes in rat brain cytosol. Although R- and S-limonene are only weak inhibitors of the isoprenylation enzymes, their major metabolites, perillic acid and perillyl alcohol, are more potent inhibitors, with IC50 values in the low mM range. The metabolites possess greater activity towards the geranylgeranyltransferase type I enzyme than farnesyltransferase, while the novel metabolite displays IC50 values similar to those of perillic acid suggesting that it may contribute to the in vivo activity of limonene.
Assuntos
Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Monoterpenos , Prenilação de Proteína/efeitos dos fármacos , Terpenos/metabolismo , Terpenos/farmacologia , Alquil e Aril Transferases/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Monoterpenos Cicloexânicos , Cicloexenos , Citosol/efeitos dos fármacos , Citosol/metabolismo , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase , Humanos , Técnicas In Vitro , Limoneno , Espectrometria de Massas , Proteínas do Tecido Nervoso/metabolismo , Ratos , Terpenos/sangueRESUMO
The drug tamoxifen shows evidence of genotoxicity, and induces liver tumors in rats. Covalent DNA adducts have been detected in the liver of rats treated with tamoxifen, and in rat hepatocytes in culture. These arise primarily from its metabolite alpha-hydroxytamoxifen, and may also arise, in part, from another metabolite, 4-hydroxytamoxifen. We have prepared two model compounds for the potential reactive metabolite formed from 4-hydroxytamoxifen in rat liver. One of these was its alpha-acetoxy ester. This was much more reactive than that from tamoxifen, and could not be isolated in pure form. It reacted with DNA in the same way that alpha-acetoxytamoxifen did, to give adducts which were isolated by hydrolysis and chromatography, and identified as alkyldeoxyguanosines. The second derivative was alpha, beta-dehydro-4-hydroxytamoxifen. This also reacts with DNA in vitro, to give the same products as those from alpha-acetoxy-4-hydroxytamoxifen. Reaction probably proceeds through the same resonance-stabilized carbocation in either case. However, when primary cultures of rat hepatocytes were treated with either 4-hydroxytamoxifen, 4,alpha-dihydroxytamoxifen, or alpha, beta-dehydro-4-hydroxytamoxifen at a concentration of 10 microM, no adducts could be detected in their DNA by the 32P-postlabeling technique. Similarly, no adducts could be found in the liver DNA of female Fischer F344 rats treated orally (at 0.12 mmol kg-1) with the same substances. If 4-hydroxytamoxifen is metabolized to 4, alpha-dihydroxytamoxifen in rat liver, then either this substance is not converted to reactive esters or they are rapidly detoxified.
Assuntos
Adutos de DNA/metabolismo , DNA/metabolismo , Antagonistas de Estrogênios/metabolismo , Fígado/metabolismo , Tamoxifeno/análogos & derivados , Animais , DNA/química , Adutos de DNA/análise , Antagonistas de Estrogênios/química , Feminino , Fígado/citologia , Ratos , Ratos Endogâmicos F344 , Tamoxifeno/química , Tamoxifeno/metabolismoRESUMO
Tamoxifen, a synthetic antiestrogen, is known for its antitumoral action in vivo; however, it is well accepted that many tamoxifen effects are elicited via estrogen receptor-independent routes. Previously, we reported that tamoxifen induces PKC translocation in fibroblasts. In the present study, we investigated the influence of tamoxifen, and several triphenylethylene derivatives, on protein kinase C (PKC) in MCF-7 human breast cancer cells. As measured by Western blot analysis, tamoxifen elicited isozyme-specific membrane association of PKC-epsilon, which was time-dependent (as early as 5 min post-treatment) and dose-dependent (5.0-20 microM). Tamoxifen did not influence translocation of alpha, beta, gamma, delta or zeta PKC isoforms. Structure-activity relationship studies demonstrated chemical requirements for PKC-epsilon translocation, with tamoxifen, 3-OH-tamoxifen and clomiphene being active. Compounds without the basic amino side chain, such as triphenylethylene, or minus a phenyl group, such as N,N-dimethyl-2-[(4-phenylmethyl)phenoxy]ethanamine, were not active. In vitro cell growth assays showed a correlation between agent-induced PKC-epsilon translocation and inhibition of cell growth. Exposure of cells to clomiphene resulted in apoptosis. Since PKC-epsilon has been associated with cell differentiation and cellular growth-related processes, the antiproliferative influence of tamoxifen on MCF-7 cells may be related to the interaction with PKC-epsilon.
Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/enzimologia , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C/metabolismo , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacocinética , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Humanos , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacocinética , Células Tumorais Cultivadas/enzimologiaRESUMO
Tamoxifen [(E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1, 2-diphenylbut-1-ene], a nonsteroidal antiestrogen, induces liver tumors in rats by a genotoxic mechanism. The mechanism of DNA adduct formation is believed to proceed via the formation of a reactive carbocation at the alpha-position from the alpha-hydroxylated metabolite. Molecular mechanics calculations [Kuramochi, H. (1996) J. Med. Chem. 39, 2877-2886] have predicted that 4-substitution will affect the stability of the carbocation and thus will alter its reactivity toward DNA. We have synthesized the putative alpha-hydroxylated metabolites of 4-hydroxytamoxifen [(E)-1-(4-(2-(N, N-dimethylamino)ethoxy)phenyl)-1-(4-hydroxyphenyl)-3-hydroxy-2-phenyl but-1-ene] and idoxifene [(Z)-1-(4-iodophenyl)-3-hydroxy-2-phenyl-1-(4-(2-(N-pyrrolidino) ethoxy)phenyl)but-1-ene] and compared their reactivities with DNA with that of alpha-hydroxytamoxifen [(E)-1-(4-(2-(N, N-dimethylamino)ethoxy)phenyl)-3-hydroxy-1,2-diphenylbut-1-ene]. As predicted, the bis-hydroxylated compound reacted with DNA in aqueous solution at pH 5 to give 12-fold greater levels of adducts than alpha-hydroxytamoxifen, whereas alpha-hydroxyidoxifene gave one-half the number of adducts. The results demonstrate that idoxifene presents a significantly lower genotoxic hazard than tamoxifen for the treatment and prophylaxis of breast cancer.
Assuntos
Antineoplásicos Hormonais/química , Adutos de DNA/química , Antagonistas de Estrogênios/química , Tamoxifeno/análogos & derivados , Tamoxifeno/químicaRESUMO
Linkage of specific residues onto steroidal estrogens through a long aliphatic side chain leads to "pure antiestrogens" devoid of residual estrogenic activity. Therefore, we assessed whether an increase in the length of the side chain of the triphenylethylenic antiestrogen idoxifene might increase its antagonistic potency. Culture of MCF-7 and tamoxifen-resistant variant RTX6 cells in the presence of CB 7675, a (CH2)8 derivative of idoxifene [(CH2)2], ruled out this possibility. This compound partly blocked MCF-7 cell growth only at 10(-6) M to almost the same extent as tamoxifen and failed to inhibit the growth of RTX6 cells, whereas the pure antiestrogen RU 58 668 was effective on both cell lines at much lower concentration. This absence of improvement was reflected in the observation of an efficiency for down-regulating progesterone receptor no better than that of tamoxifen. Pure antiestrogens are known to down-regulate the estrogen receptor, whereas triphenylethylenic antiestrogens up-regulate the receptor; CB 7675 behaves as the latter in agreement with its lack of strong antagonistic activity.
