ChemInform Abstract: 2,6-Diketopiperazines from Amino Acids: From Solution-Phase to Solid-Phase Organic Synthesis.
Department of Chemistry, Menarini Ricerche S.p.A., I-50131 Firenze, Italy.Journal of Combinatorial Chemistry (Impact Factor: 4.93). 09/2001; 3(5):453-60. DOI: 10.1021/cc0000904
A method to prepare 1,3-disubstituted 2,6-diketopiperazines (2,6-DKP) as useful heterocyclic library scaffolds in the search of new leads for drug discovery is described. The method can be used in solution-phase and solid-phase conditions. In the key step of the synthesis, the imido portion of the new molecule is formed in solution through intramolecular cyclization, under basic conditions, of a secondary amide nitrogen on a benzyl ester. A Wang resin carboxylic ester is used as the acylating agent under solid-phase conditions, allowing the cyclization to take place with simultaneous cleavage of the product from the resin ("cyclocleavage"). The synthetic method worked well with several couples of amino acids, independently from their configuration, and was used for the parallel synthesis of a series of fully characterized compounds. The use of iterative conditions in the solid phase (repeated addition of fresh solvent and potassium carbonate to the resin after filtering out the product-containing solution) allowed us to keep diastereoisomer content below the detection limit by HPLC and (1)H NMR (200 MHz).
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ABSTRACT: This report examines the current strategies used to construct diketopiperazines. Recent reports from the literature are highlighted, including the syntheses of biologically active natural products. Figure optionsView in workspaceDownload full-size imageDownload as PowerPoint slideTetrahedron 04/2002; 58(17):3297-3312. DOI:10.1016/S0040-4020(02)00239-9 · 2.64 Impact Factor
Article: NIH Public Access[Show abstract] [Hide abstract]
ABSTRACT: Diketopiperazines (DKPs) are a common motif in various biologically active natural products, and hence they may be useful scaffolds for the rational design of receptor probes and therapeutic agents. We constructed a new bicyclic scaffold that combines a DKP bridged with a 10-membered ring. In this way we obtained a three-dimensional molecular skeleton, with several amendable sites that provide a starting point to design a new combinatorial library having diverse substituent groups. Structural variation is based upon the flexibility of alkylation of the nitrogen atoms of the DKP and on the side-chain olefin. We obtained a 10-membered secondary ring through a ring-closure metathesis reaction using the second generation Grubbs catalyst. Rings containing both O-ethers and S-ethers were compared. N-Alkyl or arylalkyl groups were introduced optionally at the two Nalpha-atoms. This is a general scheme that will allow us to test rings of varying sizes, linkages, and stereochemical parameters. The DKP derivatives were tested for activity in astrocytoma cells expressing receptors coupled to phospholipase C. Inhibitory effects were observed for signaling elicited by activation of human nucleotide P2Y receptors but not m3 muscarinic receptors. Compound 20 selectively inhibited calcium mobilization (IC50 value of 486 +/- 16 nM) and phosphoinositide turnover elicited by a selective P2Y1 receptor agonist, but this compound did not compete for binding of a radiolabeled nucleotide-competitive receptor antagonist. Therefore, the new class of DKP derivatives shows utility as pharmacological tools for P2Y receptors.Organic & Biomolecular Chemistry 06/2005; 3(10):2016-25. DOI:10.1039/b416349d · 3.56 Impact Factor
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