Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation

Lichtor, Phillip A.; Miller, Scott J.

doi:10.1038/nchem.1469

Cited by 153 publications

(120 citation statements)

References 39 publications

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“…Site-selective chemistry 1–5 is essential for creating homogeneously modified biologics 6,7 , studying protein structure and function 8 , generating materials with defined composition 9 , and on-demand modification of complex small molecules 10,11 . Existing approaches for site-selective chemistry utilize either reaction pairs that are orthogonal to other functional groups on the target of interest (Fig.…”

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confidence: 99%

π-Clamp-mediated cysteine conjugation

et al. 2015

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Site-selective functionalization of complex molecules is a grand challenge in chemistry. Protecting groups or catalysts must be used to selectively modify one site among many that are similarly reactive. General strategies are rare such the local chemical environment around the target site is tuned for selective transformation. Here we show a four amino acid sequence (Phe-Cys-Pro-Phe), which we call the “π-clamp”, tunes the reactivity of its cysteine thiol for the site-selective conjugation with perfluoroaromatic reagents. We used the π-clamp to selectively modify one cysteine site in proteins containing multiple endogenous cysteine residues (e.g. antibodies and cysteine-based enzymes), which was impossible with prior cysteine modification methods. The modified π-clamp antibodies retained binding affinity to their targets, enabling the synthesis of site-specific antibody-drug conjugates (ADCs) for selective killing of HER2-positive breast cancer cells. The π-clamp is an unexpected approach for site-selective chemistry and provides opportunities to modify biomolecules for research and therapeutics.

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confidence: 99%

π-Clamp-mediated cysteine conjugation

et al. 2015

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“…Peptides 6 and 7 were identified in a one-bead-onecompound combinatorial screening and catalyze epoxidation of farnesol to the corresponding 2,3-monoepoxide and 6,7-monoepoxide derivatives, respectively, with excellent regiocontrol [18 ]. The active site of both catalysts is the carboxylic acid group of the N-terminal amino acid that is activated by hydrogen peroxide in a mixture of DIC, DMAP and HOBt to form a peracid that transfers the oxygen to the double bond.…”

Section: Peptide-catalyzed Regioselective Reactionsmentioning

confidence: 99%

Asymmetric catalysis with short-chain peptides

Lewandowski

Wennemers

2014

Current Opinion in Chemical Biology

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“…262,263 Specifically, we wondered whether minimal peptide sequences could mimic the impressive reactivity of much larger enzymes (Figure 54A). To create a peptide with activity for epoxidation, we considered aspartic acid as a potential catalytic residue.…”

Section: C–h Oxidationmentioning

confidence: 99%

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

2017

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The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogs of natural products by this approach is then described as a quintessential “late-stage functionalization” exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this review is on the recent studies of non-enzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C–H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C–C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

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Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation

Cited by 153 publications

References 39 publications

π-Clamp-mediated cysteine conjugation

π-Clamp-mediated cysteine conjugation

Asymmetric catalysis with short-chain peptides

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

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