Identification of a melampomagnolide B analog as a potential lead molecule for treatment of acute myelogenous leukemia
[Display omitted] 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 e...
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Veröffentlicht in: | Bioorganic & medicinal chemistry 2017-02, Vol.25 (3), p.1235-1241 |
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Format: | Artikel |
Sprache: | eng |
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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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ISSN: | 0968-0896 1464-3391 |
DOI: | 10.1016/j.bmc.2016.12.036 |