Solid-Phase Synthesis of Diverse Peptide Tertiary Amides By Reductive Amination

Pels, Kevin; Kodadek, Thomas

doi:10.1021/acscombsci.5b00007

Cited by 40 publications

(41 citation statements)

References 20 publications

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“…Formation of urea linkages following nucleophilic addition to an isocyanate proceeds with high yield and 61% DNA remaining. Reductive amination 39 of an aldehyde with a resin-bound amine proved to be an ideal reaction, proceeding with 90% yield and no detectable loss in DNA amplifiability. Suzuki-Miyaura cross-coupling, 40 a carbon-carbon bond forming reaction of a boronic acid and resin-bound aryl iodide, was optimized to 93% yield of biphenyl product and 47% DNA remaining.…”

Section: Resultsmentioning

confidence: 99%

What is a “DNA-Compatible” Reaction?

2016

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DNA-encoded synthesis can generate vastly diverse screening libraries of arbitrarily complex molecules as long as chemical reaction conditions do not compromise DNA’s informational integrity, a fundamental constraint that “DNA-compatible” reaction development does not presently address. We devised DNA-encoded reaction rehearsal, an integrated analysis of reaction yield and impact on DNA, to acquire these key missing data. Magnetic DNA-functionalized sensor beads quantitatively report the % DNA template molecules remaining viable for PCR amplification after exposure to test reaction conditions. Analysis of solid-phase bond forming (e.g., Suzuki-Miyaura cross-coupling, reductive amination) and deprotection reactions (e.g., allyl esters, silyl ethers) guided the definition and optimization of DNA-compatible reaction conditions (> 90% yield, > 30% viable DNA molecules), most notably in cases that involved known (H+, Pd) and more obscure (Δ, DMF) hazards to DNA integrity. The data provide an empirical yet mechanistically consistent and predictive framework for designing successful DNA-encoded reaction sequences for combinatorial library synthesis.

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Section: Resultsmentioning

confidence: 99%

What is a “DNA-Compatible” Reaction?

2016

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“…14A). It is possible to include N-alkylated derivatives of many different amino acids into a library 102 , but in this case, the N-alkylated amino acid (where the side chain is larger than methyl) must be followed by a peptoid unit since chloroacetyl chloride is the only acylating agent that couples in high enough yield to the sterically congested amine to support the synthesis of high-quality libraries 32 .…”

Section: Libraries Of Conformationally-restricted Oligomers: Ptas Andmentioning

confidence: 99%

“…Therefore, in the future it will be important to develop new library designs of different types of molecules that can be made with gentler reactions. For example, we have found that reductive amination 102 is a “freebie” with little or no damage to the DNA. We are working on adapting to the solid phase various reactions that are efficient in solution under conditions that are not DNA damaging.…”

Section: Dna-encoded Oboc Librariesmentioning

confidence: 99%

Towards vast libraries of scaffold-diverse, conformationally constrained oligomers

Kodadek

McEnaney

2016

Chem. Commun.

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There is great interest in the development of probe molecules and drug leads that would bind tightly and selectively to protein surfaces that are difficult to target with traditional molecules, such as those involved in protein-protein interactions. The currently available evidence suggests that this will require molecules that are larger and have quite different chemical properties than typical Lipinski-compliant molecules that target enzyme active sites. We describe here efforts to develop vast libraries of conformationally constrained oligomers as a potentially rich source of these molecules.

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“…One of the simplest examples of this approach is the construction of libraries of peptide tertiary amides (PTAs), in other words, oligomers of N -alkylated amino acids 110,111,114 (Fig. 11).…”

Section: Introductionmentioning

confidence: 99%

Chemical Tools To Monitor and Manipulate Adaptive Immune Responses

2016

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Methods to monitor and manipulate the immune system are of enormous clinical interest. For example, the development of vaccines represents one of the earliest and greatest accomplishments of the biomedical research enterprise. More recently, drugs capable of “reawakening” the immune system to cancer have generated enormous excitement. But, much remains to be done. All drugs available today that manipulate the immune system cannot distinguish between “good” and “bad” immune responses and thus drive general and systemic immune suppression or activation. Indeed, with the notable exception of vaccines, our ability to monitor and manipulate antigen-specific immune responses is in its infancy. Achieving this finer level of control would be highly desirable. For example, it might allow the pharmacological editing of pathogenic immune responses without restricting the ability of the immune system to defend against infection. On the diagnostic side, a method to comprehensivel y monitor the circulating, antigen-specific antibody population could provide a treasure trove of clinically useful biomarkers, since many diseases expose the immune system to characteristic molecules that are deemed foreign and elicit the production of antibodies against them. This perspective will discuss the state-of-the-art of this area with a focus on what we consider seminal opportunities for the chemistry community to contribute to this important field.

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Solid-Phase Synthesis of Diverse Peptide Tertiary Amides By Reductive Amination

Cited by 40 publications

References 20 publications

What is a “DNA-Compatible” Reaction?

What is a “DNA-Compatible” Reaction?

Towards vast libraries of scaffold-diverse, conformationally constrained oligomers

Chemical Tools To Monitor and Manipulate Adaptive Immune Responses

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