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

描述(申请人提供)：这项提案的长期目标是开发一种基于植物衍生化合物巴特内酯(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对原代人类白血病标本具有高度的细胞毒性，但对正常的造血组织无毒。因此，集体证据表明，PTL作为一种抗癌药物具有广阔的潜力。然而，尽管这种化合物具有显著的性质，但临床开发一直非常有限，可能是由于PTL的药理性质较差。事实上，据我们所知，唯一进入临床试验阶段的基于PTL的化合物是二甲氨基帕特内酯(DMAPT)，这是我们之前开发的一种口服生物可用PTL类似物。因此，展望未来，我们认为，应用新的策略来创造更多药理上有用的基于PTL的药物是一个高度优先的任务。在对PTL进行各种化学改性的过程中，证明了C-10甲基可以通过与合适的氧化剂反应而羟化。这个反应将C-9-C-10双键的几何构型从Z改变为E，得到了羟甲基1(10)-顺式巴特内酯类似物，以前被描述为黑色素内酯B(MM-B)。有趣的是，MM-B的生物学活性与PTL相同，保留了对白血病细胞的强烈特异性。C-10羟甲基的存在现在为设计一类全新的PTL类似物创造了机会。因此，在本申请中，我们建议开发和测试基于MM-B的新型产品。具体地说，这项研究的目的将是1)合成新型水溶性MM-B前体药物，2)进行药理和生物功效研究，以及3)对MM-B的作用机制进行分子和细胞表征。综上所述，这些研究将创造并验证一种全新的抗癌剂。此外，通过表征这种新的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。 与公共卫生相关：该项目的目标是确定治疗白血病的新的、更好的方法。我们建议开发从天然化合物巴特内酯衍生出来的新药，这种化合物已显示出显著的抗白血病活性。我们的研究将合成和测试新的口服巴特内酯衍生物。

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. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify new and better ways to treat leukemia. We propose to develop new drugs derived from the naturally occurring compound parthenolide, which has shown significant activity as an anti-leukemia agent. Our studies will synthesize and test novel orally-available parthenolide derivatives