Assuntos
Neoplasias da Mama/patologia , Antagonistas de Estrogênios/farmacologia , Tamoxifeno/análogos & derivados , Divisão Celular/efeitos dos fármacos , Feminino , Humanos , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Progesterona/efeitos dos fármacos , Relação Estrutura-Atividade , Tamoxifeno/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
The drug tamoxifen shows evidence of genotoxicity and induces liver tumours in rats. Covalent DNA adducts have been detected in the liver of rats treated with tamoxifen and these arise, at least in part, from its metabolite alpha-hydroxytamoxifen. This probably undergoes conjugation in the liver tissue to give an ester, which alkylates DNA. We have prepared alpha-acetoxytamoxifen as a model for this reactive intermediate and studied its reaction with DNA in vitro. The products of this reaction were chromatographically identical to DNA adducts found in the liver of rats treated with tamoxifen. We have isolated three of these products as the nucleosides TG1, TG2 and TA1 and identified them by ultraviolet, mass and proton magnetic resonance spectroscopy. TG1 and TG2 were tamoxifen-deoxyguanosine adducts in which the alpha-position of tamoxifen was linked to the amino group of guanine; TG1, (E)-4-[4-[2-(dimethylamino)ethoxy]phenyl]-3,4-diphenyl-2-(9beta-de oxyribofuranosyl-6-oxopurin-2-ylamino)-3-butene; TG2, (Z) isomer of TG1. In TG2, the tamoxifen group had undergone trans-cis isomerization. The minor product TA1 was a tamoxifen-deoxyadenosine adduct, where linkage was through the amino group of adenine: (E)-4-[4-[2-(dimethylamino) ethoxy]phenyl]-3,4-diphenyl-2-(9beta-deoxyribofuranosylpurin -6-ylamino)-3-butene. These three adducts accounted for >90% of the reaction products (approximately 67% TG1, 18% TG2 and 7% TA1); trace products included other stereoisomers of these and dinucleotide adducts which resisted enzymatic digestion.
Assuntos
Carcinógenos/metabolismo , Adutos de DNA/análise , DNA/efeitos dos fármacos , Tamoxifeno/análogos & derivados , Animais , Biotransformação , Carcinógenos/efeitos adversos , Fígado/química , Fígado/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Proteína 2 Glutamina gama-Glutamiltransferase , Ratos , Espectrofotometria Ultravioleta , Tamoxifeno/efeitos adversos , Tamoxifeno/análise , Tamoxifeno/metabolismoRESUMO
A series of homologs of idoxifene [1a, (E)-1-[4-(N-pyrrolidinoethoxy)phenyl]-1-(4-iodophenyl)-2-phenyl-1-butene ] and selected homologs of 4-iodotamoxifen [2a,(E)-1-[4-(N-dimethylamino)-ethoxy]phenyl]-1-(4-iodophenyl)-2-phenyl -1-butene] with the side chain (CH(2))(n) varying in length from n=3 (1b,2b) to n=10(1i,2i) have been synthesized and tested for antagonism of of the calmodulin-dependent activity of cAMP phosphodiesterase and for binding affinity to rat uterine estrogen receptor. Compared with 1a (IC(50) =1.5 microM), the homologs showed a progressive increase in calmodulin antagonism with a maximum inhibition at n=7-9 (1f-h)(IC(50)=0.2 microM), declining at n=10 (1i) to IC(50) =1.6 microM. In the pyrrolidino series, estrogen receptor binding affinity peaked at n=3 (1b, RBA= 23; estradiol = 100), declining by n=10 (1i) to RBA = 0.4, but the homolog n=8 (1g, RBA = 3.5) was still comparable to tamoxifen (RBA = 3.9). A similar pattern of activity was seen for the dimethylamino counterparts. These compounds represent a new class of antiestrogens with potent calmodulin antagonism.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Calmodulina/antagonistas & inibidores , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/metabolismo , Receptores de Estrogênio/metabolismo , Tamoxifeno/análogos & derivados , Tamoxifeno/síntese química , Animais , Ligação Competitiva , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1 , Citosol/metabolismo , Dietilestilbestrol/farmacologia , Estradiol/metabolismo , Antagonistas de Estrogênios/farmacologia , Feminino , Cinética , Estrutura Molecular , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Tamoxifeno/química , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia , Útero/metabolismoRESUMO
The metabolic activation of tamoxifen and its metabolite alpha-hydroxytamoxifen in primary cultures of rat, mouse and human hepatocytes has been compared. The extent of formation of DNA adducts in these cells was measured by 32P-postlabelling, using either nuclease P1 digestion or sorbent extraction of DNA digests to enhance the sensitivity of the assay. DNA adducts were readily detected in rat hepatocytes treated with 1 or 10 microM tamoxifen (mean levels 18.2 and 89.8 adducts/10(8) nucleotides respectively). Similar levels of adducts were formed by mouse hepatocytes (15.0 +/- 1.8 adducts/10(8) nucleotides, 10 microM tamoxifen). However DNA adducts were not detected in tamoxifen-treated human hepatocytes with a detection limit for the assay of 4 adducts/10(10) nucleotides. Treatment of rat cells with alpha-hydroxytamoxifen resulted in 15- to 63-fold higher levels of adducts than with comparable concentrations of tamoxifen. A similar level of adducts was also seen in mouse hepatocytes treated with alpha-hydroxytamoxifen at the 1 microM concentration (173.9 +/- 4.1 adducts/10(8) nucleotides). Treatment of human cells with alpha-hydroxytamoxifen resulted in DNA adduct formation at levels (1.94 +/- 0.89 and 18.9 +/- 17.9 adducts/10(8) nucleotides at 1 and 10 microM respectively) approximately 300-fold lower than those in rat hepatocytes. The presence of alpha-hydroxytamoxifen in the culture medium from experiments where cells were incubated with tamoxifen was monitored by mass spectrometry. Concentrations were found to be approximately 50-fold lower in the medium from human hepatocytes than from rat and mouse hepatocytes.
