Solid-Phase and Microwave-Assisted Syntheses of 2,5-Diketopiperazines:Small Molecules with Great Potential

Abstract

Diketopiperazines (DKPs) are a well-known class of heterocycles that have recently 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, therefore, the discovery of active compounds. To date, certain DKPs have shown potent activities against a range of diseases and biological phenomena, including bacterial infections, various cancers, asthma, infertility, premature labor, and HIV. Recent applications of solid-phase DKP synthesis, with a particular focus on cyclative cleavage and microwave-assisted reactions, are highlighted herein.

Discovery of a Class of Diketopiperazines as Antiprion Compounds

“…[32] Therefore, it seemed conceivable that DKPs carrying (Z)-alkene units of general structure I (Figure 1) could serve as a template for a diverse array of pharmacophores towards the identification of novel bifunctional structures for the treatment of prion diseases. Building on this, a compound library was generated by appending several aromatic and heteroaromatic rings in positions 3 and 6 of the 3,6-dimethylenepiperazine-2,5-dione scaffold.…”

Novel conformationally constrained pyrazole derivatives as potential anti-cancer agents

“…In particular, numerous synthetic small molecules from various groups of azaheterocycles have been reported to influence carcinogenesis and are currently in clinical trials [2,3] or approved for the treatment of various cancer types [3,4]. Indicatively, carbazoles possessing a unique tricyclic ring system have been permitted for the treatment of cancer [5], while phenazines [6] and several piperazines [7] have been found to display IC 50 values in the nanomolar range against quinone reductase inhibitors. Recently, azoaryl sulfides were proved as selective antibreast cancer agents with IC 50 values in the low micromolar range [8,9].…”

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

“…9,10 Recent advances in solid-phase combinatorial DKP synthesis, including secondary acylation and N -alkylation strategies and multiple component reactions (MCRs), have provided the tools needed for the rapid synthesis of DKPs. 11, 12 For example, we recently reported a water-assisted Ugi 4CR for the solid-phase synthesis of DKPs that made use of Armstrong’s convertible isonitrile and a photocleavable linkage strategy (Figure 1, route A). 6 …”

“…11, 12 These strategies yield DKPs in high purities, as the cleavage releases only the cyclic products. One such solid-phase strategy utilizes the Ugi 4CR to simultaneously introduce three additional points of diversity onto support-bound amines.…”