title: Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality.
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.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-0810, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Besada
authors.forename: Liaman
authors.initials: L
authors.lastname: Mamedova
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D054659:Diketopiperazines; D019281:Dimerization; D004563:Electrochemistry; D009682:Magnetic Resonance Spectroscopy; D008855:Microscopy, Electron, Scanning; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013056:Spectrophotometry, Ultraviolet
chemical_list: D001643:Bridged Bicyclo Compounds; D054659:Diketopiperazines; D010879:Piperazines