Assuntos
Adutos de DNA/metabolismo , Antagonistas de Estrogênios/metabolismo , Fígado/metabolismo , Tamoxifeno/metabolismo , Adolescente , Adulto , Animais , Biotransformação , Criança , Feminino , Humanos , Fígado/citologia , Masculino , Camundongos , Pessoa de Meia-Idade , Ratos , Ratos Endogâmicos F344 , Especificidade da EspécieRESUMO
The antiestrogenic drug tamoxifen induces liver tumors in rats by a genotoxic mechanism. The key step has been proposed to be the formation of a reactive carbocation from the metabolite alpha-hydroxytamoxifen. This compound reacts with DNA in vitro to a small extent (1 in 10(5) DNA bases), giving products identical to those found in rat liver cells treated with tamoxifen. Now we have prepared the more reactive alpha-acetoxytamoxifen, which reacts with DNA in vitro to a much greater extent (1 in 50 bases). The products of this reaction were subjected to 32P postlabeling and shown by both TLC and reverse-phase liquid chromatography to be identical to those isolated from DNA treated with alpha-hydroxytamoxifen and to those found in the liver DNA of rat hepatocytes treated with tamoxifen or of the livers of rats treated with tamoxifen. The major product was also isolated as the nucleoside and characterized by UV, mass, and proton magnetic resonance spectroscopy. It is an adduct of tamoxifen and deoxyguanosine in which the alpha position of tamoxifen is linked covalently to the exocyclic amino group of deoxyguanosine.
Assuntos
Antineoplásicos Hormonais/farmacologia , Adutos de DNA/metabolismo , DNA/metabolismo , Desoxiguanosina/metabolismo , Fígado/metabolismo , Tamoxifeno/farmacologia , Animais , Antineoplásicos Hormonais/metabolismo , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Ratos , Tamoxifeno/metabolismoRESUMO
A variety of analogues of tamoxifen were tested for inhibition of protein kinase C (PKC) activity in MCF-7 breast cancer cells. These results were compared with the calmodulin antagonism exhibited by the analogues as measured by inhibition of calmodulin-dependent cyclic AMP phosphodiesterase. The same structural features that enhanced PKC inhibition also led to an increase in calmodulin antagonism, namely 4-iodination and elongation of the basic side-chain. The most potent analogue has a 4-iodine substituent and eight carbon atoms in its basic side-chain with IC50 values of 38 microM for PKC inhibition and 0.3 microM for calmodulin antagonism, which compares with 92 and 6.8 microM, respectively, for tamoxifen. Some selectivity was achieved with a ring-fused analogue that retained the potency of tamoxifen as a PKC inhibitor, but lacked calmodulin antagonism.
Assuntos
Calmodulina/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Tamoxifeno/farmacologia , Humanos , Ligação de Hidrogênio , Relação Estrutura-Atividade , Tamoxifeno/análogos & derivados , Tamoxifeno/química , Células Tumorais CultivadasRESUMO
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.