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

???新型基于 melampomagnolide B 的前药用于治疗白血病???

• 批准号: 8185539
• 负责人: Peter Anthony Crooks
• 金额: $ 0.19万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2011-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185539
• 关键词: Animal Model; Antineoplastic Agents; Bioavailable; Biochemical; Biological; Biological Models; Biological Process; Biotin; Blood; Brain; Buffers; Cells; Chemicals; Clinical; Clinical Trials; Colon; Data; Development; Disease; Drug Kinetics; Family; Goals; Half-Life; Hematologic Neoplasms; Hematopoietic Neoplasms; Human; Hydrolysis; In Vitro; Kidney; Kinetics; Lactones; Lead; Liquid substance; Liver; Lung; Malignant - descriptor; Malignant Neoplasms; Metabolic; Modification; Molecular; Molecular Mechanisms of Action; Nature; Normal Cell; Normal tissue morphology; Oral; Oral Administration; Oxidants; Pancreas; Parents; Pharmaceutical Preparations; Pharmacologic Substance; Phase I Clinical Trials; Plants; Plasma; Prodrugs; Property; Prostate; Reaction; Relative (related person); Reporting; Role; Series; Sesquiterpenes; Simulate; Solid Neoplasm; Specificity; Specimen; Staging; Structure; Testing; Therapeutic Agents; Time; Tissues; Toxic effect; Toxicology; Water; Work; analog; aqueous; base; bone; cancer cell; carbene; cell type; cytotoxic; design; drug development; efficacy testing; gastrointestinal; improved; in vivo; killings; leukemia; malignant breast neoplasm; member; methyl group; novel; novel strategies; parthenolide; pi bond; pre-clinical

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

描述（由申请人提供）：该提案的长期目标是基于植物衍生的复合Parthenolide（PTL）开发一种新型的抗癌剂。先前的研究表明，PTL对广泛的恶性肿瘤具有有效的细胞毒性活性，包括乳房，肺，前列腺，结肠，肝脏，肾脏，胰腺，胰腺，脑和骨骼的癌症。除了实体瘤研究外，包括我们自己在内的几个小组都集中在人类白血病（或相关的血液性恶性肿瘤）上。我们已经证明，PTL对原发性人性白血病标本高度细胞毒性，但对正常的血液形成组织无毒。因此，集体证据表明，PTL作为抗癌药具有广泛的潜力。然而，尽管这种化合物具有显着的特性，但临床发育仍非常有限，这可能是由于PTL的药理特性不佳。实际上，据我们所知，唯一基于PTL的化合物可以达到临床试验阶段工作，是二甲基氨基parthenolide（DMAPT），我们先前以口服生物利用的PTL类似物开发。因此，向前看，我们认为，采用新颖的策略来创建基于PTL的代理的更有用的药理学形式是一个重点。在进行PTL的各种化学修饰过程中，证明C-10甲基可以通过与合适的氧化剂反应进行羟基化。该反应将C-9-C-10双键从Z到E的几何形状变为提供羟甲基1（10）-Cis- parthenolide类似物，该化合物先前被描述为Melampomagagnolide 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特特异性。现在，C-10羟基基团的存在为设计全新的PTL类似物设计创造了机会。因此，在本应用程序中，我们建议开发和测试新型MM-B基产品。具体而言，该研究的目的将是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，以及3）对MM-B作用机理进行分子和细胞表征。综上所述，这些研究将创建并验证一种全新的抗癌剂。另外，通过表征这种新型PTL衍生物的分子作用机理，应该可以进一步完善策略，以选择性地消除癌细胞。 公共卫生相关性：该项目的目的是确定治疗白血病的新方法。我们建议开发出源自天然化合物parthenolide的新药物，该药物作为抗白血病药物表现出显着的活性。我们的研究将合成和测试新型口服可用的parthenolide衍生物