Globally Distributed Drug Discovery of New Antibiotics: Design and Combinatorial Synthesis of Amino Acid Derivatives in the Organic Chemistry Laboratory

Abstract

An experiment for the synthesis of N-acyl derivatives of natural amino acids has been developed as part of the Distributed Drug Discovery (D3) program. Students use solid-phase synthesis techniques to complete a three-step, combinatorial synthesis of six products, which are analyzed using LC−MS and NMR spectroscopy. This protocol is suitable for introductory organic laboratory students and has been successfully implemented at multiple academic sites internationally. Accompanying prelab activities introduce students to SciFinder and to medicinal chemistry design principles. Pairing of these activities with the laboratory work provides students an authentic and cohesive research project experience.

Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds

“…Because of the brevity of the procedure and the availability of inexpensive combinatorial reagents, a large number of student researchers prepared variants of 1 ( Table 1 ). 15 …”

“…Large numbers of molecules with diverse functionality are readily and reproducibly available through the Distributed Drug Discovery (D3) program implemented at a network of global schools. − Briefly, D3 enlists undergraduate students enrolled in organic chemistry laboratory courses to prepare combinatorial compound arrays for biological evaluation. To date, D3 has successfully synthesized analogs of antimelanoma compounds, for example .…”

Synthesis and Biological Assay of Small-Molecule Quorum Sensing Inhibitors: A Three-Week Course-Based Undergraduate Research Experience

“…At the time of this writing, there is a large literature of CUREs, with the majority in the biological sciences , and biochemistry and a growing but smaller number of CUREs in chemistry, − specifically in the field of organic chemistry. − The application of synthetic organic chemistry in the context of a medicinal-chemistry-inspired project involving library synthesis and a biological assay lends itself well to the CURE model. − The number of CUREs in organic and medicinal chemistry is growing, and all have their own specific merits. However, there are some limitations that are addressed by the CURE presented herein.…”

“…For example, some CUREs require a full semester, which, while providing ample time for iteration and failure, can limit implementation in institutions that lack flexibility in their laboratory course curricula. Additionally, while some CUREs allow students to synthesize a small-molecule library for biological testing, in many cases the students are not able to carry out the biological assay themselves. ,− While this model allows students who do not have access to a biology laboratory to carry out medicinal-chemistry-inspired research, it does limit students’ participation in truly collaborative research. Furthermore, some CUREs use reagents that pose significant safety hazards (i.e., sodium cyanide, potassium cyanide, OsO 4 , pyrophoric reagents such as LAH, NaH in DMF, and/or TFA , ) or require the target compounds to be rigorously pure for biological assays .…”

“…Additionally, while some CUREs allow students to synthesize a small-molecule library for biological testing, in many cases the students are not able to carry out the biological assay themselves. ,− While this model allows students who do not have access to a biology laboratory to carry out medicinal-chemistry-inspired research, it does limit students’ participation in truly collaborative research. Furthermore, some CUREs use reagents that pose significant safety hazards (i.e., sodium cyanide, potassium cyanide, OsO 4 , pyrophoric reagents such as LAH, NaH in DMF, and/or TFA , ) or require the target compounds to be rigorously pure for biological assays . Finally, while some CUREs provide students with the opportunity to troubleshoot routes to synthesize known bioactive molecules, in many cases the biological activities of these compounds are already known, , preventing students from having the opportunity to analyze how simple changes in molecular structure can have an impact in a given biological system.…”