RESUMEN
The oxidation of volatile organic compounds in the atmosphere produces organic hydroperoxides (ROOHs) that typically possess not only -OOH but also other functionalities such as -OH and -C(îO). Because of their high hydrophilicity and low volatility, such multifunctionalized ROOHs are expected to be taken up in atmospheric condensed phases such as aerosols and fog/cloud droplets. However, the characteristics of ROOHs that control their fates and lifetimes in liquid phases are poorly understood. Here, we report a study of the liquid-phase decomposition kinetics of multifunctionalized α-alkoxyalkyl-hydroperoxides (α-AHs) that possessed an ether, a carbonyl, a hydroperoxide, and two hydroxy groups. These ROOHs were synthesized by ozonolysis of α-terpineol in water in the presence of 1,3-propanediol, 1,4-butanediol, or 1,5-pentanediol. Their decomposition products were detected as chloride anion adducts by electrospray mass spectrometry as a function of reaction time. Experiments using H218O and D2O revealed that hemiacetal species were α-AH decomposition products that further transformed into other products. The result that the rate coefficients (k) of the decomposition of C15 α-AHs increased exponentially from pH 5.0 to 3.9 was consistent with an H+-catalyzed decomposition mechanism. The temperature dependence of k and an Arrhenius plot yielded activation energies (Ea) of 15.7 ± 0.8, 15.0 ± 2.4, and 15.9 ± 0.3 kcal mol-1 for the decomposition of α-AHs derived from the reaction of α-terpineol CIs with 1,3-propanediol, 1,4-butanediol, and 1,5-pentanediol, respectively. The determined Ea values were compared with those of related ROOHs. We found that alkyl chain length is not a critical factor for the decomposition mechanism, whereas the presence of additional -OH groups would modulate the reaction barriers to decomposition via the formation of hydrogen-bonding with surrounding water molecules. The derived Ea values for the decomposition of the multifunctionalized, terpenoid-derived α-AHs will facilitate atmospheric modeling by serving as representative values for ROOHs in atmospheric condensed phases.
Asunto(s)
Atmósfera , Peróxido de Hidrógeno , Aerosoles , Alcoholes , AguaRESUMEN
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.
Asunto(s)
Azulenos/síntesis química , Neoplasias de la Mama/metabolismo , Estradiol/farmacología , Moduladores de los Receptores de Estrógeno/síntesis química , Receptores de Estrógenos/metabolismo , Sesquiterpenos de Guayano/química , Azulenos/química , Azulenos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Desarrollo de Medicamentos , Sinergismo Farmacológico , Moduladores de los Receptores de Estrógeno/química , Moduladores de los Receptores de Estrógeno/farmacología , Femenino , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Unión Proteica , Conformación Proteica , Receptores de Estrógenos/química , Tamoxifeno/análogos & derivados , Tamoxifeno/química , Tamoxifeno/farmacologíaRESUMEN
Latency-reversing agents (LRAs) are considered a potential strategy for curing cells of HIV-1 infection. Certain protein kinase C (PKC) activators have been previously reported to be LRAs because they can reverse HIV latency. In the present study, we examined the activities of a panel of benzolactam derivatives against cells latently infected with HIV. Using determination of p24 antigen in cell supernatants or altered intracellular GFP expression to measure HIV reactivation from latently infected cells along with a cytotoxicity assay, we found that some of the compounds exhibited latency-reversing activity, which was followed by enhanced release of HIV particles from the cells. One derivative, BL-V8-310, displayed activity in ACH-2 and J-Lat cells latently infected with HIV at a concentration of 10 nm or higher, which was superior to the activity of another highly active PKC activator, prostratin. These results were confirmed with peripheral blood cells from HIV-infected patients. We also found that these drugs up-regulate the expression of caspase 3 and enhance apoptosis specifically in latently HIV-infected cells. Moreover, combining BL-V8-310 with a bromodomain-containing 4 (BRD4) inhibitor, JQ1, not only enhanced HIV latency-reversing activity, but also reduced the effect on cytotoxic cytokine secretion from CD4+ T-cells induced by BL-V8-310 alone. Our results suggest that BL-V8-310 and its related benzolactam derivatives are potential LRA lead compounds that are effective in reversing HIV latency and reducing viral reservoirs in HIV-positive individuals with few adverse effects.
