The present day importance of cyclopentenone derivatives in preparative organic chemistry and especially in natural product chemistry is demonstrated by the stereoselective synthesis of substituted and annelated cyclopentanone derivatives. It has been found that 4‐oxo‐2‐cyclopentenyl acetate (“4‐acetoxy‐2‐cyclopenten‐1‐one”) can be used in many reactions as a substitute for cyclopentadienone, which is itself too unstable to be isolated. A large variety of polyfunctionalized cyclopentanone derivatives, as well as carbocyclic and heterocyclic annelation products, can thus be obtained in a simple way. Various stereoselective transformations of the adducts so formed are presented, using the total synthesis of brefeldin A—a typical natural product of this series—as example. Several methods for the synthesis of 4‐oxo‐2‐cyclopentenyl acetate are outlined and, in addition, the more important methods for the enantioselective synthesis of other 4‐substituted 2‐cyclopenten‐1‐ones are discussed.
Abstract. The NHE-1 isoform of the Na + /H + exchanger is excessively activated in cardiac cells during ischemia. Hence NHE-1 specific inhibitors are being developed since they could be of beneficial influence under conditions of cardiac ischemia and reperfusion. In this study, the Cytosensor microphysiometer was used to measure the potency of four new drug molecules, i.e., EMD 84021, EMD 94309, EMD 96785 and HOE 642 which are inhibitors of the isoform 1 of the Na + /H + exchanger. The experiments were performed with Chinese hamster ovary cells (CHO K1) which are enriched in the NHE-1 isoform of the Na + /H + antiporter. The Na + /H + exchanger was stimulated with NaCl and the rate of extracellular acidification was quantified with the Cytosensor. The proton exchange rate was measured as a function of the NaCl concentration in the range of 10-138 mM NaCl stimulation. The proton exchange rate followed Michaelis-Menten kinetics with a K M ס 30 ± 4 mM for Na + . Addition of either one of the four inhibitors decreased the acidification rate. The IC 50 values of the four compounds could be determined as 23 ± 7 nM for EMD 84021, 5 ± 1 nM for EMD 94309, 9 ± 2 nM for EMD 96785 and 8 ± 2 nM for HOE 642 at 138 mM NaCl, in good agreement with more elaborate biological assays. The IC 50 values increased with the NaCl concentration indicating competitive binding of the inhibitor. The microphysiometer approach is a fast and simple method to measure the activity of the Na + /H + antiporter and allows a quantitative kinetic analysis of the proton excretion rate.
The synthesis of a series of RGD mimetics is described. All compounds consist of a central 2,5-disubstituted tetrahydrofuran core, a variable linker to a guanidino group, and a beta-amino alanine unit to mimic the carboxylic acid. Three types of linkers were investigated: a simple four-atom methylene chain (type A, compounds 14, 15, 16, and 17), a four-atom methylene chain with an additional chiral center, and a nitrogen substituent (type B, compounds 38, 39, and 40), and an amide linker of different length with an additional chiral center (type C, compounds 59, 60, 61, and 62). A variety of compounds were tested as potential integrin antagonists in a receptor binding assay (alphaIIbbeta3, alphavbeta3, and alphavbeta5). The relative and absolute configuration of the chiral centers at the THF ring had a pronounced effect on the binding activity and selectivity. Compound 14 proved to be a selective inhibitor of alphaIIbbeta3 (IC50=20nM), whereas compound 40 exhibited high activity for binding of alphaIIbbeta3 (IC50=67nM) and alphavbeta3 (IC50=52nM).
Incorporation of beta-alanine or gamma-aminobutyric acid in position P2 of ACHPA or Leu psi [CHOHCH2]Val-based tetrapeptides gave highly active renin inhibitors (compounds V, VI, and XVII) with high specificity for renin and a remarkable stability against chymotrypsin. Replacement of the amide bond between P2 and P3 by isosteres (ketomethylenes, hydroxyethylenes, and the corresponding thio-insertion analogues) led to compounds (VIII-XIII, XVIII, and XIX) with renin inhibitory activity in the nanomolar range. Oral activity was achieved by incorporation of polar functionalities at the N-terminus of beta-alanine-containing tetrapeptides. One of these compounds (XXVIII) was chosen for further studies. This inhibitor demonstrated excellent efficacy and a long duration of action after intravenous and oral administration to cynomolgus monkeys.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.