Synthesis of Vinblastine Analogues with Improved Physiochemical Properties

描述（由申请人提供）：长春花碱(1)和长春新碱(2)是最广泛区分的长春花生物碱，因为它们在临床用作抗肿瘤治疗药物。这些生物碱是第一批被确定为微管和有丝分裂抑制剂的化合物，被认为是癌症化疗的关键靶点。其他几种1和2的类似物已经成功地用作抗肿瘤药物，如长春地辛(3)，长春瑞滨(4)，以及最近该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出具有更好代谢稳定性的1和7的类似物。代谢稳定性在药物发现过程中是至关重要的，因为它决定了清除率、半衰期和生物利用度。所提出的1的类似物具有改进的物理化学性质，对于治疗乳腺癌、膀胱癌、小细胞肺癌以及白血病和淋巴瘤应该证明是重要的。该提案的长期目标是开发1的类似物，从而产生一系列新的具有更好疗效的长春花生物碱，最终产生新一代癌症化疗药物。提出了1的几个类似物，每个类似物都包含对代谢降解改善稳定性的各种模式。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细化，将导致复杂的生物碱类似物10和11，它们将稳定C7的代谢氧化位置。类似地，提出了四种vindoline(7)类似物，具有c3 -生物等异体替代品。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位置具有更高的稳定性。

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.