RESUMEN
BACKGROUND: The tubulin depolymerizing drug Combretastatin A-1 phosphate (CA1P), a water-soluble derivative of combretastatin A-1, has been recently shown to have a better efficacy in experimental models than the clinically active, close structural analogue, combretastatin A-4 phosphate (CA4P). Previous studies with CA4P in combination with standard anti-cancer agents have demonstrated improved efficacy relative to the standard agents. MATERIALS AND METHODS: In this study the synergistic effects of administering CA1P in combination with cisplatin (CPL) in a well-differentiated transplantable murine colon model (MAC 29) was evaluated. RESULTS: CA1P at 100 mgkg-1 significantly potentiated the anti-tumour effects of CPL. The effect with CPL was similar to that seen for CA1P at its maximum tolerated dose (MTD) alone. CONCLUSION: These data demonstrate that the combination of CA1P and CPL has significant preclinical antitumour activity against a transplantable murine adenocarcinoma model that is related to the antivascular effects of CA1P.
Asunto(s)
Adenocarcinoma Mucinoso/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/farmacología , Neoplasias del Colon/patología , Estilbenos/farmacología , Adenocarcinoma Mucinoso/irrigación sanguínea , Adenocarcinoma Mucinoso/patología , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Antineoplásicos/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Ratones , Ratones Endogámicos , Trasplante de Neoplasias , Estilbenos/administración & dosificaciónRESUMEN
In view of the clinical potential of a number of natural products, Combretastatin A-1 phosphate was developed as a water-soluble derivative of combretastatin A-1. This study examined the anti-tumour activity of this compound against an experimental colon tumour (MAC29) in mice. A comparison was made with the clinically active combretastatin A-4 phosphate. The new compound was well-tolerated up to a dose of 250 mg/kg and was more effective at producing tumour growth delays than the A-4 analogue. Significant growth delays were seen at a dose of 50 mg/kg whereas the A-4 phosphate produced no measurable growth delay until a dose of 150 mg/kg was administered. Histological examination of treated tumours indicated that combretastatin A-1 phosphate caused very severe haemorrhagic necrosis in the tumour tissue and analysis of the sections indicated that almost 94 percent of the tumour was dead within 24 hours of treatment. The mechanism of action of combretastatin A-1 phosphate appears to be similar to the A-4 phosphate in that tumour vascular shutdown occurs within 4 hours of treatment. In summary combretastatin A-1 phosphate, the water-soluble analogue of combretastatin A-1, is more potent against a well-vascularised murine colon tumour than its predecessor, combretastatin A-4 phosphate. These data suggest this compound may have potential for clinical development.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Experimentales/irrigación sanguínea , Neovascularización Patológica/tratamiento farmacológico , Profármacos/farmacología , Estilbenos/farmacología , Animales , Antineoplásicos Fitogénicos/metabolismo , División Celular/efectos de los fármacos , Femenino , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Fosfatos/metabolismo , Fosfatos/farmacología , Profármacos/metabolismo , Estilbenos/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
In an attempt to develop biologically active compounds from the inactive trans isomer (3a) of stilbene 1a, after asymmetric dihydroxylation to optically pure (R,R)-diol 8 the unexpected racemic diphenylacetaldehyde (9) was generated via a Pinacol rearrangement. Several derivatives of diphenylacetaldehyde 9 were synthesized (11-15) and reported. Further reaction of aldehyde 9 during desilylation through autoxidative decarbonylation afforded benzophenone 2b, designated hydroxyphenstatin, a potent antitumor and antimitotic agent. Hydroxyphenstatin showed potent inhibition of the tubulin assembly (IC(50) 0.82 microM) and exhibited an ED(50) of 2.5 microg/mL against the P388 lymphocytic leukemia cell line.
Asunto(s)
Antineoplásicos/síntesis química , Benzofenonas/síntesis química , África , Cristalografía por Rayos X , Indicadores y Reactivos , Conformación Molecular , Oxidación-Reducción , Plantas Medicinales/químicaRESUMEN
The original synthesis of combretastatin A-1 (1) was modified to allow an efficient scale-up procedure for obtaining this anti-neoplastic stilbene. Subsequent conversion to a useful prodrug was accomplished by diphosphorylation (to 10), with in situ formation of dibenzylchlorophosphite, followed by cleavage of the benzyl ester protecting groups with trimethyliodosilane. The phosphoric acid intermediate was treated with sodium methoxide to complete a practical route to the sodium phosphate prodrug (4). Selective hydrogenation of phosphate 10 and treatment of the product with sodium methoxide led to combretastatin B-1 prodrug (5). The phosphoric acid precursor of prodrug 4 was employed in a parallel series of reactions to produce a selection of metal and ammonium cation prodrug candidates. Each of the phosphate salts was evaluated from the perspective of relative solubility behavior and cancer cell growth inhibition. The sodium phosphate prodrug of combretastatin A-1 (4) was selected for detailed antineoplastic studies.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Profármacos/síntesis química , Estilbenos/síntesis química , Animales , Antineoplásicos Fitogénicos/farmacología , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Organofosfatos/síntesis química , Organofosfatos/farmacología , Profármacos/farmacología , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/farmacología , Solubilidad , Estilbenos/farmacología , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
The synthetic (E)-isomer (3b) of natural combretastatin A-1 (1a) isolated from the African bushwillow Combretum caffrum was the focus of chiral hydroxylation (Sharpless) reactions as part of a structure-activity relationship study. The resulting (R,R)- and (S,S, )-diols (6 and 7) and synthetic intermediates were evaluated against a series of cancer cell lines, microorganisms, and tubulin. Chiral diols 6 and 7 showed increased activity against the P-388 murine lymphocytic leukemia cell line with ED(50) values of 3.9 and 2.9 microg/mL, respectively, when compared to the precursor (E)-stilbene 3b. In contrast, (E)-stilbene 3b exhibited more potent antibiotic activity than the chiral diols (6 and 7). Both diols, (R,R)-6 and (S, S)-7, displayed less cancer cell growth inhibition and less antibiotic activity than did natural combretastatin A-1 (1a) (P-388 ED(50) 0.25 microg/mL).
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Glicoles de Etileno/síntesis química , Guayacol/análogos & derivados , Estilbenos/química , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Glicoles de Etileno/química , Glicoles de Etileno/farmacología , Guayacol/síntesis química , Guayacol/química , Guayacol/farmacología , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Sondas Moleculares , Estereoisomerismo , Relación Estructura-Actividad , Árboles/química , Células Tumorales CultivadasRESUMEN
A high-yield regioselective synthesis of (E)-combretastatin A-1 2b was completed using methoxymethyl (MOM) protection and a Wadsworth-Emmons reaction as key steps. In turn, (E)-stilbene 11 was converted by convenient syntheses to both (S,S)- and (R,R)-1,3-dioxolanes 5a and 6a. A Sharpless asymmetric dihydroxylation reaction was employed for preparation of intermediates (S,S)-12 and (R,R)-13. The (4S,5S)-4-(2',3'-dihydroxy4'-methoxyphenyl)-5-(3",4",5"-trimethoxyphenyl)-1, 3-dioxolane 5a was found to be a highly potent inhibitor of microtubule assembly (IC50 = 0.59 microM) and was designated dioxostatin. Conversion to sodium phosphate 17 (P388 lymphocytic leukemia cell line: ED50 = 0.2 microg/ml) provided a very useful water-soluble prodrug.