Asunto(s)
Apoptosis/efectos de los fármacos , Benzodiazepinonas/farmacología , Linfocitos T CD4-Positivos/metabolismo , Infecciones por VIH/metabolismo , VIH-1/fisiología , Proteína Quinasa C/metabolismo , Latencia del Virus/efectos de los fármacos , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Caspasa 3/biosíntesis , Caspasa 3/genética , Proteínas de Ciclo Celular , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Infecciones por VIH/genética , Infecciones por VIH/patología , Humanos , Masculino , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteína Quinasa C/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
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.
Asunto(s)
Antagonistas de Receptores Androgénicos/química , Compuestos de Boro/química , Sistemas de Liberación de Medicamentos/métodos , Simulación de Dinámica Molecular , Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/administración & dosificación , Antagonistas de Receptores Androgénicos/metabolismo , Compuestos de Boro/administración & dosificación , Compuestos de Boro/metabolismo , Estructura Secundaria de Proteína , Receptores Androgénicos/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Boranos/farmacología , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/antagonistas & inhibidores , Fenoles/farmacología , Antineoplásicos , Sitios de Unión/efectos de los fármacos , Boranos/síntesis química , Boranos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/metabolismo , Humanos , Ligandos , Células MCF-7 , Simulación del Acoplamiento Molecular , Estructura Molecular , Fenoles/síntesis química , Fenoles/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Boranos/química , Boranos/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismoRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Antagonistas de Estrógenos/farmacología , Moduladores de los Receptores de Estrógeno/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Antagonistas de Estrógenos/síntesis química , Moduladores de los Receptores de Estrógeno/síntesis química , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Interacciones Hidrofóbicas e Hidrofílicas/efectos de los fármacos , Células MCF-7 , Relación Estructura-Actividad , Azufre/químicaRESUMEN
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.
Asunto(s)
Antagonistas de Receptores Androgénicos/síntesis química , Boranos/química , Diseño de Fármacos , Glicerol/química , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Glicerol/metabolismo , Glicerol/farmacología , Humanos , Simulación del Acoplamiento Molecular , Mutagénesis Sitio-Dirigida , Receptores Androgénicos/química , Receptores Androgénicos/genética , EstereoisomerismoRESUMEN
Feline leukemia virus (FeLV) subgroups have emerged in infected cats via the mutation or recombination of the env gene of subgroup A FeLV (FeLV-A), the primary virus. We report the isolation and characterization of a novel env gene, TG35-2, and report that the TG35-2 pseudotype can be categorized as a novel FeLV subgroup. The TG35-2 envelope protein displays strong sequence identity to FeLV-A Env, suggesting that selection pressure in cats causes novel FeLV subgroups to emerge.
