RESUMO
Tamoxifen, a therapeutic agent for breast cancer, has been associated with genetic polymorphisms in the metabolism of N,N-dialkylaminoethyl substituent, which plays an important role in the expression of selective estrogen receptor modulator (SERM) activity. To solve this problem, we developed a novel estrogen receptor (ER) modulator, Az-01, on the basis of the aromaticity, dipole moment, and isopropyl group of guaiazulene. Az-01 showed four-fold lower binding affinity for ER than E2 but had similar ER-binding affinity to that of 4-hydroxytamoxifen (4-HOtam). Unlike tamoxifen, Az-01 acted as a partial agonist with very weak estrogenic activity at high concentrations when used alone, and it showed potent anti-estrogenic activity in the presence of E2. The cell proliferation and inhibition activities of Az-01 were specific to ER-expressing MCF-7 cells, and no effect of Az-01 on other cell proliferation signals was observed. These findings are important for the development of new types of SERMs without the N,N-dialkylaminoethyl substituent as a privileged functional group for SERMs.
Assuntos
Azulenos/síntese química , Neoplasias da Mama/metabolismo , Estradiol/farmacologia , Moduladores de Receptor Estrogênico/síntese química , Receptores de Estrogênio/metabolismo , Sesquiterpenos de Guaiano/química , Azulenos/química , Azulenos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenvolvimento de Medicamentos , Sinergismo Farmacológico , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Receptores de Estrogênio/química , Tamoxifeno/análogos & derivados , Tamoxifeno/química , Tamoxifeno/farmacologiaRESUMO
Androgen receptor (AR) has a key role in the development and progression of prostate cancer, and AR antagonists are used for its remedy. Recently, carborane derivatives, which are carbon-containing boron clusters have attracted attention as new AR ligands. Here we determined the force field parameters of 10-vertex and 12-vertex p-carborane to facilitate in silico drug design of boron clusters. Then, molecular dynamics (MD) simulations of complexes of AR-carborane derivatives were performed to evaluate the parameters and investigate the influences of carborane derivatives on the three-dimensional structure of AR. Energy profiles were obtained using quantum chemical calculations, and the force-field parameters were determined by curve fitting of the energy profiles. The results of MD simulations indicated that binding of the antagonist-BA341 changed some hydrogen-bond formations involved in the structure and location of helix 12. Those results were consistent with previously reported data. The determined parameters are also useful for refining the structure of the carborane-receptor complex obtained by docking simulations and development of new ligands with carborane cages not only for AR but also for various receptors.
Assuntos
Antagonistas de Receptores de Andrógenos/química , Compostos de Boro/química , Sistemas de Liberação de Medicamentos/métodos , Simulação de Dinâmica Molecular , Receptores Androgênicos/química , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/metabolismo , Compostos de Boro/administração & dosagem , Compostos de Boro/metabolismo , Estrutura Secundária de Proteína , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
Estrogen receptor (ER) exhibits two subtypes, ERα and ERß, whose biological functions are quite different despite expression in the same tissues. We developed diiodo-m-carborane derivative 3a, which showed 14-fold selectivity for ERß with high binding affinity toward ERß. Interestingly, introduction of an alkyl group into the carbon atom of the m-carborane cage of 3a markedly enhanced the binding affinity toward ERα and decreased affinity toward ERß. C-n-propyl derivative 3d showed 28-fold selectivity for ERα in an ER binding assay and promoted proliferation of MCF-7 breast cancer cells. Docking simulation studies suggest that the directions of the n-propyl group and the diiodo substituent introduced on the m-carborane cage play important roles for the control of ER subtype selectivity. As 3a and 3d showed ERß and ERα selectivity with high binding affinity, respectively, these ligands may be useful as biological tools to aid in understanding the different roles of ER subtypes.
