???Novel melampomagnolide B-based prodrugs for the treatment of leukemia???

描述（由申请人提供）：本申请的长期目标是开发一类基于植物衍生化合物parthenolide （PTL）的新型抗癌药物。先前的研究表明，PTL对多种恶性肿瘤具有强大的细胞毒活性，包括乳腺癌、肺癌、前列腺癌、结肠癌、肝癌、肾癌、胰腺癌、脑癌和骨癌。除了实体肿瘤研究，包括我们自己在内的几个小组也专注于人类白血病（或相关的血液恶性肿瘤）。我们已经证明，PTL对原发性人类白血病标本具有高度的细胞毒性，但对正常造血组织无毒。因此，综合证据表明，PTL作为抗癌药物具有广泛的潜力。然而，尽管该化合物具有显著的特性，但临床开发非常有限，可能是由于PTL的药理特性较差。事实上，据我们所知，唯一基于PTL的化合物达到临床试验阶段的工作是二甲氨基parthenolide (DMAPT)，我们之前开发了一种口服生物可利用的PTL类似物。因此，展望未来，我们相信应用新的策略来创造更多的药理学上有用的基于ptl的药物形式是一个高度优先考虑的问题。在对PTL进行各种化学修饰的过程中，证明了C-10甲基可以通过与合适的氧化剂反应而羟基化。这个反应改变了C-9-C-10双键的几何形状，从Z到E，得到了羟基甲基1(10)-顺式parthenolide类似物，这种化合物以前被称为三聚氰马甘醇内酯B （MM-B）。有趣的是，MM-B的生物活性与PTL相同，对白血病细胞具有很强的特异性。C-10羟甲基的存在为设计一种全新的PTL类似物创造了机会。因此，在目前的应用中，我们建议开发和测试基于mm -b的新型产品。具体而言，本研究的目的将是1)合成新的水溶性MM-B前药，2)进行药理学和生物学功效研究，3)对MM-B的作用机制进行分子和细胞表征。综合这些研究将创造并验证一种全新的抗癌剂。此外，通过表征这种新型PTL衍生物的分子作用机制，应该有可能进一步完善选择性根除癌细胞的策略。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to develop a novel class of anti-cancer agents based on the plant derived compound parthenolide (PTL). Previous studies have demonstrated that PTL has potent cytotoxic activity against a broad range of malignancies, including cancers of the breast, lung, prostate, colon, liver, kidney, pancreas, brain, and bone. In addition to solid tumor studies, several groups including our own have focused on human leukemia (or related hematologic malignancies). We have demonstrated that PTL is highly cytotoxic to primary human leukemia specimens, but non-toxic to normal blood-forming tissues. Thus, the collective evidence suggests that PTL has broad potential as an anti-cancer agent. However, despite the remarkable properties of this compound, clinical development has been very limited, likely due to the poor pharmacological properties of PTL. Indeed, to our knowledge the only PTL-based compound to reach clinical trial stage work is dimethylamino parthenolide (DMAPT), which we previously developed as an orally bioavailable PTL analog. Thus, going forward we believe that applying novel strategies to create more pharmacologically useful forms of PTL-based agents is a high priority. In the course of performing various chemical modifications of PTL, it was demonstrated that the C-10 methyl group can be hydroxylated by reaction with a suitable oxidizing agent. This reaction changes the geometry of the C-9-C-10 double bond from Z to E to afford a hydroxymethyl 1(10)-cis-parthenolide analogue, a compound previously described as melampomagnolide B (MM-B). Intriguingly, the biological activity of MM-B is identical to PTL, retaining strong specificity for leukemia cells. The presence of the C-10 hydroxymethyl group now creates the opportunity for designing an entirely new class of PTL analog. Thus, in the present application we propose to develop and test novel MM-B-based products. Specifically, the aims of the study will be to 1) synthesize novel water-soluble MM-B prodrugs, 2) perform pharmacological and biological efficacy studies, and 3) perform molecular and cellular characterization of the mechanism of action of MM-B. Taken together these studies will create and validate an entirely new type of anti-cancer agent. In addition, by characterizing the molecular mechanism of action of this novel PTL derivative, it should be possible to further refine strategies for the selective eradication of cancer cells.