Synthesis of Vinblastine Analogues with Improved Physiochemical Properties

Scripps Research Institute, The, La Jolla CA

Investigators

Abstract

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.