Efficient Construction of Diketopiperazine Macroarrays Through a Cyclative-Cleavage Strategy and Their Evaluation as Luminescence Inhibitors in the Bacterial Symbiont Vibrio fischeri

Abstract

Diketopiperazines (DKPs) are a well-known class of heterocycles that have emerged as a promising biologically active scaffold. Solid-phase organic synthesis has become an important tool in the combinatorial exploration of these privileged structures, expediting the synthesis and, often, the discovery of active compounds. We recently identified several DKPs that are capable of inhibiting the luminescence response of the bacterial symbiont Vibrio fischeri, and we sought to further test the scope of this biological activity. Herein, we report the synthesis of DKP macroarrays using a SPOT-synthesis approach based on an Ugi/DeBoc/Cyclize strategy. Neither a spacer nor a linker was required for macroarray construction on cellulose support, and the cyclative cleavage produced high purity DKPs in good yields. Using this protocol, we prepared a library of 400 DKPs on cellulose support and evaluated its members as luminescence inhibitors in V. fischeri. We found six DKPs capable of inhibiting luminescence by greater than 80% at 500 μM. Collectively, this work serves to further highlight the utility of the small molecule macroarray platform for the synthesis and evaluation of focused libraries.

Antimicrobial and Biofilm Inhibiting Diketopiperazines

“…It turned out that only six of them were inhibitor of the luminescence and none was found acting as agonist. The active compounds 80 -85 contain either glycine, isoleucine or phenylalanine but similar compounds where these amino acids have been replaced either by alanine or 4-chloro-phenylalanine were not active [126] ( Figure 5). …”

Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

“…Numerous biologically active molecules contain cyclic peptide and peptidomimetic structural units including diketopiperazines (DKPs, the smallest possible cyclic peptides) and many compounds incorporating macrocyclic peptides and peptidomimetics are also known to be capable of modulating biological systems [29,35,[37][38][39][40][41].…”

Chemical methods to interrogate bacterial quorum sensing pathways

“…45 B. Macroarray synthesis of diketopiperazines (DKPs) by Campbell et al . 46 C. 3D microarrays devised by Spring and co-workers. 50–52 Top : individual amino-containing compounds can be printed on an N -hydroxysuccinimide activated slide.…”