RESUMO
Synthesis of 11-substituted estradiol derivatives (12-17) has been carried out by the Grignard reaction with alkyl, allyl, and benzyl halides on 17beta-hydroxy-3-methoxy-11-oxo-estra-1,3,5(10),8(9)-tetraene (10). The novel compounds (10 and 12-17) were evaluated for their preliminary post-coital contraceptive (anti-implantation) activity in Sprague-Dawley rats. The tested compounds were administered orally and showed significant anti-implantation activity. Compound 13 is the most potent compound in the series which showed 100% contraceptive efficacy at 1.25 mg kg(-1).
Assuntos
Anticoncepcionais/síntese química , Anticoncepcionais Pós-Coito/síntese química , Implantação do Embrião/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/síntese química , Administração Oral , Animais , Química Farmacêutica/métodos , Anticoncepcionais/farmacologia , Anticoncepcionais Pós-Coito/farmacologia , Desenho de Fármacos , Estradiol/farmacologia , Feminino , Modelos Químicos , Ratos , Ratos Sprague-Dawley , Temperatura , Resultado do TratamentoRESUMO
omega-(2-Naphthyloxy) amino alkanes, obtained as major by-product during course of synthesis of carbamate esters from omega-(2-naphthyloxy) alkyl halides and amines, showed significant anti-hyperglycemic and lipid lowering activities in various test models as a novel class of compounds. Compounds were tested in rat GLM, SLM, STZ, and STZ-S models at 100mg/kg dose. Of these compound 13 was found to be the most active which caused lowering of sugar by 33.6%, 31.0%, 28.5%, and 73.8% in GLM, SLM, STZ, STZ-S, and db/db mice models, respectively. It also significantly effected lowering of LDL in rat model and also in Hamster model without reducing HDL. Most of the compounds showing anti-diabetic and lipid lowering activity have shown promising PPAR-alpha/gamma/delta-activity. Compounds 6, 13, and 19 have shown very good PPAR-alpha/gamma/delta activity.
Assuntos
Alcanos/síntese química , Alcanos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Hipolipemiantes/síntese química , Hipolipemiantes/farmacologia , Naftalenos/química , Alcanos/química , Alcanos/classificação , Alquilação , Aminação , Animais , Hipoglicemiantes/química , Hipoglicemiantes/classificação , Hipolipemiantes/química , Hipolipemiantes/classificação , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Estrutura Molecular , PPAR gama/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Centchroman (INN: Ormeloxifene), a reversible post-coital/weekly oral contraceptive (half-life of about 168 hours), designed and developed at CDRI, Lucknow is the only non-steroidal oral contraceptive in clinical use in the world today. Synthesized in 1967 and completing pre-clinical and clinical studies in 1989, this drug was approved for marketing in 1991, social marketing in 1995 and NFPW in April 2016. It acts by preventing implantation of blastocyst in endometrium. It is the only contraceptive which neither suppresses ovulation nor interferes with the hypothalamic-pituitary-ovarian axis. It has high level of safety and is virtually free from side effects except for a delay in about 8% menstrual cycles which is not confined to any women/cycle. Besides contraception, this SERM is also clinically useful in the management of DUB, mastalgia and fibroadenoma and has promising therapeutic efficacy in a variety of cancers including breast cancer. Due to estrogenic activity, this drug also has anti-osteoporotic and cardioprotective activity. Thus, Centchroman is likely to show other curative and prophylactic activity in a wide range of other disorders.
Assuntos
Centocromano/uso terapêutico , Anticoncepcionais Pós-Coito/uso terapêutico , Adulto , Animais , Centocromano/administração & dosagem , Centocromano/farmacocinética , Anticoncepcionais Pós-Coito/administração & dosagem , Anticoncepcionais Pós-Coito/farmacocinética , Feminino , Haplorrinos , Humanos , Ratos , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/uso terapêuticoRESUMO
Substituted amidoalkyl derivatives of 2,3-diarylacrylophenones carrying the amide chain on the 3-aryl residue have been prepared by reacting corresponding phenolic 2,3-diarylacrylophenones with haloalkyl carboxylic acid esters, their hydrolysis and subsequent treatment with different alkyl amines. Compounds thus prepared were evaluated for their relative binding affinity (RBA) towards estrogen receptors (ER), estrogen agonistic and antagonistic activities. Out of eleven amide derivatives thus prepared, compounds 7, 13, 15-19, 23, 24 showed significant estrogen antagonistic activity. Interestingly the phenolic compound 7 and the acid ester 18 also exhibited estrogen inhibiting property. Majority of the dimethoxy derivatives (R = OCH(3)) showed significantly high estrogenic activity. In order to throw light on their SAR, In silico docking of the acrylophenone derivatives in the ligand binding site of the ERalpha and their comparison with pure steroidal estrogen antagonist ICI-164,384 and the non-steroidal antiestrogen raloxifene, was carried out. Crystal structure of compound 6 revealed relative trans-geometry of the 2(B) and 3(C) phenyl rings.
