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）： 长春花碱 (1) 和长春新碱 (2) 由于其作为抗肿瘤治疗剂的临床用途而成为最广泛区分的长春花生物碱。这些生物碱是首批被确定为微管和有丝分裂抑制剂的化合物之一，被视为癌症化疗的关键靶点。 1 和 2 的其他几种类似物已成功用作抗肿瘤药物，例如长春地辛 (3)、长春瑞滨 (4)，以及最近此类的第三种半合成成员长春氟宁 (5)。这些药物的成功促使我们设计具有改善代谢稳定性的 1 和 7 的类似物。代谢稳定性在药物发现过程中至关重要，因为它控制着清除率、半衰期和生物利用度。所提出的1的类似物具有改善的理化性质，对于治疗乳腺癌、膀胱癌、小细胞肺癌以及白血病和淋巴瘤具有重要意义。该提案的长期目标是开发 1 的类似物，从而产生一系列具有更好功效的新长春花生物碱，最终产生新一代癌症化疗药物。 提出了1的几种类似物，每种类似物都包含针对代谢降解的改进稳定性的多种模式。第一组类似物 10 和 11 将利用现代氟化方法合成制备。随后使用所提出的策略对这些类似物进行精制将产生复杂的生物碱类似物 10 和 11，它们将稳定代谢氧化的 C7 位置。类似地，提出了四种文多灵 (7) 类似物，它们具有 C3-生物等排体替代物。这些类似物具有双重影响。首先，与通常不稳定的甲酯相比，它们在 C3 位具有更高水平的稳定性。 其次，它们应该对用于获取文多灵及其类似物的中心核心的[4+2]/[3+2]级联反应具有显着影响。最后，将制备 C5-三氟甲基类似物 (35)，用作乙基替代物。最近发现 CF3 基团的大小与乙基比异丙基更相似。此外，通过使用captodative烯烃（36），[4+2]/[3+2]反应级联的范围将扩大，以适应带有σ缺电子取代基（-CF3、-F、 -Br 等），这将允许直接访问具有深层次变化的关键 Vindolin 类似物。提出了替代策略，可以解释 [4+2]/[3+2] 反应级联的 Diels-Alder 部分中 36 的反应性降低。这些策略包括使用路易斯酸催化和使用带有所提出的生物等排体的替代二烯底物，这可以有效降低HOMO二烯体-LUMO二烯间隙。这些试剂的设计和合成不仅对于获取这些化合物进行生物学评价很重要，而且还将作为扩展和发展 [4+2]/[3+2] 反应级联影响的富有洞察力的平台，因此对于建立复杂的文多灵核心至关重要。 公共健康相关性：该提案描述了几种有价值的长春花碱类似物 (1) 的有效合成，这些类似物具有改善的代谢稳定性，从而提高了功效。长春花碱 (1) 及其 N-甲酰基类似物长春新碱 (2) 是标准化疗方案的重要组成部分，用于四种可通过化疗治愈的恶性肿瘤的一线治疗方案，并且是联合治疗的组成部分用于急性白血病、淋巴瘤和小细胞肺癌。所提出的 1 和 2 类似物将通过稳定长春花碱核心内的代谢敏感位置，从而显着提高这些化合物的整体功效，包括清除率、半衰期和生物活性。