Synthesis of Vinblastine Analogues with Improved Physiochemical Properties

性状（由申请方提供）：由于长春碱（1）和长春新碱（2）在临床上用作抗肿瘤治疗药物，因此是最广泛区分的生物碱。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之一，微管和有丝分裂抑制剂被认为是癌症化疗中的关键靶点。1和2的其他几种类似物已成功用作抗肿瘤剂，如长春地辛（3）、长春瑞滨（4）和最近的第三种半合成长春氟宁（5）。这些药物的成功促使我们设计具有改善的代谢稳定性的1和7的类似物。代谢稳定性在药物发现过程中至关重要，因为它决定了清除率、半衰期和生物利用度。建议的类似物1，具有改善的物理化学性质，应该证明是重要的乳腺癌，膀胱癌，小细胞肺癌以及白血病和淋巴瘤的治疗。该提案的长期目标是开发1的类似物，从而产生具有更好疗效的新系列的Escherichia生物碱，最终产生新一代癌症化疗剂。 提出了1的几种类似物，每种类似物都含有对代谢降解稳定性改善的各种模式。第一组类似物，10和11，将通过利用现代生物化学方法合成制备。随后使用所提出的策略对这些类似物进行精制将产生复合生物碱类似物10和11，其将稳定C7位置以进行代谢氧化。类似地，提出了四种具有C3-生物电子等排体取代的文多灵（7）类似物。这些类似物具有双重影响。首先，与通常不稳定的甲酯相比，它们将在C3位赋予更高水平的稳定性。 其次，它们应该对用于接近文多灵及其类似物的中心核的[4+2]/[3+2]级联反应具有显著影响。最后，将制备C5-三氟甲基类似物（35），其将用作乙基替代物。最近发现CF 3基团在大小上比异丙基更接近乙基。此外，通过加入捕获烯烃（36），[4+2]/[3+2]反应级联的范围将被扩展以适应带有σ贫电子取代基（-CF 3、-F、-Br等）的富π电子烯烃。这将允许直接获得具有深层变化的关键文多林类似物。提出了替代策略，可以解释在[4+2]/[3+2]反应级联的Diels-Alder部分中36的反应性降低。这些策略包括采用刘易斯酸催化和实施携带所提出的生物电子等排体的替代二烯底物，其可以有效地降低HOMO亲二烯体-LUMO二烯间隙。这些试剂的设计和合成不仅对获得这些化合物进行生物学评价很重要，而且还将作为一个有见地的平台，用于扩大和发展[4+2]/[3+2]反应级联的影响，这在建立复杂的文多灵核心中至关重要。 公共卫生相关性：该提案描述了几种有价值的长春碱类似物（1）的有效合成，具有改善的代谢稳定性，从而提高疗效。长春碱（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选择，也是急性白血病、淋巴瘤和小细胞肺癌联合治疗的组成部分。所提出的1和2的类似物将通过稳定长春碱核心内的易代谢位置而导致这些化合物的总体功效（包括清除率、半衰期和生物活性）的显著进步。

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.