Mannich reactions and the synthesis of heterocycles as antiproliferative agents in cancer and neglected tropical disease

Efficient construction of C-N bonds and nitrogen-containing heterocycles is instrumental in synthesizing chemical building blocks with direct applicability to the pharmaceutical industry. Three projects incorporating this theme to address unmet scientific challenges are reported herein: quinolinone inhibitors of LSF, pyrazolopyrrolidnones for the treatment of leishmaniasis, and an asymmetric Petasis reaction to synthesize chiral 1,2-amino alcohols. Quinolinone inhibitors of LSF, an oncogenic transcription factor overexpressed in several liver cancers, were previously reported as potential cancer therapies, however; they exhibited poor oral bioavailability, and the series was optimized for improved pharmacokinetics. Newly synthesized analogs demonstrate nanomolar potency against liver cancer cells in vitro with improved pharmacokinetic properties. Furthermore, the synthetic route was optimized to deliver lead compounds in multi-gram quantities, and to establish regio-control over the final intramolecular Friedel-Crafts cyclization. A series of pyrazolopyrrolidinones was developed to address an unmet medical need for new treatments against the parasitic disease leishmaniasis. Over 200 analogs were generated via parallel synthesis, which were assayed in a high-throughput phenotypic screen and many demonstrated low-micromolar to nanomolar potency against Leishmania parasites in vitro. SAR trends and in vivo pharmacokinetic and efficacy studies identified a critical balance between physiochemical properties (solubility, lipophilicity, plasma protein binding) and potency that appear to limit expected in vivo efficacy. These trends informed subsequent analog design to further optimize the physiochemical properties for in vivo efficacy, with further studies pending. Chiral 1,2-amino alcohols are valuable building blocks found in drugs, natural products, and organocatalysts. To enable their synthesis, an asymmetric multicomponent Petasis reaction was developed using boronic acids or boronates, primary or secondary amines, and glycolaldehyde, catalyzed by chiral biphenols. The reactions are run in ethanol or trifluorotoluene with commercially available starting materials, accommodate electron deficient and electron rich boron reagents, and afford products in up to 99% yield and >99:1 er. The reaction is scalable to generate decagram quantities of product, and an extractive purification procedure allows for chromatography-free product isolation and catalyst recovery.2022-06-04T00:00:00