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

描述（由申请人提供）：本提案的长期目标是开发基于植物衍生化合物孤雌菊（PTL）的新型抗癌剂。先前的研究已经证明，PTL对广泛的恶性肿瘤具有有效的细胞毒性活性，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。除了实体瘤研究，包括我们自己在内的几个研究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细胞毒性，但对正常造血组织无毒。因此，集体证据表明PTL具有作为抗癌剂的广泛潜力。然而，尽管该化合物具有显著的性质，但临床开发非常有限，可能是由于PTL的药理学性质较差。事实上，据我们所知，唯一达到临床试验阶段工作的基于PTL的化合物是二甲氨基银胶菊（DMAPT），我们先前将其开发为口服生物可利用的PTL类似物。因此，展望未来，我们认为，应用新的策略来创造更有用的基于PTL的药物形式是一个高度优先事项。在进行PTL的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。该反应将C-9-C-10双键的几何结构从Z改变为E，得到羟甲基1（10）-顺式-小白菊素类似物，一种先前描述为黑素Magnesium B（MM-B）的化合物。有趣的是，MM-B的生物活性与PTL相同，保留了对白血病细胞的强特异性。C-10羟甲基的存在现在为设计全新类型的PTL类似物创造了机会。因此，在本申请中，我们提出开发和测试新颖的基于MM-B的产品。具体而言，本研究的目的是1）合成新型水溶性MM-B前药，2）进行药理学和生物学疗效研究，3）对MM-B的作用机制进行分子和细胞表征。这些研究将创造和验证一种全新的抗癌药物。此外，通过表征这种新型PTL衍生物的分子作用机制，应该可以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.