RESUMO
The syntheses of 21 analogs of 2-methoxyestradiol are presented, including ENMD-1198 which was selected for advancement into Phase 1 clinical trials in oncology. These analogs were evaluated for antiproliferative activity using breast tumor MDA-MB-231 cells, for antiangiogenic activity in HUVEC proliferation assays, and for estrogenic activity in MCF-7 cell proliferation. The most active analogs were evaluated for iv and oral pharmacokinetic properties via cassette dosing in rat and in mice pharmacokinetic models.
Assuntos
Antineoplásicos Hormonais/síntese química , Estradiol/análogos & derivados , 2-Metoxiestradiol , Animais , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacocinética , Linhagem Celular Tumoral , Estradiol/síntese química , Estradiol/química , Estradiol/farmacocinética , Estrenos/química , Estrenos/farmacocinética , Humanos , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
The syntheses of 2-methoxyestradiol analogs with modifications at the 3-position are described. The analogs were assessed for their antiproliferative, antiangiogenic, and estrogenic activities. Several lead substituents were identified with similar or improved antitumor activities and reduced metabolic liability compared to 2-methoxyestradiol.
Assuntos
Estradiol/análogos & derivados , Fuso Acromático/efeitos dos fármacos , 2-Metoxiestradiol , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Estradiol/farmacologia , Estradiol/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/estatística & dados numéricosRESUMO
A novel series of 17-modified and 2,17-modified analogs of 2-methoxyestradiol (2ME2) were synthesized and characterized. These analogs were designed to retain or potentiate the biological activities of 2ME2 and have diminished metabolic liability. The analogs were evaluated for antiproliferative activity against MDA-MB-231 breast tumor cells, antiangiogenic activity in HUVEC, and estrogenic activity on MCF-7 cell proliferation. Several analogs were evaluated for metabolic stability in human liver microsomes and in vivo in a rat cassette dosing model. This study lead to several 17-modified analogs of 2ME2 that have similar or improved antiproliferative and antiangiogenic activity, lack estrogenic properties and have improved metabolic stability compared to 2ME2.
Assuntos
Proliferação de Células/efeitos dos fármacos , Estradiol/análogos & derivados , Estrona/síntese química , Estrona/farmacologia , 2-Metoxiestradiol , Animais , Linhagem Celular , Estradiol/farmacologia , Estrona/química , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
Clinical studies using the microtubule-targeting agent 2-methoxyestradiol (2ME2; Panzem) in cancer patients show that treatment is associated with clinical benefit, including prolonged stable disease, complete and partial responses, and an excellent safety profile. Studies have shown that 2ME2 is metabolized by conjugation at positions 3 and 17 and oxidation at position 17. To define structure-activity relationships for these positions of 2ME2 and to generate metabolically stable analogues with improved anti-tubulin properties, a series of analogues was generated and three lead analogues were selected, ENMD-1198, ENMD-1200, and ENMD-1237. These molecules showed improved metabolic stability with >65% remaining after 2-h incubation with hepatocytes. Pharmacokinetic studies showed that oral administration of the compounds resulted in increased plasma levels compared with 2ME2. All three analogues bind the colchicine binding site of tubulin, induce G(2)-M cell cycle arrest and apoptosis, and reduce hypoxia-inducible factor-1alpha levels. ENMD-1198 and ENMD-1200 showed improved in vitro antiproliferative activities. Significant reductions in tumor volumes compared with vehicle-treated mice were observed in an orthotopic breast carcinoma (MDA-MB-231) xenograft model following daily oral treatment with all compounds (ANOVA, P < 0.05). Significantly improved median survival time was observed with ENMD-1198 and ENMD-1237 (200 mg/kg/d) in a Lewis lung carcinoma metastatic model (P < 0.05). In both tumor models, the high-dose group of ENMD-1198 showed antitumor activity equivalent to that of cyclophosphamide. ENMD-1198 was selected as the lead molecule in this analogue series and is currently in a phase I clinical trial in patients with refractory solid tumors.
Assuntos
Antineoplásicos/farmacologia , Estrenos/farmacologia , Microtúbulos/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , 2-Metoxiestradiol , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Estradiol/análogos & derivados , Estradiol/química , Estrenos/administração & dosagem , Estrenos/química , Estrenos/farmacocinética , Fase G2/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitose/efeitos dos fármacos , Ratos , Análise de Sobrevida , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacocinéticaRESUMO
The syntheses and antimitotic activity of several novel analogs of 2-methoxyestradiol are described. Structural modifications include ring-D homologation, aromatization of the six-membered ring-D to a chrysine type molecule, and introduction of unsaturation in five-membered ring-D along with substitution of alkyl and ethynyl groups for the 17beta-hydroxy function. Of nine analogs synthesized, five have demonstrated superior antiproliferative activities compared to 2-methoxyestradiol.
