A5072194506- Pharmacogenetics and Drug Metabolism
- Synthesis and Catalytic Reactions
- Asymmetric Hydrogenation and Catalysis
- Enzyme Catalysis and Immobilization
- Chemistry and Chemical Engineering
- Biochemical and Molecular Research
- Metal-Catalyzed Oxygenation Mechanisms
- Porphyrin and Phthalocyanine Chemistry
- interferon and immune responses
- Microbial Natural Products and Biosynthesis
- RNA and protein synthesis mechanisms
- Sesquiterpenes and Asteraceae Studies
- Chemical Synthesis and Analysis
- Microbial Metabolic Engineering and Bioproduction
- Synthetic Organic Chemistry Methods
- Catalytic C–H Functionalization Methods
- HIV/AIDS drug development and treatment
Merck & Co., Inc., Rahway, NJ, USA (United States)
2019-2024
University of Rochester
2013-2020
Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification intermediates. They also allow be linked together overcome an unfavorable equilibrium or accumulation unstable inhibitory We report in vitro cascade synthesis investigational HIV...
Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising a range of oxidations, practical use enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering application non-heme iron α-ketoglutarate-dependent dioxygenase direct stereo- regio-selective non-native fluoroindanone en route to oncology treatment belzutifan, replacing five-step...
Cytochrome P450 enzymes can effectively promote the activation and cyclization of carbonazidate substrates to yield oxazolidinones via an intramolecular nitrene C–H insertion reaction. Investigation substrate scope shows that while benzylic/allylic bonds are most readily aminated by these biocatalysts, stronger, secondary also accessible functionalization. Leveraging this "non-native" reactivity assisted fingerprint-based predictions, improved active-site variants bacterial CYP102A1 could be...
The sesquiterpene lactone parthenolide has recently attracted considerable attention owing to its promising antitumor properties, in particular the context of stem-cell cancers including leukemia. Yet, lack viable synthetic routes for re-elaborating this complex natural product represented a fundamental obstacle toward further optimization pharmacological properties. Here, we demonstrate how challenge could be addressed via selective, late-stage sp3 C–H bond functionalization mediated by...
An improved synthesis has been developed for belzutifan, a novel HIF-2α inhibitor the treatment of Von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC). The efficiency previous supply and commercial routes was encumbered by lengthy 5-step sequence, needed to install chiral benzylic alcohol traditional methods. Identification directed evolution FoPip4H, an iron/α-ketoglutarate dependent hydroxylase, enabled direct enantioselective C–H hydroxylation simple indanone starting...
The development of effective strategies for modulating the reactivity and selectivity cytochrome P450 enzymes represents a key step toward expediting use these biocatalysts synthetic applications. We have investigated potential unnatural amino acid mutagenesis to aid efforts in this direction. Four acids with diverse aromatic side chains were incorporated at 11 active-site positions substrate-promiscuous CYP102A1 variant. resulting "uP450s" then tested their catalytic activity...
Cytochromes P450 have been recently identified as a promising class of biocatalysts for mediating C–H aminations via nitrene transfer, valuable transformation forging new C–N bonds. The catalytic efficiency P450s in these non-native transformations is however significantly inferior to that exhibited by enzymes their native monooxygenase function. Using mechanism-guided strategy, we report here the rational design series P450BM3-based variants with dramatically enhanced amination activity...
Belzutifan has been approved recently by the U.S. Food and Drug Administration (FDA) for treating patients with certain types of Von Hippel-Lindau (VHL) disease-associated tumors. Although a commercial synthetic process established to make belzutifan, further optimized fewer steps, improved cost-effectiveness, smaller environmental footprint is always in demand. In new route, single-step biocatalytic hydroxylation reaction was used replace five chemical steps required previous route....
Abstract Biocatalytic oxidations are an emerging technology for selective C−H bond activation. While promising a range of oxidations, practical use enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering application non‐heme iron α‐ketoglutarate‐dependent dioxygenase direct stereo‐ regio‐selective non‐native fluoroindanone en route to oncology treatment belzutifan, replacing...