Distributed Drug Discovery, Part 1: Linking Academia and Combinatorial Chemistry to Find Drug Leads for Developing World Diseases

Scott, William L.; O’Donnell, Martin J.

doi:10.1021/cc800183m

Cited by 44 publications

(58 citation statements)

References 112 publications

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“…14−16 These procedures are often adapted 15,16 from published chemistry. 1,15,18 We were developing a new D3 laboratory, The Combinatorial Synthesis of N-Acylated Unnatural Amino Acid Amides, based on the published reaction sequence shown in Scheme 3.…”

Section: Resultsmentioning

confidence: 99%

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

et al. 2014

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Remote amide bonds in simple N-acyl amino acid amide or peptide derivatives 1 can be surprisingly unstable hydrolytically, affording, in solution, variable amounts of 3 under mild acidic conditions, such as trifluoroacetic acid/water mixtures at room temperature. This observation has important implications for the synthesis of this class of compounds, which includes N-terminal-acylated peptides. We describe the factors contributing to this instability and how to predict and control it. The instability is a function of the remote acyl group, R2CO, four bonds away from the site of hydrolysis. Electron-rich acyl R2 groups accelerate this reaction. In the case of acyl groups derived from substituted aromatic carboxylic acids, the acceleration is predictable from the substituent’s Hammett σ value. N-Acyl dipeptides are also hydrolyzed under typical cleavage conditions. This suggests that unwanted peptide truncation may occur during synthesis or prolonged standing in solution when dipeptides or longer peptides are acylated on the N-terminus with electron-rich aromatic groups. When amide hydrolysis is an undesired secondary reaction, as can be the case in the trifluoroacetic acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize that hydrolysis.

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Section: Resultsmentioning

confidence: 99%

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

et al. 2014

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“…1 Combinatorial chemistry is central to its enablement. Herein is reported the first example of a key component of D 3 : the distributed rehearsal of reagents and their subsequent use in real and virtual catalog production.…”

Section: Introductionmentioning

confidence: 99%

Distributed Drug Discovery, Part 2: Global Rehearsal of Alkylating Agents for the Synthesis of Resin-Bound Unnatural Amino Acids and Virtual D³Catalog Construction

et al. 2008

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Distributed Drug Discovery (D3) proposes solving large drug discovery problems by breaking them into smaller units for processing at multiple sites. A key component of the synthetic and computational stages of D3 is the global rehearsal of prospective reagents and their subsequent use in the creation of virtual catalogs of molecules accessible by simple, inexpensive combinatorial chemistry. The first section of this article documents the feasibility of the synthetic component of Distributed Drug Discovery. Twenty-four alkylating agents were rehearsed in the United States, Poland, Russia, and Spain, for their utility in the synthesis of resin-bound unnatural amino acids 1, key intermediates in many combinatorial chemistry procedures. This global reagent rehearsal, coupled to virtual library generation, increases the likelihood that any member of that virtual library can be made. It facilitates the realistic integration of worldwide virtual D3 catalog computational analysis with synthesis. The second part of this article describes the creation of the first virtual D3 catalog. It reports the enumeration of 24 416 acylated unnatural amino acids 5, assembled from lists of either rehearsed or well-precedented alkylating and acylating reagents, and describes how the resulting catalog can be freely accessed, searched, and downloaded by the scientific community.

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“…Each product from this laboratory was subsequently purified by manual silica gel chromatography, six compounds at a time, using a Bill-Board 1,8 setup modified for purification rather than synthesis. The final products were, on average, >95% pure by LC/MS.…”

Section: Resultsmentioning

confidence: 99%

Distributed Drug Discovery, Part 3: Using D³ Methodology to Synthesize Analogs of an Anti-Melanoma Compound

et al. 2008

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For the successful implementation of Distributed Drug Discovery (D3) (outlined in the accompanying Perspective), students, in the course of their educational laboratories, must be able to reproducibly make new, high quality, molecules with potential for biological activity. This article reports the successful achievement of this goal. Using previously rehearsed alkylating agents, students in a second semester organic chemistry laboratory performed a solid-phase combinatorial chemistry experiment in which they made 38 new analogs of the most potent member of a class of antimelanoma compounds. All compounds were made in duplicate, purified by silica gel chromatography, and characterized by NMR and LC/MS. As a continuing part of the Distributed Drug Discovery program, a virtual D3 catalog based on this work was then enumerated and is made freely available to the global scientific community.

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Distributed Drug Discovery, Part 1: Linking Academia and Combinatorial Chemistry to Find Drug Leads for Developing World Diseases

Cited by 44 publications

References 112 publications

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

Distributed Drug Discovery, Part 2: Global Rehearsal of Alkylating Agents for the Synthesis of Resin-Bound Unnatural Amino Acids and Virtual D³Catalog Construction

Distributed Drug Discovery, Part 3: Using D³ Methodology to Synthesize Analogs of an Anti-Melanoma Compound

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Distributed Drug Discovery, Part 1: Linking Academia and Combinatorial Chemistry to Find Drug Leads for Developing World Diseases

Cited by 44 publications

References 112 publications

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

Distributed Drug Discovery, Part 2: Global Rehearsal of Alkylating Agents for the Synthesis of Resin-Bound Unnatural Amino Acids and Virtual D3Catalog Construction

Distributed Drug Discovery, Part 3: Using D3 Methodology to Synthesize Analogs of an Anti-Melanoma Compound

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Product

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Distributed Drug Discovery, Part 2: Global Rehearsal of Alkylating Agents for the Synthesis of Resin-Bound Unnatural Amino Acids and Virtual D³Catalog Construction

Distributed Drug Discovery, Part 3: Using D³ Methodology to Synthesize Analogs of an Anti-Melanoma Compound