Rejean Ruel

The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs

Stable cell lines that individually express the eight known human prostanoid receptors (EP(1), EP(2), EP(3), EP(4), DP, FP, IP and TP) have been established using human embryonic kidney (HEK) 293(EBNA) cells. These recombinant cell lines have been employed in radioligand binding assays to determine the equilibrium inhibitor constants of known prostanoid receptor ligands at these eight receptors. This has allowed, for the first time, an assessment of the affinity and selectivity of several novel compounds at the individual human prostanoid receptors. This information should facilitate interpretation of pharmacological studies that employ these ligands as tools to study human tissues and cell lines and should, therefore, result in a greater understanding of prostanoid receptor biology.

Hsp60 accelerates the maturation of pro‐caspase‐3 by upstream activator proteases during apoptosis

The activation of caspases represents a critical step in the pathways leading to the biochemical and morphological changes that underlie apoptosis. Multiple pathways leading to caspase activation appear to exist and vary depending on the death‐inducing stimulus. We demonstrate that the activation of caspase‐3, in Jurkat cells stimulated to undergo apoptosis by a Fas‐independent pathway, is catalyzed by caspase‐6. Caspase‐6 was found to co‐purify with caspase‐3 as part of a multiprotein activation complex from extracts of camptothecin‐treated Jurkat cells. A biochemical analysis of the protein constituents of the activation complex showed that Hsp60 was also present. Furthermore, an interaction between Hsp60 and caspase‐3 could be demonstrated by co‐immunoprecipitation experiments using HeLa as well as Jurkat cell extracts. Using a reconstituted in vitro system, Hsp60 was able to substantially accelerate the maturation of procaspase‐3 by different upstream activator caspases and this effect was dependent on ATP hydrolysis. We propose that the ATP‐dependent ‘foldase’ activity of Hsp60 improves the vulnerability of pro‐caspase‐3 to proteolytic maturation by upstream caspases and that this represents an important regulatory event in apoptotic cell death.

Prostaglandin E2-Bisphosphonate conjugates : Potential agents for treatment of osteoporosis

Conjugates of bisphosphonates (potential bone resorption inhibitors) and prostaglandin E2 (a bone formation enhancer) were prepared and evaluated for their ability to bind to bone and to liberate, enzymatically, free PGE2. The conjugate 3, an amide at C-1 of PGE2 proved to be too stable in vivo while conjugate 6, a thioester, was too labile. Several PGE2, C-15 ester-linked conjugates (18, 23, 24 and 31) were prepared and conjugate 23 was found to bind effectively to bone in vitro and in vivo and to liberate PGE2 at an acceptable rate. A 4-week study in a rat model of osteoporosis showed that 23 was better tolerated and more effective as a bone growth stimulant than daily maximum tolerated doses of free PGE2.

Structure–Activity Relationship of Biaryl Acylsulfonamide Analogues on the Human EP3 Prostanoid Receptor

Potent and selective ligands for the human EP3 prostanoid receptor are described. Biaryl compounds bearing a tethered ortho substituted acidic moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinity of key compounds on all eight human prostanoid receptors is reported.

New class of biphenylene dibenzazocinones as potent ligands for the human EP1 prostanoid receptor

A new class of potent and selective ligands for the human EP1 prostanoid receptor is described. SAR studies reported herein allowed the identification of several potent dibenzazocinones bearing an acylsulfonamide side chain. The binding affinity of these compounds on all eight human prostanoid receptors is reported.

Reduction of olefins on solid support using diimide

Abstract The reduction of solid supported olefinic substrate using diimide is described. The diimide, prepared from sulfonylhydrazide, was found to efficiently reduce the olefinic substrates. Typically, the reaction proceeds in over 90% yield to afford the reduction product cleanly after cleavage from the Wang resin.

Synthesis of succinic diesters via reductive coupling of α-haloesters using samarium (II) iodide and HMPA

Abstract Primary and secondary α-haloesters are converted to succinic diesters in good yield by treatment with SmI 2 -HMPA.