FR900482 and the mitomycins are two intriguing classes of alkaloid natural products that have analogous biological mechanisms and obvious structural similarity. Both classes possess potent anti-cancer activity, a feature that has led to their investigation and implementation for the clinical treatment of human cancer. Given the structural similarity between these natural products, we envisioned a common synthetic strategy by which both classes could be targeted through assembling the mitomycin skeleton prior to further oxidative functionalization. Realization of this strategy with respect to FR900482 was accomplished through the synthesis of 7-epi-FR900482, which displayed equal potency relative to the natural product against two human cancer cell lines. With the challenging goal of a synthesis of either mitomycin or FR900482 in mind, several methodologies where explored. While not all of these methods ultimately proved useful for our synthetic goal, a number of them led to intriguing findings that provide a more complete understanding of several methodologies. In particular, amination via π-allyl palladium complexes for the synthesis of tetrahydroquinolines, 8-membered heterocycle formation via carbonylative lactamization, and amination through late-stage C-H insertion via rhodium catalysis all featured prominently in our synthetic studies.
We report the determination of the full stereostructure of (-)-ushikulide A (1), a spiroketal containing macrolide by total synthesis. Ushikulide A (1) was isolated from a culture broth of Streptomyces sp. IUK-102 and exhibits potent immunosuppressant activity (IC 50 = 70 nM). To embark upon an ushikulide A synthesis, a tentative assignment was made based on analogy to cytovaricin (2), a related macrolide isolated from a culture of Streptomyces diastatochromogenes whose full structure was previously established via synthesis and X-ray crystallography. This report delineates studies on several key steps, namely a direct aldol reaction catalyzed by the dinuclear zinc ProPhenol complex, a metal catalyzed spiroketalization, as well as application of an unprecedented asymmetric alkynylation of a simple saturated aldehyde with methyl propiolate to prepare the nucleophilic partner for a Marshall-Tamaru propargylation. These studies culminated in the first total synthesis and stereochemical assignment of (-)-ushikulide A and significantly extended the scope of the abovementioned methodologies.
In spite of the tremendous advances in modern spectroscopic methods, organic synthesis continues to play a pivotal role in elucidating the full structures of complex natural products. This method has the advantage that even in the absence of a firm structural assignment, a combination of logic and spectroscopic comparison can arrive at the correct structure. Herein, we report execution of this strategy with respect to ushikulide A, a newly isolated and previously stereochemically-undefined member of the oligomycin-rutamycin family. To maximize synthetic efficiency, we envisioned chemoselective manipulation of orthogonally reactive functional groups, notably alkenes and alkynes as surrogates for certain carbonyl and hydroxyl functionalities. This approach has the dual effect of minimizing the number of steps and protecting groups required for our synthetic route. This strategy culminated in the efficient synthesis and stereochemical assignment of ushikulide A.
FR900482 is a potent anti-tumor therapeutic that has been investigated as a replacement candidate for the clinically useful Mitomycin C. Herein, we report synthesis and biological testing of 7-Epi (+)-FR900482, which demonstrates equal potency relative to the natural product against several cancer cell lines. Highlights of this work include utilization of our palladium-catalyzed DYKAT methodology and development of a Polonovski oxidative ring expansion strategy to yield this equipotent epimer in 23 linear steps.
Dedicated to Professor JosØ Barluenga on the occasion of his 70th birthdayThe Heck reaction has proven to be an exceptionally useful tool for the construction of carbon-carbon bonds. The traditional Heck reaction consists of oxidative addition by palladium(0) to a carbon-halogen bond, followed by migratory insertion into a carbon-carbon p-system and finally b-hydrogen elimination. A number of clever domino reactions [1] have been implemented using either sequential Heck reactions [2] or an initial Heck reaction in tandem with another palladium catalyzed process. [3] During efforts toward the synthesis of FR900482, [4] we intended to utilize an 8-exo-trig Heck reaction to forge the benzazacine core of the molecule (Scheme 1). Instead when 3 was exposed to Heck reaction conditions [5] a remarkable result was obtained. Rather than the expected exocyclic olefin 2, bicycle 6 was formed in remarkable yield with no trace of the expected Heck product [Eq. (1)]. This result represented an unprecedented domino Heck/alkylation, even in the presence of geometrically accessible b-hydrogen atoms. We were intrigued by this demonstration that b-hydrogen elimination may not always be kinetically preferred over alternative terminating steps. This possibility would open many alternative synthetic disconnections if it could be employed in a predictable manner.Several mechanistic scenarios could account for this remarkable transformation (Scheme 2). We believe the most likely mechanism for the observed product is oxidative addition of Pd 0 to the carbon-iodine bond of 3 yielding 3 a, followed by migratory insertion through an 8-exo-trig pathway to afford intermediate 3 d. Rather than the expected b-hydrogen elimination, which is not geometrically inaccessible, a transannular alkylation reaction ensued. This most likely occurs by nucleophilic displacement of palladium by nitrogen, which regenerated the Pd 0 catalyst and yielded tetracycle 6. A reductive elimination pathway to form the C À N bond is also conceivable, however, the lack of reported C À N reductive elimination with this catalyst system causes us to favor an alkylation pathway. The surprising reluctance of 3 d[a] Prof.
CDK4/6 inhibitors give clinical benefit in the treatment of metastatic ER+/HER2- breast cancer (mBC) in combination with endocrine therapy. Although this class of inhibitor has been extensively studied in several other cancer types, CDK4/6 inhibitors have not been approved as a treatment for outside of ER+/HER2- cancer. We evaluated the clinically approved CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib—in a 500+ cell line screening platform and identified several cancers outside of breast that may have subpopulations that are sensitive to CDK4/6 inhibitors. Kinome and KiNativ analyses helped identify differences in sensitivity/selectivity that we observed between each CDK4/6 inhibitor. Comprehensive molecular profiling of the cell lines at baseline allowed us to screen for potential associations with sensitivity to these compounds. These analyses identified potential biomarkers of sensitivity in non-small cell lung carcinoma (NSCLC) and colorectal cancer (CRC) that will later be evaluated in human clinical studies. Having thoroughly studied the CDK4/6 class and discovered new opportunities for clinical development, we set out to develop a CDK4/6 inhibitor that would have the best properties of the two distinguished class members. Using our proprietary chemistry, we developed UCT-03-008, a potent CDK4/6 small molecular inhibitor with a pharmacology known to enhance therapeutic benefit in mBC. Pharmacokinetic properties of UCT-03-008 are improved over those of other CDK4/6 inhibitors. UCT-03-008 has activity in preclinical models as a monotherapy and yields in vivo efficacy in multiple cancer models outside of ER+/HER2- breast cancer, including CRC and NSCLC. In summary, UCT-03-008 is a CDK4/6 inhibitor with optimized pharmacological properties. Clinical development of this compound will be guided by the biomarker hypotheses developed here. We are currently enrolling patients for treatment with UCT-03-008 in a Phase 1 clinical trial of advanced solid tumors (NCT05103046). Citation Format: Neil A. O'Brien, Martina S. McDermott, Brendan M. O'Boyle, Justin A. Hilf, Oliver Loson, Kevin Chau, Weiping Jia, Naeimeh Kamranpour, Tong Luo, Raul Ayala, Shawnt Issakhanian, John A. Glaspy, Brian M. Stoltz, Dennis J. Slamon. Development and characterization of a novel CDK4/6 inhibitor for the treatment of CDK4/6 dependent cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5991.
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