Synthesis of Vinblastine Analogues with Improved Physiochemical Properties

具有改善的理化性质的长春花碱类似物的合成

• 批准号: 8396178
• 负责人: Richard M Cross
• 金额: $ 4.92万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8396178
• 关键词: Accounting; Acids; Acute leukemia; Aldehydes; Alder plant; Alkaloids; Alkenes; Antimitotic Agents; Binding; Biochemical; Biological; Biological Availability; Bladder; Breast; Carbon; Catalysis; Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Combined Modality Therapy; Complement 5a; Complex; Development; Drug Kinetics; Electrons; Employment; Esters; Ethers; Evaluation; Face; Fluorine; Generations; Half-Life; Isomerism; Lead; Malignant Neoplasms; Metabolic; Methodology; Microtubules; Modification; Oral; Outcome; Oxazolidinones; Positioning Attribute; Process; Property; Reaction; Route; Series; Site; Therapeutic; Toxic effect; Tubulin; Vinblastine; Vinca Alkaloids; Vincristine; Vindesine; Vindoline; Vinorelbine; analog; antitumor agent; chemotherapy; design; diene; drug discovery; enol; improved; insight; leukemia/lymphoma; lung small cell carcinoma; member; metabolic abnormality assessment; oxidation; success; vinflunine; ylide

DESCRIPTION (provided by applicant): Vinblastine (1) and vincristine (2) are amongst the most widely distinguished Vinca alkaloids due to their clinical use as antitumor therapeutics. These alkaloids were amongst the first compounds identified as microtubule and mitosis inhibitors which are regarded as critical targets in cancer chemotherapies. Several other analogues of 1 and 2 have had success as antitumor agents such as vindesine (3), vinorelbine (4), and more recently a third semi-synthetic member of this class vinflunine (5). The success of these agents has prompted us to design analogues of 1 and 7 with improved metabolic stability. Metabolic stability is paramount in the drug discovery process as it governs clearance, half-life, and bioavailability. The proposed analogues of 1, possessing improved physicochemical properties, should prove important for the treatment of breast, bladder, and small cell lung cancers as well leukemia and lymphoma. The long term objectives of the proposal are the development of analogues of 1 leading to a new series of Vinca alkaloids with better efficacy ultimately yielding a new generation of cancer chemotherapy agents. Several analogues of 1 are proposed which each contains various modes of improved stability towards metabolic degradation. The first set of analogues, 10 and 11, will be prepared synthetically by utilizing modern fluorination methodologies. Subsequent elaboration of these analogues using the proposed strategy will lead to the complex alkaloid analogues 10 and 11 which will stabilize the C7 position to metabolic oxidation. Similarly, four vindoline (7) analogues are proposed that possess C3-bioisostere replacements. These analogues have a two-fold impact. Firstly, they will impart a higher level of stability at the C3 position as compared to the often labile methyl ester. Secondly, they should have a significant impact on the [4+2]/[3+2] cascade reaction that is employed to access the central core of vindoline and analogues thereof. Finally, a C5-trifluoromethyl analogue (35) will be prepared that will serve as an ethyl replacement. The CF3 group was recently discovered to more closely resemble the ethyl group than the isopropyl group in size. Furthermore, by enlisting the captodative olefin (36) the scope of the [4+2]/[3+2] reaction cascade will be expanded to accommodate pi electron-rich olefins bearing sigma electron-poor substituents (-CF3, -F, -Br, etc.) which will allow for direct access to key vindolin analogues with deep-seated changes. Alternative strategies are proposed that could account for reduced reactivity of 36 in the Diels-Alder portion of the [4+2]/[3+2] reaction cascade. These strategies include employment of Lewis acid catalysis and implementation of alternative diene substrates bearing the proposed bioisosteres which could effectively lower the HOMOdienophile-LUMOdiene gap. The design and synthesis of these agents is not only important to access these compounds for biological evaluation but will also serve as an insightful platform for expanding and developing the impact of the [4+2]/[3+2] reaction cascade which is so critical in the establishment of the complex vindoline core. PUBLIC HEALTH RELEVANCE: The proposal describes the efficient synthesis of several valuable analogues of vinblastine (1) with improved metabolic stability resulting in enhanced efficacy. Vinblastine (1) and its N-formyl analogue, vincristine (2), are essential components of the standard chemotherapy regimes that are used in first-line treatment options for four of the malignancies that can be cured through chemotherapy and are components of combination therapy in acute leukemia, lymphoma, and small cell lung cancer. The proposed analogues of 1 and 2 will lead to significant advances in the overall efficacy of these compounds including clearance, half-life, and biological activity by stabilizing metabolically liable positions within he vinblastine core.

