Efficient construction of diketopiperazine macroarrays through a cyclative-cleavage strategy and their evaluation as luminescence inhibitors in the bacterial symbiont Vibrio fischeri.
Diketopiperazines (DKPs) are a well-known class of heterocycles that have emerged as promising biologically active scaffolds. 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 at least 80% at 500 muM. Collectively, this work serves to further highlight the utility of the small molecule macroarray platform for the synthesis and evaluation of focused libraries.
Campbell
Jennifer
J
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706-1322, USA.
Blackwell
Helen E
HE
D048908:Aliivibrio fischeri / Q000187:drug effects*; D002482:Cellulose / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D049449:Luminescence; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013237:Stereoisomerism
D054659:Diketopiperazines; D002482:Cellulose