Asunto(s)
Virus de la Leucemia Felina/fisiología , Proteínas del Envoltorio Viral/genética , Interferencia Viral , Secuencia de Aminoácidos , Animales , Gatos , Línea Celular , Células Cultivadas , Humanos , Datos de Secuencia Molecular , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Receptores Virales/metabolismo , Alineación de Secuencia , Proteínas del Envoltorio Viral/química , Tropismo Viral , Replicación ViralRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Receptor beta de Estrógeno/agonistas , Fenoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ligandos , Células MCF-7 , Estructura Molecular , Fenoles/síntesis química , Fenoles/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Boranos/farmacología , Inhibidores Enzimáticos/farmacología , Estradiol/análogos & derivados , Estradiol/metabolismo , 2-Metoxiestradiol , Antineoplásicos/síntesis química , Antineoplásicos/química , Boranos/síntesis química , Boranos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estradiol/química , Estradiol/farmacología , Humanos , Estructura Molecular , Polimerizacion/efectos de los fármacos , Esteril-Sulfatasa/antagonistas & inhibidores , Esteril-Sulfatasa/metabolismo , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismoRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Boranos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Diseño de Fármacos , Ácidos Sulfónicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Boranos/síntesis química , Boranos/química , Neoplasias de la Mama/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Ácidos Sulfónicos/síntesis química , Ácidos Sulfónicos/químicaRESUMEN
Carboranes are a class of carbon-containing polyhedral boron cluster compounds with globular geometry and hydrophobic surface that interact with hormone receptors such as estrogen receptor (ER) and androgen receptor (AR). We have synthesized BA321, a novel carborane compound, which binds to AR. We found here that it also binds to ERs, ERα and ERß. In orchidectomized (ORX) mice, femoral bone mass was markedly reduced due to androgen deficiency and BA321 restored bone loss in the male, whilst the decreased weight of seminal vesicle in ORX mice was not recovered by administration of BA321. In female mice, BA321 acts as a pure estrogen agonist, and restored both the loss of bone mass and uterine atrophy due to estrogen deficiency in ovariectomized (OVX) mice. In bone tissues, the trabecular bone loss occurred in both ORX and OVX mice, and BA321 completely restored the trabecular bone loss in both sexes. Cortical bone loss occurred in ORX mice but not in OVX mice, and BA321 clearly restored cortical bone loss due to androgen deficiency in ORX mice. Therefore, BA321 is a novel selective androgen receptor modulator (SARM) that may offer a new therapy option for osteoporosis in the male.
Asunto(s)
Andrógenos/metabolismo , Boranos/administración & dosificación , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/metabolismo , Animales , Huesos/efectos de los fármacos , Huesos/metabolismo , Boranos/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Gónadas/efectos de los fármacos , Gónadas/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos , Orquiectomía , Osteoporosis/patología , Ovariectomía , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Compuestos de Bencidrilo/química , Compuestos de Bencidrilo/farmacología , Moduladores de los Receptores de Estrógeno/química , Moduladores de los Receptores de Estrógeno/farmacología , Receptor alfa de Estrógeno/metabolismo , Fenoles/química , Fenoles/farmacología , Piperidinas/química , Piperidinas/farmacología , Animales , Compuestos de Bencidrilo/síntesis química , Compuestos de Bencidrilo/metabolismo , Moduladores de los Receptores de Estrógeno/síntesis química , Moduladores de los Receptores de Estrógeno/metabolismo , Humanos , Hígado/metabolismo , Células MCF-7 , Fenoles/síntesis química , Fenoles/metabolismo , Piperidinas/síntesis química , Piperidinas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Profármacos/farmacología , Tranilcipromina/farmacología , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Liberación de Fármacos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células Epiteliales , Histona Demetilasas/metabolismo , Humanos , Células MCF-7 , Estructura Molecular , Profármacos/química , Relación Estructura-Actividad , Tranilcipromina/químicaRESUMEN
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.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , PPAR gamma/metabolismo , Receptores X Retinoide/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Tetrahidronaftalenos/farmacología , Animales , Bexaroteno , Isquemia Encefálica/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Accidente Cerebrovascular/metabolismoRESUMEN
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.
Asunto(s)
Compuestos de Boro/síntesis química , Compuestos de Boro/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Receptor alfa de Estrógeno/antagonistas & inhibidores , Humanos , Células MCF-7 , Modelos Moleculares , Conformación Molecular , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Boranos/farmacología , Diseño de Fármacos , Receptor beta de Estrógeno/antagonistas & inhibidores , Boranos/síntesis química , Boranos/química , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Simulación de Dinámica Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Difenilamina/química , Difenilamina/farmacología , Antagonistas del Receptor de Estrógeno/química , Antagonistas del Receptor de Estrógeno/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Células MCF-7 , Relación Estructura-ActividadRESUMEN
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.