Identification of a melampomagnolide B analog as a potential lead molecule for treatment of acute myelogenous leukemia

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• 作者：Zaineb A.F. Albayati^a ; Venumadhav Janganati^a ; Zheng Chen^a ; Jessica Ponder^c ; Philip J. Breen^a ; Craig T. Jordan^b ; Peter A. Crooks^a ; ^{pacrooks@uams.edu}
• 关键词：Leukemia ; Melampomagnolide B ; Carbamates ; LC/MS/MS ; Pharmacokinetic properties ; Bioavailability
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：1235-1241
• 全文大小：913 K
• 卷排序：25

文摘

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 = 0.90–3.93 μM) when compared to parthenolide and the parent sesquiterpene, MMB (EC50 = 7.0 μM and 15.5 μM, respectively). The imidazole carbamate analog, 8a (EC50 = 0.9 μM), 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.