Identification of a melampomagnolide B analog as a potential lead molecule for treatment of acute myelogenous leukemia.
Bioorg Med Chem
; 25(3): 1235-1241, 2017 02 01.
Article
em En
| MEDLINE
| ID: mdl-28049618
ABSTRACT
A series of carbamate derivatives of the antileukemic sesquiterpene melampomagnolide B (MMB) has been synthesized utilizing a 1,2,4-triazole carbamate conjugate of MMB as an intermediate synthon. Five imidazole- and benzimidazole-carbamate analogs of MMB (8a-8e) were prepared and evaluated for anti-leukemic activity against cultured M9 ENL1 AML cells. All the analogs exhibited improved anti-leukemic activity (EC50=0.90-3.93µM) when compared to parthenolide and the parent sesquiterpene, MMB (EC50=7.0µM and 15.5µM, respectively). The imidazole carbamate analog, 8a (EC50=0.9µM), was 16 times more potent than MMB. The comparative bioavailabilities of 8a and MMB were determined in BALB/c mice following oral dosing of these compounds. It has been demonstrated that the absolute plasma bioavailabilities of MMB and 8a were 6.7±0.8%, and 45.5±2%, respectively. These results indicate that, compared to MMB, the PK parameters for 8a display significantly improved bioavailability and exposure after oral administration. Analog 8a is considered to be a potential clinical candidate for treatment of acute myelogenous leukemia.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sesquiterpenos
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Leucemia Mieloide Aguda
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Antineoplásicos
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article