Assuntos
Amidas/química , Moduladores de Receptor Estrogênico/química , Hidrocarbonetos Aromáticos/química , Receptores de Estrogênio/efeitos dos fármacos , Simulação por Computador , Cristalografia por Raios X , Antagonistas de Estrogênios/química , Ligantes , Fenóis/química , Ligação Proteica , Receptores de Estrogênio/metabolismo , Relação Estrutura-AtividadeRESUMO
7-Methoxy-3-phenyl-4-phenylvinyl benzopyran-2-ones and the corresponding 2,2-dimethyl-benzopyrans, substituted with different alkylamino residues were synthesized. Except compound 13e, all compounds showed high level of estrogen agonistic activity (>81 %) whereas, compounds 13 b-e and 15a showed significant estrogen antagonistic activity (>20 %). X-Ray analysis of a 7-methoxy-3-phenyl-4-phenylvinyl benzopyran-2-one derivative 13d showed its structural resemblance to endogenous estrogen, 17beta-estradiol. Estrogenic and antiestrogenic activities of these derivatives demonstrate their estrogen receptor (ER) binding ability. The lack of hydroxyl groups at appropriate positions resulted in poor Relative Binding Affinity (RBA).
Assuntos
Benzopiranos/síntese química , Estradiol/química , Receptores de Estrogênio/metabolismo , Benzopiranos/química , Benzopiranos/metabolismo , Cristalografia por Raios X , Estradiol/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Espectrofotometria InfravermelhoRESUMO
Increasing knowledge on structure and function of estrogen receptors is providing information on the mechanism of action of estrogen agonists, as well as antagonists, and in understanding their tissue-selective action. However, there are still many factors associated with estrogen response which are poorly understood. Therefore, the task of designing a tissue-selective estrogen for use as a pharmaceutical in estrogen-dependent disorders remains an uncertain game. This review provides information on the current status of estrogen receptors for a better understanding.
Assuntos
Receptores de Estrogênio/metabolismo , Animais , Sistemas de Liberação de Medicamentos/métodos , Antagonistas de Estrogênios/metabolismo , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Terapia de Reposição de Estrogênios/métodos , Humanos , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/química , Receptores de Estrogênio/classificaçãoRESUMO
7-Methoxy-4-(4-methoxybenzylidene)-2-substituted phenyl-benzopyrans I and 4-[bis-(4-methoxyphenyl)-methylene-2-substituted phenyl-benzopyrans II carrying different alkylamino residues, designed as estrogen receptor (ER) binding ligands, were successfully synthesized through the McMurry coupling reaction of substituted benzaldehyde/substituted benzophenones and 2-hydroxyphenyl-7-methoxy-chroman-4-one in presence of lithium aluminum hydride and titanium (IV) chloride (LAH-TiCl(4)). Self-coupling of carbonyl reactants led to the formation of several side products. The prototypes were evaluated for their relative binding affinity (RBA), as well as their estrogenic and antiestrogenic activities. High order of estrogenic activity (>50% gain) observed with compounds 3, 7a, 7b, 7c, 8, and 10a and also their partial estrogen antagonistic activity (> or =15%) at the uterine level points toward successful designing of the compounds. Compounds 4, 7a, 7b, 7c, and 10a also possessed significant anticancer activity against human adenocarcinoma cell line (MCF-7 cell line) that may be related to their estrogen-dependent action.
Assuntos
Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estrogênios/agonistas , Estrogênios/metabolismo , Flavonoides/síntese química , Flavonoides/metabolismo , Humanos , Metilação , Estrutura Molecular , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Mono- and bis-benzo[b]oxepine derivatives have been rationally synthesized to meet the molecular requirement for interaction with estrogen receptor. Bis-benzo[b]oxepines (7 and 9) and mono-benzo[b]oxepine (10) acquire geometry with phenolic groups disposed in a fashion to stimulate estrogen receptor. Structure-based investigation, in vivo activity and docking studies have been described and correlated to demonstrate a practical approach for suitable ligand design.