Assuntos
Boranos/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/antagonistas & inibidores , Fenóis/farmacologia , Antineoplásicos , Sítios de Ligação/efeitos dos fármacos , Boranos/síntese química , Boranos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Receptor beta de Estrogênio/metabolismo , Humanos , Ligantes , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Relação Estrutura-AtividadeRESUMO
m-Carborane-containing compound 1a was identified as a cell growth inhibitor from a random screening of a boron compound library. As 1a is a mixture of diastereomers due to the presence of two chiral carbons, we designed achiral derivatives 2-4 and studied the structure-activity relationships of the methoxy groups on the benzene ring. 3,4,5-Trimethoxybenzyl derivative 2a and 3,4,5-trimethoxybenzoyl derivative 3a showed more potent anti-cancer activity against the human breast cancer cell line MDA-MB-453 than lead compound 1a. Compound 3a inhibited tubulin polymerization in a dose-dependent manner.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Boranos/química , Boranos/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismoRESUMO
Based upon hydrophobic feedback approaches, we designed and synthesized novel sulfur-containing ERα modulators (4 and 5) as breast cancer therapeutic drug candidates. The tetrahydrothiepine derivative 5a showed the highest binding affinity toward ERα because of its high hydrophobicity, and it acted as an agonist toward MCF-7 cell proliferation. The corresponding alkylamino derivative 5d maintained high binding affinity to ERα and potently inhibited MCF-7 cell proliferation (IC50: 0.09 µM). Docking simulation studies of compound 5d with the ERα BD revealed that the large hydrophobic moiety of compound 5d fit well into the hydrophobic pocket of the ERα LBD and that the sulfur atom of compound 5d formed a sulfur-π interaction with the amino acid residue His524 of the ERα LBD. These interactions play important roles for the binding affinity of compound 5d to the ERα LBD.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Antagonistas de Estrogênios/síntese química , Moduladores de Receptor Estrogênico/síntese química , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Células MCF-7 , Relação Estrutura-Atividade , Enxofre/químicaRESUMO
Xanthine oxidase (XO) is an enzyme that contains molybdenum at the active site and catalyzes the oxidation of purine bases to uric acid. Even though XO inhibitors are widely used for the treatment of hyperuricemia and gout, only very few such compounds are clinically used as drugs for the treatment of these diseases. Given the unique physicochemical properties of tropolone, i.e., its chelating effect and the pKa value that is similar to that of carboxylic acid, we have synthesized 22 5-arylazotropolone derivatives as potential XO inhibitors. In vitro enzyme-inhibitory assays for XO revealed that 3-nitro derivative 1j showed the most potent XO inhibitory activity, which is by one order of magnitude more potent than allopurinol. An enzyme-kinetic study revealed that 1j inhibited the production of uric acid by XO both competitively and non-competitively. A docking-simulation study of 1j with XO suggested that the carbonyl and hydroxyl groups of the tropolone ring interact with the hydroxy group that acts as a ligand for molybdenum and the amino acid residues around the active site of XO.
Assuntos
Inibidores Enzimáticos/farmacologia , Tropolona/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Bovinos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Leite/enzimologia , Estrutura Molecular , Relação Estrutura-Atividade , Tropolona/síntese química , Tropolona/química , Xantina Oxidase/metabolismoRESUMO
Based on the co-crystal structure of bicalutamide with a T877A-mutated androgen receptor (AR), glycerol and aminoglycerol derivatives were designed and synthesized as a novel type of carborane-containing AR modulators. The (R)-isomer of 6c, whose chirality is derived from the glycerol group, showed 20 times more potent cell inhibitory activity against LNCaP cell lines expressing T877A-mutated AR than the corresponding (S)-isomer. Docking studies of both isomers with AR suggested that (R)-6c is in closer spatial proximity to helix-12 of the AR than (S)-6c, which is the most important common motif in the secondary structure of AR for the expression of antagonistic activity.
Assuntos
Antagonistas de Receptores de Andrógenos/síntese química , Boranos/química , Desenho de Fármacos , Glicerol/química , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glicerol/metabolismo , Glicerol/farmacologia , Humanos , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Receptores Androgênicos/química , Receptores Androgênicos/genética , EstereoisomerismoRESUMO
The selectivity and the binding affinity of previously reported carborane-containing ligands 2 and 3 toward ERß remains to be optimized. To improve their biological profiles, a series of iodinated carboranyl phenol derivatives (4-6) were designed and synthesized as prospective ERß-selective ligands with high affinity. Several iodinated carboranyl phenols showed high relative binding affinity (RBA) values for both ERs, and especially for ERß, due to suitable hydrophobic interactions of the iodine atoms with the hydrophobic amino acid residues of the ERß ligand-binding domains. Among these derivatives, 9,10-diiodo-m-carborane 5f exhibited a more than 100% increase of the RBA values toward ERß, a 14-fold increased selectivity for ERß over ERα, and ER-agonistic activity in MCF-7 cell proliferation assays.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Receptor beta de Estrogênio/agonistas , Fenóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Células MCF-7 , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Relação Estrutura-AtividadeRESUMO
The female hormone 17 ß-estradiol (E2) is synthesized from estrone by steroid sulfatase (STS), and metabolized into 2-methoxyestradiol (2-ME), whereby the biological activity of the latter is substantially different from that of E2. Based on the metabolic pathways of E2, a carborane-containing 2-ME mimic (1c) and its derivatives (1 and 2) were designed and synthesized as novel multitarget anticancer agents. Bissulfamate 1f exhibited potent STS-inhibitory activity and tubulin-polymerization-inhibitory activity. Moreover, the cell-growth-inhibitory (CGI) activity of 1f was similar to that of 2-ME in a panel screening against 39 human cancer cell lines. Accordingly, 1f should be a promising perspective therapeutic agent for hormone-dependent breast tissue.
