On the prevalence of bridged macrocyclic pyrroloindolines formed in regiodivergent alkylations of tryptophan

Rose, Tristin E.; Curtin, Brice H.; Lawson, Kenneth V.; Simon, Adam J.; Houk, K. N.; Harran, Patrick G.

doi:10.1039/c5sc04612b

Cited by 16 publications

(18 citation statements)

References 55 publications

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“…For those studies to be successful, predicted binding interactions will need to be experimentally validated. Our prior experimental results suggest a majority of macrocyclization reactions simulated by CPMG will proceed (15)(16)(17)(18)(19)(20). In a series of studies, we demonstrated that the phenol of tyrosine and the indole of tryptophan react internally with the cinnamyl carbocation-regardless of the 1.…”

Section: Chemistry Biophysics and Computational Biologymentioning

confidence: 84%

“…distance between reacting positions in acyclic precursors (17,19). Heterocycles shown at the top of Fig.…”

Section: Chemistry Biophysics and Computational Biologymentioning

confidence: 99%

“…The methodology was designed to allow systematic alteration of product topology and properties by engaging a broad range of native peptide functional groups in carbon-heteroatom and carbon-carbon bond-forming reactions. Our experimental studies have demonstrated that templates G1-G3 engage aromatic side chains (including but not limited to phenol, indole, and imidazole) on the polyamides to participate in Friedel Crafts alkylation, metal-catalyzed allylic substitutions (also known as Tsuji-Trost reactions), and N-acyliminium ion-mediated cyclizations (15)(16)(17)(18)(19)(20). For example, macrocyclization under Pd 0 -catalysis affords C-O or C-N bonded macrocycles, wherein chemoselectivity is switchable by the addition of Cs 2 CO 3 (1 or 2).…”

mentioning

confidence: 97%

“…1). We have designed scaffolding reagents that are easily integrated into peptide structure to afford diverse ring connectivities and embedded heterocyclic motifs (15)(16)(17)(18)(19)(20). These structural features have been shown to improve target binding, the ability to passively transverse lipid membranes and resist proteolytic degradation (12).…”

mentioning

confidence: 99%

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Computational generation of an annotated gigalibrary of synthesizable, composite peptidic macrocycles

Saha

Dang

Svatunek

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Peptidomimetic macrocycles have the potential to regulate challenging therapeutic targets. Structures of this type having precise shapes and drug-like character are particularly coveted, but are relatively difficult to synthesize. Our laboratory has developed robust methods that integrate small-peptide units into designed scaffolds. These methods create macrocycles and embed condensed heterocycles to diversify outcomes and improve pharmacological properties. The hypothetical scope of the methodology is vast and far outpaces the capacity of our experimental format. We now describe a computational rendering of our methodology that creates an in silico three-dimensional library of composite peptidic macrocycles. Our open-source platform, CPMG (Composite Peptide Macrocycle Generator), has algorithmically generated a library of 2,020,794,198 macrocycles that can result from the multistep reaction sequences we have developed. Structures are generated based on predicted site reactivity and filtered on the basis of physical and three-dimensional properties to identify maximally diverse compounds for prioritization. For conformational analyses, we also introduce ConfBuster++, an RDKit port of the open-source software ConfBuster, which allows facile integration with CPMG and ready parallelization for better scalability. Our approach deeply probes ligand space accessible via our synthetic methodology and provides a resource for large-scale virtual screening.

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Section: Chemistry Biophysics and Computational Biologymentioning

confidence: 84%

“…distance between reacting positions in acyclic precursors (17,19). Heterocycles shown at the top of Fig.…”

Section: Chemistry Biophysics and Computational Biologymentioning

confidence: 99%

mentioning

confidence: 97%

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confidence: 99%

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Computational generation of an annotated gigalibrary of synthesizable, composite peptidic macrocycles

Saha

Dang

Svatunek

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Examples of such molecules are tetrahydro‐β‐carbolines, obtained from starting indole derivatives or heterocyclic systems obtained by oxa‐Pictet‐Spengler reactions …”

Section: Introductionmentioning

confidence: 99%

Theoretical insights into the regioselectivity of a Pictet-Spengler reaction: Transition state structures leading to salsolinol and isosalsolinol

Almodóvar

Rezende

Cassels

et al. 2016

J. Phys. Org. Chem.

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The mechanism of the cyclization step of the Pictet‐Spengler reaction between acetaldehyde and dopamine to give salsolinol and isosalsolinol was studied computationally, using density functional theory. The preferential formation in acidic media of salsolinol, the product of para‐cyclization, and the requirement of a neutral pH for the formation of the ortho‐cyclized isosalsolinol are explained in terms of 2 different mechanistic routes with an iminium ion or a phenolate‐iminium zwitterion as starting reactants.

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Achieving Skeletal Diversity in Peptide Macrocycles through The Use of Heterocyclic Grafts

Kaldas

Yudin

2018

Chemistry A European J

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Despite their therapeutic potential, peptide macrocycles often suffer from drawbacks such as low membrane permeability, proteolytic instability, and conformational lability. As a result, there have been significant efforts to "depeptidize" amino acid-rich macrocycles through the incorporation of heterocyclic grafts into their backbones. In this concept article, we summarize selected recent methodologies that can be used to introduce heterocycles into cyclic peptides.

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On the prevalence of bridged macrocyclic pyrroloindolines formed in regiodivergent alkylations of tryptophan

Abstract: Brønsted acid promotes internal cinnamylations of tryptophan to form structurally complex pyrroloindolines within unique collections of ansa-bridged composite macrocycles.

Cited by 16 publications

References 55 publications

Computational generation of an annotated gigalibrary of synthesizable, composite peptidic macrocycles

Computational generation of an annotated gigalibrary of synthesizable, composite peptidic macrocycles

Theoretical insights into the regioselectivity of a Pictet-Spengler reaction: Transition state structures leading to salsolinol and isosalsolinol

Achieving Skeletal Diversity in Peptide Macrocycles through The Use of Heterocyclic Grafts

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