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

Abstract

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.

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

“…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.…”

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

“…(2) Cleavage of 6 to 8 by transesterification with methanol in triethylamine at 55 °C for 48 h proceeded smoothly and with good conversion. In the student laboratory, this modified route to compounds 8 proceeded uneventfully.…”

“…See the earlier article for a more complete discussion of these stereochemical issues. (2) The compound structures in the virtual catalog were further adjusted to take into consideration possible transformations in the final methanolysis step 11−16 (e.g., transesterification of ethyl esters to methyl esters).…”

“…2,6 The four-step sequence involves the alkylation of resin-bound glycinate ( 3 → 4 ), followed by imine hydrolysis ( 4 → 5 ), N-acylation ( 5 → 6 ), and final cleavage from the resin ( 6 → 7 ). It was apparent that modification of this procedure (modified route, Scheme 1) could produce numerous phenylalanine methyl ester analogs, 8 , of 1 and 2 .…”

Solid-phase synthesis for beginners: Choice of tools and techniques for implementation of multistage transformations

“…Synthesis and subsequent testing are planned from a united center [8]. The contribution of the Moscow team into this project is described in a separate paper [9].…”