Assuntos
Antineoplásicos/farmacologia , Boranos/farmacologia , Inibidores Enzimáticos/farmacologia , Estradiol/análogos & derivados , Estradiol/metabolismo , 2-Metoxiestradiol , Antineoplásicos/síntese química , Antineoplásicos/química , Boranos/síntese química , Boranos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estradiol/química , Estradiol/farmacologia , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Esteril-Sulfatase/antagonistas & inibidores , Esteril-Sulfatase/metabolismo , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismoRESUMO
The development of multitarget anticancer agents is of high interest to medicinal chemists in terms of overcoming drug resistance and preventing cancer-cell migration. Based on the structure of the potent carborane-containing estrogen BE120, non-steroidal multitarget anti-breast cancer agent candidates 1a-1j were designed and synthesized. Compound 1f shows potent STS-inhibitory activity (IC50â¯=â¯1.8⯵M), cell-growth-inhibitory (CGI) activity against 39 human cancer cell lines (MG-MIDâ¯=â¯2.8⯵M), and tubulin-polymerization-inhibitory (TPI) activity. An analysis of the DNA content for MDA-MB-453 breast cancer cells revealed that 1f arrests the cell cycle in the G2/M phase and induces apoptosis. Accordingly, 1f should be a promising therapeutic agent for hormone-dependent breast cancer.
Assuntos
Antineoplásicos/farmacologia , Boranos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenho de Fármacos , Ácidos Sulfônicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Boranos/síntese química , Boranos/química , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/químicaRESUMO
We designed and synthesized 4,4'-(piperidin-4-ylidenemethylene)bisphenol derivatives as novel tunable estrogen receptor (ER) modulators. The introduction of hydrophobic substituents on the nitrogen atom of the piperidine ring enhanced ERα binding affinity. In addition, the introduction of four methyl groups adjacent to the piperidine ring nitrogen atom remarkably enhanced ERα binding affinity. N-Acetyl-2,2,6,6-tetramethylpiperidine derivative 3b showed high ERα binding affinity, high MCF-7 cell proliferation inducing activity, and high metabolic stability in rat liver S9 fractions.
Assuntos
Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/metabolismo , Fenóis/química , Fenóis/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Animais , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/metabolismo , Moduladores de Receptor Estrogênico/síntese química , Moduladores de Receptor Estrogênico/metabolismo , Humanos , Fígado/metabolismo , Células MCF-7 , Fenóis/síntese química , Fenóis/metabolismo , Piperidinas/síntese química , Piperidinas/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer-targeting methods. Herein, we focused on lysine-specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans-2-phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA-drug conjugate (PDC) prototypes, we designed PCPA-tamoxifen conjugates 1 a and 1 b, which released 4-hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.