描述（由申请人提供）：Vinblastine（1）和Vincristine（2）是由于临床用作抗肿瘤疗法的临床用途，是最广泛的Vinca生物碱。这些生物碱是最早被鉴定为微管和有丝分裂抑制剂的化合物，这些化合物被视为癌症化学疗法中的关键靶标。 1和2的其他几个类似物也成功地是抗肿瘤剂，例如Vindesine（3），Vinorelbine（4），最近是该类Vinflunine（5）的第三个半合成成员。这些代理的成功促使我们设计了1和7的类似物，并改善了代谢稳定性。代谢稳定性在药物发现过程中至关重要，因为它控制着清除，半衰期和生物利用度。提出的类似物具有改善的物理化学特性，对治疗乳腺，膀胱和小细胞肺癌以及白血病和淋巴瘤的治疗应很重要。该提案的长期目标是开发1个类似物，从而导致一系列新系列的Vinca生物碱，最终产生了新一代的癌症化学疗法剂。 提出了几种类似物，每个类似物都包含各种改善代谢降解的稳定性模式。第一组类似物（10和11）将通过使用现代氟化方法来合成制备。随后使用提出的策略对这些类似物进行详细说明将导致复杂的生物碱类似物10和11，这将稳定C7位置以代谢氧化。同样，提出了具有C3生物膜替代品的四个Vindoline（7）类似物。这些类似物具有两倍的影响。首先，与经常不稳定的甲酯相比，它们将在C3位置赋予更高水平的稳定性。 其次，它们应该对[4+2]/[3+2]级联反应产生重大影响，该反应用于进入Vindoline及其类似物的中心核心。最后，将准备一个C5-三氟甲基类似物（35​​），将作为乙基替代品。最近发现，与异丙基组相比，CF3组的大小更为类似于乙基。此外，通过捕获粘剂烯烃（36）[4+2]/[3+2]反应级联的范围将扩展以适应带有Sigma Electron poor poor取代基（-cf3，-f，-f，-f，-br等）的富含Pi电子的烯烃的范围，这将使您可以直接访问与密钥替代的替代替代替代替代替代替代替代替补元素。提出了替代策略，可以说明[4+2]/[3+2]反应级联的Diels-Alder部分中的反应性降低。这些策略包括使用刘易斯酸催化和实施替代的二烯底物，这些二烯底物具有拟议的生物同体，这些基质可以有效地降低同叶二烯二苯性间隙。这些药物的设计和合成不仅对于访问这些化合物进行生物学评估很重要，而且还将成为扩展和发展[4+2]/[3+2]反应级联的影响的有见地的平台，这对于建立复杂的Vindoline Core至关重要。 公共卫生相关性：该提案描述了葡萄碱（1）的几种有价值的类似物的有效合成，并改善了代谢稳定性，从而提高了疗效。葡萄蛋白（1）及其N-纤维基类似物vincristine（2）是标准化学疗法方案的必不可少的成分，用于四种恶性肿瘤的一线治疗选择中，可以通过化学疗法治愈，并且是急性白血病，淋巴瘤和小细胞肺癌的组合治疗成分。提出的类似物的1和2类似物将通过稳定vinblastine核心内的代谢责任位置，从而在这些化合物的总体疗效中取得重大进展。