Christopher J. Burns

THE SOLUTION PHASE SYNTHESIS OF DIKETOPIPERAZINE LIBRARIES VIA THE UGI REACTION : NOVEL APPLICATION OF ARMSTRONG'S CONVERTIBLE ISONITRILE

Abstract This communication describes the generation of high-yielding solution phase diketopiperazine libraries via a ‘3-step, 1-pot’ procedure, employing the Ugi multi-component reaction (MCR), followed by BOC deprotection and cyclization to diketopiperazine (DKP). Exploitation of Armstrongs convertible isonitrile in the Ugi reaction utilising an ‘internal nucleophile’ approach for diketopiperazine formation is presented.

Solid-phase synthesis of an arylsulfone hydroxamate library

Synthesis of an arylsulfone hydroxamate lead optimization library is presented. Biological activity of representative examples is given to demonstrate the value of this approach for lead optimization.

Characterization of the bisphosphonate recognition site on hydroxyapatite using radioligand binding techniques with [14C]citric acid

SummaryThe present studies characterize the binding of [14C]citric acid to synthetic hydroxyapatite (HA) crystals. [14C]Citric acid specifically bound to HA and was dependent upon the concentration of HA in the assay. The binding of [14C]citric acid to HA reached equilibrium within 20 min and remained stable for at least 90 min. Dissociation of bound [14C]citric acid was biphasic in nature since both rapid and more slowly reversible binding components were detected. Saturation experiments also indicated that [14C]citric acid labeled two recognition sites with different affinity (KdH=42 nM and KdL=24,000 nM) and density (BmaxH=161 fmol/μg HA and BmaxL=8.8 pmol/μg HA). Ligand competition experiments revealed that compounds that are known to readily bind bone (e.g., sodium pyrophosphate, methylene diphosphonic acid, etidronate) potently inhibited the binding of [14C]citric acid to HA, whereas compounds known to have poorer affinity for bone (e.g., oxalic acid and GABA) did not. Computer analysis of these inhibition curves revealed specific ligand interactions at two different affinity recognition sites. The present results indicate that [14C]citric acid binds discrete sites on synthetic HA in a fashion consistent with a specific labeling of the bisphosphonate recognition site. Analysis of the binding of [14C]citric acid to HA provides a useful method to further explore the structure activity relationships of novel compounds that have binding affinity for bone.

SYNTHESE VON INHIBITOREN FUR ZWEI FAMILIEN BIOLOGISCHER TARGETS IN EINER SEQUENZ : EIN NACHSTER SCHRITT BEIM AUFBAU KOMBINATORISCHER BIBLIOTHEKEN ?

Uber nureinen Syntheseweg lassen sich Bibliotheken aus niedermolekularen Verbindungen aufbauen, die auf zwei Targetfamilien mit unterschiedlichen Funktionalitaten ausgerichtet sind. Dies wurde anhand der Entdeckung des Strukturtemplats 1 deutlich, das voneinander unabhangige pharmakophore Muster enthalt, uber die Mitglieder aus einer von zwei Targetfamilien, den Matrix-Metalloproteinasen (MMPs) oder den Phosphodiesterasen (PDEs), inhibiert werden konnen. Durch den Einbau von Bausteinen, die gegen mehrere Targets gerichtet sind, in eine Verbindungsbibliothek kann man so moglicherweise das Auffinden pharmazeutischer Leitstrukuren beschleunigen. Z=OR′ (PDE4), H (MMPs).

Analogues of Human Parathyroid Hormone (1–31)NH2: Further Evaluation of the Effect of Conformational Constraint on Biological Activity

A series of conformationally-restricted analogues of hPTH was prepared, based on the parent peptide agonist, cyclo(Lys(18)-Asp(22))[Ala(1),Nle(8),Lys(18),Asp(22),Leu(27)]hPTH(1-31)NH(2) (2, EC(50)=0.29nM). Truncation of 2 at either the N- or C-termini resulted in peptides with reduced agonist activity as measured by stimulation of adenylate cyclase activity in the rat osteosarcoma cell line (ROS 17/2.8). Alanine- and glycine-scanning at the N-terminus of 2 was consistent with data previously obtained on linear hPTH(1-34). Other locations within the primary sequence of hPTH(1-31)NH(2) were evaluated by the placement of the [i, i+4] lactam constraining element. Ring size and lactam orientations at the 18-22 positions were also examined.