Assuntos
Antineoplásicos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Pró-Fármacos/farmacologia , Tranilcipromina/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Epiteliais , Histona Desmetilases/metabolismo , Humanos , Células MCF-7 , Estrutura Molecular , Pró-Fármacos/química , Relação Estrutura-Atividade , Tranilcipromina/químicaRESUMO
The identification of novel drug targets for the treatment of ischemic stroke is currently an urgent challenge. Recent experimental findings have highlighted the neuroprotective potential of immunomodulatory strategies, based on polarization of myeloid cells toward non-inflammatory, beneficial phenotypes. Given the role of retinoid X receptors (RXR) in myeloid cells differentiation and polarization, here we have explored the neuroprotective potential of the RXR agonist bexarotene in mice subjected to focal cerebral ischemia. Acute administration of bexarotene significantly reduced blood brain barrier leakage, brain infarct damage and neurological deficit produced by transient middle cerebral artery occlusion in mice, without affecting cerebral blood flow. The rexinoid exerted neuroprotection with a wide time-window, being effective when administered up to 4.5h after the insult. The amelioration of histological outcome, as well as the ability of bexarotene to revert middle cerebral artery occlusion (MCAo)-induced spleen atrophy, was antagonised by BR1211, a pan-RXR antagonist, or by the selective peroxisome proliferator-activated receptor (PPAR)γ antagonist bisphenol A diglycidyl ether (BADGE), highlighting the involvement of the RXR/PPARγ heterodimer in the beneficial effects exerted by the drug. Immunofluorescence analysis revealed that bexarotene elevates Ym1-immunopositive N2 neutrophils both in the ipsilateral hemisphere and in the spleen of mice subjected to transient middle cerebral artery occlusion, pointing to a major role for peripheral neutrophil polarization in neuroprotection. Thus, our findings suggest that the RXR agonist bexarotene exerts peripheral immunomodulatory effects under ischemic conditions to be effectively repurposed for the acute therapy of ischemic stroke.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , PPAR gama/metabolismo , Receptores X de Retinoides/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Tetra-Hidronaftalenos/farmacologia , Animais , Bexaroteno , Isquemia Encefálica/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/metabolismoRESUMO
We designed and synthesized novel m-carborane-containing selective estrogen receptor modulator (SERM) candidates using previously reported m-carborane-containing ER partial agonist 1 as the lead compound. Biological activities were evaluated by means of ERα competitive binding assay and MCF-7 cell proliferation assay. Re-positioning the N,N-dimethylaminoethyloxy group at the para position of 1 to the meta position enhanced the ERα-binding affinity, and 4c showed the highest relative binding affinity (RBA: 83 vs 17ß-estradiol = 100) among the tested compounds. Compound 4b showed the most potent ER-agonist activity (EC50: 1.4 nM) and the lowest maximal efficacy (Emax: 50%) in MCF-7 cell proliferation assay. Inhibition of 0.1 nM 17ß-estradiol-induced MCF-7 cell proliferation by 4b (IC50: 0.4 µM) was at least 10 times more potent than that of the lead compound 1.
Assuntos
Compostos de Boro/síntese química , Compostos de Boro/farmacologia , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Receptor alfa de Estrogênio/antagonistas & inibidores , Humanos , Células MCF-7 , Modelos Moleculares , Conformação Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Candidates for highly selective estrogen receptor-beta (ERß) ligands (6a-c, 7a-c, 8a and 8b) were designed and synthesized based on carborane-containing ER ligands 1 and 2 as lead compounds. Among them, p-carboranylcyclohexanol derivatives 8a and 8b exhibited high ERß selectivity in competitive binding assay: for example, 8a showed 56-fold selectivity for ERß over ERα. Docking studies of 8a and 8b with the ERα and ERß ligand-binding domains (LBDs) suggested that the p-carborane cage of the ligands is located close to key amino acid residues that influence ER-subtype selectivity, that is, Leu384 in the ERα LBD and Met336 in the ERß LBD. The p-carborane cage in 8a and 8b appears to play a crucial role in the increased ERß selectivity.
Assuntos
Boranos/farmacologia , Desenho de Fármacos , Receptor beta de Estrogênio/antagonistas & inibidores , Boranos/síntese química , Boranos/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We have reported the design and synthesis of novel estrogen receptor (ER) agonists with a diphenylamine skeleton, which has several advantages over the formerly used diphenylmethane skeleton for drug development. Here, we confirmed the versatility of the diphenylamine skeleton by designing and synthesizing ER antagonist candidates bearing a basic alkylamino side chain on one of the two phenol groups of the diphenylamine agonist core structure. Among the tested compounds, cyclic alkylamine-containing derivatives showed more potent ER-antagonistic activity than the corresponding acyclic derivatives in cell proliferation assay using the MCF-7 cell line. Compound 5e showed the most potent antiestrogenic activity (IC50: 1.3×10(-7)M), being 10times more potent than tamoxifen.
