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.

中文翻译：

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确定melampomagnolide B类似物作为治疗急性骨髓性白血病的潜在先导分子

利用MMB的1,2,4-三唑氨基甲酸酯共轭物作为中间合成子，合成了一系列抗白血病倍半萜倍半萜烯内酯B（MMB）的氨基甲酸酯衍生物。制备了5种MMB（8a-8e）的咪唑和苯并咪唑氨基甲酸酯类似物，并评估了其对培养的M9 ENL1 AML细胞的抗白血病活性。与苯二酚和倍半萜母体MMB（分别为EC ₅₀ =7.0μM和15.5μM ）相比，所有类似物均显示出改善的抗白血病活性（EC ₅₀ = 0.90–3.93μM ）。氨基甲酸咪唑类似物8a（EC ₅₀=0.9μM）的效力是MMB的16倍。口服这些化合物后，在BALB / c小鼠中确定了8a和MMB的相对生物利用度。已经证明，MMB和8a的绝对血浆生物利用度分别为6.7±0.8％和45.5±2％。这些结果表明，与MMB相比，口服后8a的PK参数显示出显着改善的生物利用度和暴露。类似物8a被认为是治疗急性骨髓性白血病的潜在临床候选者。