Assuntos
Antimitóticos/síntese química , Estradiol/análogos & derivados , 2-Metoxiestradiol , Antimitóticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/citologia , Estradiol/síntese química , Estradiol/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade , Veias UmbilicaisRESUMO
The syntheses and antimitotic activity of several novel 18a-homo-analogs of 2-methoxyestradiol are described. Structural modifications of the parent 2-methoxy-18a-homoestradiol include introduction of unsaturation in the D-ring and methylation of the 17-OH. Of seven analogs synthesized, one has demonstrated superior biological activities compared to 2-methoxyestradiol. The relationship between biological activity and the conformational preference of the 13-ethyl group as determined by computational analysis is discussed.
Assuntos
Antimitóticos/síntese química , Estradiol/análogos & derivados , 2-Metoxiestradiol , Antimitóticos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Estradiol/síntese química , Estradiol/farmacologia , Humanos , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade , Moduladores de TubulinaRESUMO
A series of 16-modified 2-methoxyestradiol analogs were synthesized and evaluated for antiproliferative activity toward HUVEC and MDA-MB-231 cells, and for susceptibility to conjugation. In addition, the estrogenicity of these analogs was accessed by measuring cell proliferation of the estrogen-dependent cell line MCF7 in response to compound treatment. It was observed that antiproliferative activity dropped as the size of the 16 substituent increased. Selected analogs tested in glucuronidation assays had similar rates of clearance to 2-methoxyestradiol, but had enhanced clearance in sulfonate conjugation assays.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Estradiol/análogos & derivados , 2-Metoxiestradiol , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Estradiol/química , Estradiol/uso terapêutico , Feminino , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Thalidomide has recently been shown to be useful in the treatment of multiple myeloma and may also be useful in the treatment of other hematological malignancies. We have identified a new derivative of thalidomide, S-3-[3-amino-phthalimido]-glutarimide (S-3APG) with dual activity against B-cell neoplasias. S-3APG was able to directly inhibit the proliferation of myeloma and Burkitt's lymphoma cell lines in vitro without showing toxicity to normal bone marrow stromal cells or hematopoietic progenitor cells. In vivo, S-3APG treatment of drug resistant myeloma cell tumors in mice was able to produce complete and sustained regressions without any observed toxicity. Additionally, S-3APG induced complete regressions of Burkitt's lymphoma cell tumors. Furthermore, S-3APG inhibited angiogenesis more potently than thalidomide in the murine corneal micropocket model. We conclude that S-3APG is a powerful anti-myeloma and anti-B-cell-lymphoma agent that has both antiproliferative and antiangiogenic effects.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Linfoma de Burkitt/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/farmacologia , Células 3T3 , Animais , Linfoma de Burkitt/patologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/patologia , Divisão Celular/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Humanos , Interleucina-6/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Mieloma Múltiplo/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Talidomida/análogos & derivados , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The solution structure of an 11-mer DNA duplex, d(CGGTCA*CGAGG) x d(CCTCGTGACCG), containing a 10R adduct at dA* that corresponds to the cis addition of the N(6)-amino group of dA(6) to (+)-(9S,10R)-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene was studied by 2D NMR methods. The NOESY cross-peak patterns indicate that the hydrocarbon is intercalated on the 5'-side of the modified base. This observation is the same as that observed for other oligonucleotides containing (10R)-dA adducts but opposite to that observed for the corresponding (10S)-dA adducts which are intercalated on the 3'-side of the modified base. The hydrocarbon is intercalated from the major groove without significant disruption of either the anti glycosidic torsion angle of the modified residue or the base pairing of the modified residue with the complementary residue on the opposite strand. The ensemble of 10 structures determined exhibits relatively small variations (6-15 degrees) in the characteristic hydrocarbon-base dihedral angles (alpha' and beta') as well as the glycosidic torsion angle chi. These angles are similar to those in a previously determined cis-opened benzo[a]pyrene diol epoxide-(10R)-dA adduct structure. Comparison of the present structure with the cis-opened diol epoxide adduct suggests that the absence of the 7- and 8-hydroxyl groups results in more efficient stacking of the aromatic moiety with the flanking base pairs and deeper insertion of the hydrocarbon into the helix. Relative to normal B-DNA, the duplex containing the present tetrahydroepoxide adduct is unwound at the lesion site, whereas the diol epoxide adduct structure is more tightly wound than normal B-DNA. Buckling of the adducted base pair as well as the C(5)-G(18) base pair that lies immediately above the hydrocarbon is much less severe in the present adducted structure than its cis-opened diol epoxide counterpart.