The enantioselective total synthesis of (-)-tetrodotoxin [(-)-TTX] and 4,9-anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]-sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11-norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms.

No abstract

The enantioselective total synthesis of (À)

Cyclin-dependent kinase 9 (CDK9) has long been considered an attractive therapeutic target for modulating transcription in cancers of high unmet clinical need. CDK9 coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release state and is considered an important co-factor for oncogenic transcription factors that drive transcription in an addictive manner. CDK9 modulation offers an approach for attenuating transcriptional dysregulation driven by amplified or overexpressed transcription factors, such as c-MYC. However, targeting CDK9 in the clinic has proven very challenging. This stems from the often highly intolerable cytotoxic effects likely due to off-target effects. Targeted protein degradation offers a novel approach for engineering enhanced selectivity and mitigating other liabilities of the conventional inhibition-driven approach that have been applied to date. Here, we present the design and characterization of a focused library of highly selective CDK9 degrader molecules with rapid kinetics and potency (half-degrading concentration of <1nM). We carry out transcriptional and phosphoproteomics profiling to comprehensively characterize the downstream effects and cellular adaptations resulting from CDK9 degradation. We gain new insights into adaptive responses to CDK9 modulation and the biological contexts most responsive for therapeutic application. Citation Format: Mohammed A. Toure, Keisuke Motoyama, André Richters, Angela N. Koehler. Design and characterization of highly potent and selective CDK9 heterobifunctional degraders [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 3409.