RESUMEN
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.
Asunto(s)
Antineoplásicos Hormonales/síntesis química , Estradiol/análogos & derivados , 2-Metoxiestradiol , Animales , Antineoplásicos Hormonales/química , Antineoplásicos Hormonales/farmacocinética , Línea Celular Tumoral , Estradiol/síntesis química , Estradiol/química , Estradiol/farmacocinética , Estrenos/química , Estrenos/farmacocinética , Humanos , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Estradiol/análogos & derivados , Huso Acromático/efectos de los fármacos , 2-Metoxiestradiol , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales , Estradiol/farmacología , Estradiol/uso terapéutico , Humanos , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/estadística & datos numéricosRESUMEN
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.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Estradiol/análogos & derivados , Estrona/síntesis química , Estrona/farmacología , 2-Metoxiestradiol , Animales , Línea Celular , Estradiol/farmacología , Estrona/química , Humanos , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Estrenos/farmacología , Microtúbulos/efectos de los fármacos , Moduladores de Tubulina/farmacología , 2-Metoxiestradiol , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colchicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Estradiol/análogos & derivados , Estradiol/química , Estrenos/administración & dosificación , Estrenos/química , Estrenos/farmacocinética , Fase G2/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Endogámicos C57BL , Mitosis/efectos de los fármacos , Ratas , Análisis de Supervivencia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/administración & dosificación , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacocinéticaRESUMEN
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.
Asunto(s)
Antimitóticos/síntesis química , Estradiol/análogos & derivados , 2-Metoxiestradiol , Antimitóticos/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Endotelio Vascular/citología , Estradiol/síntesis química , Estradiol/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Relación Estructura-Actividad , Venas UmbilicalesRESUMEN
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.
Asunto(s)
Antimitóticos/síntesis química , Estradiol/análogos & derivados , 2-Metoxiestradiol , Antimitóticos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Estradiol/síntesis química , Estradiol/farmacología , Humanos , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad , Moduladores de TubulinaRESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Estradiol/análogos & derivados , 2-Metoxiestradiol , Antineoplásicos/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Estradiol/química , Estradiol/uso terapéutico , Femenino , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Linfoma de Burkitt/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico , Talidomida/farmacología , Células 3T3 , Animales , Linfoma de Burkitt/patología , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Carcinoma Pulmonar de Lewis/patología , División Celular/efectos de los fármacos , Inhibidores de Crecimiento/farmacología , Humanos , Interleucina-6/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Mieloma Múltiple/patología , Neovascularización Fisiológica/efectos de los fármacos , Talidomida/análogos & derivados , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.