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

Abstract

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.

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.…”

Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs

“…These compounds are derived from combinatorial scaffolds 1 – 3 (Scheme ) with “sites of diversity” to which new chemical groups can be added (e.g., new α‐side chains, N ‐terminal substituents, and/or various carboxylic acid derivatives: –CO 2 H, –CO 2 Me, and –CONH 2 ). The simple solid‐phase reactions employed in D3 can also be readily adapted to an educational setting with undergraduate or graduate students …”

“…Virtual compound catalogs/libraries can be useful sources of candidate molecules for drug discovery. However, two major factors often limit their utility: (i) Member compounds and analogs may be difficult to synthesize or (ii) there is no inherent probability of biological activity.…”

“…However, two major factors often limit their utility: (i) Member compounds and analogs may be difficult to synthesize or (ii) there is no inherent probability of biological activity. To the first issue, we have created large virtual catalogs of N ‐acyl α‐amino acids and their methyl ester and primary amide derivatives based on reproducible procedures and demonstrated student syntheses of individual catalog members 1 2, and, presented here for the first time, 3 (Figure ).…”

Peptoids advance multidisciplinary research and undergraduate education in parallel: Sequence effects on conformation and lipid interactions

“…Peptoid synthesis also showcases multistep synthesis, another central concept in organic chemistry courses that can be challenging to incorporate into laboratory coursework. In addition to reinforcing lecture topics, peptoid synthesis provides a platform to introduce modern research techniques less commonly seen at the introductory level, such as combinatorial chemistry and solid phase synthesis …”