Assuntos
Difenilamina/química , Difenilamina/farmacologia , Antagonistas do Receptor de Estrogênio/química , Antagonistas do Receptor de Estrogênio/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , Relação Estrutura-AtividadeRESUMO
Monoalkylated bis(4-hydroxyphenyl)methanes (e.g., 1) are reported to show weak binding affinity for estrogen receptor (ER). We hypothesized that introduction of appropriately located hydrophobic substituents in these compounds would increase the binding affinity. Indeed, we found that bis(4-hydroxyphenyl)methane bearing a 3,3-dimethylcyclohexyl group (7) shows potent ERα binding affinity, comparable to that of estradiol. Bulkier substituents could be introduced at the 3,3-position without decreasing the affinity. However, the position of the substituents was critical: the 4,4-dimethylcyclohexyl derivative (2) showed very weak binding affinity. The compounds with high ER-binding affinity showed predominantly agonistic activity, together with weak antagonistic activity at high concentration, in cell proliferation assay with human breast cancer cell line MCF-7. Further structure-function studies of these compounds and their derivatives might lead to the development of more selective and potent estrogen receptor modulators.
Assuntos
Compostos Benzidrílicos/química , Receptor alfa de Estrogênio/química , Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Estradiol/química , Estradiol/metabolismo , Moduladores de Receptor Estrogênico/síntese química , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
We previously discovered m-carborane-containing estrogen receptor (ER) modulator 4, which exhibits weak ER-agonistic and antagonistic activities in transactivation assays. With the aim of developing novel ER partial agonists, we designed and synthesized various analogues of 4 with a bent-core structure, that is, pseudo cyclic structure (5), tetrahydropyrimidinone (6), m-benzene (7), adamantane (8), and 9,10-dimethyl-m-carborane (9), in place of the m-carborane moiety. Compound 9 showed greater binding affinity than 4 in ER-binding assay using [6,7-(3)H]-17ß-estradiol and was a more effective partial agonist than 4 in MCF-7 cell proliferation assay. It appears to be a promising candidate as a selective ER modulator (SERM).
Assuntos
Antineoplásicos/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/agonistas , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Moduladores de Receptor Estrogênico/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The two subtypes of estrogen receptor (ER), ERα and ERß, differ greatly in expression pattern and biological functions, and ERß-selective ligands candidates to treat immune-related disorders. ERß-selective ligands have mostly been designed based the idea of introducing a substituent that interferes sterically with the ligand's interaction with Met421 to selectively decrease the affinity for ERα (the equivalent residue in ERß is Ile373). Therefore, we designed and synthesized a series of carboranyl phenol derivatives bearing an aliphatic substituent as candidate ERß-selective ligands. Introduction of a longer aliphatic substituent into the carboranyl moiety enhanced the ERß selectivity of o-carboranyl phenol derivatives 4, but not m-carboranyl bisphenol derivatives 5. Compound 4c showed 7.4-fold ERß selectivity in ER-binding assay and exhibited moderate estrogenic activity in cell proliferation assay using MCF-7 cell line.
Assuntos
Compostos de Boro/química , Compostos de Boro/farmacologia , Receptor beta de Estrogênio/metabolismo , Fenol/química , Relação Estrutura-Atividade , Ligação Competitiva , Compostos de Boro/síntese química , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica/métodos , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Humanos , Ligantes , Células MCF-7/efeitos dos fármacos , Metionina , Simulação de Acoplamento MolecularRESUMO
We previously showed that fluorination of the carborane-containing selective estrogen receptor modulator (SERM) BE360 altered the agonist/antagonist activity balance and the estrogen receptor (ER) α/ß subtype selectivity. Here, we designed and synthesized a series of fluorinated carboranyl phenols as candidate ERß-selective ligands. Introduction of a fluorine atom onto the carborane cage commonly reduced the binding affinity for ERα, to an extent that depended on the other substituents present. The B-fluorinated m-carboranyl phenol 4a showed fourfold more potent ERß-binding affinity than the parent non-fluorinated compound 7. 1-Iodo-9-fluoro-m-carboranyl phenol 4f showed high ERß-binding affinity with an ERß/ERα selectivity ratio of 8.2. Among the compounds tested, 6 showed the highest ERß selectivity (10.1-fold) and the highest ER-agonistic activity (EC50: 5.1×10(-10) M) in MCF-7 cell proliferation assay.