New inhibitors of human renin that contain novel Leu-Val replacements

Abstract

Stereoselective syntheses of several nonpeptide fragments that function as Leu10-Val11 scissile bond replacements in human angiotensinogen are presented. The opening of N-protected aminoalkyl epoxide 3 with a variety of sulfur, oxygen, nitrogen, and carbon nucleophiles is a key reaction in the preparation of these novel fragments 4-8. The coupling of these fragments to protected dipeptides that mimic positions 8 and 9 in angiotensinogen produces inhibitors of human renin even though the molecules contain no functionality beyond what is formally the Val11 side chain of angiotensinogen. R groups that closely resemble that of the Val side chain are preferable; thus, isopropyl greater than or equal to higher alkyl greater than phenyl greater than substituted phenyl. Sulfur is the best X group; oxidation leads to slight (X = SO2) and significant (X = SO) decreases in inhibitory potency. One such inhibitor, 60, has an IC50 of 13 nM when tested with purified human renin at pH 6.0. The significant activity of these small inhibitors is thought to be due in part to the hydroxyl group of the fragment functioning as a transition-state analogue. Of these, the inhibitors that contain histidine show marked selectivity toward renin over a related aspartic proteinase, pepsin.

Highly regioselective thiolysis of oxiranes under supramolecular catalysis involving β-cyclodextrin in water

“…The reactions were carried out by the in situ formation of the ␤-cyclodextrin complex of the epoxide (1) in water followed by the addition of thiophenoxide (2) and stirred at room temperature to give the corresponding ␤-hydroxy sulfides (3) in impressive yields ( Table 1). The reaction goes smoothly with thiophenoxides in a span of 15 min at room temperature without the formation of any side products or rearrangements.…”

“…The oxirane ring opening with thiols is of great significance in the field of natural products especially for the synthesis of leukotrienes such as LTC 4 and LTD 4 [1] and various pharmaceuticals [2]. Apart from this, the resulting ␤-hydroxy sulfides are also versatile synthetic intermediates for allylic alcohols [3], benzoxathiepines [4], benzodiazepines [5], ␣-thioketones [6], ␣-substituted ␣,␤-unsaturated enones [7], and different natural products [8].…”

An Efficient Scalable Synthesis of 2,3-Epoxypropyl Phenylhydrazones

“…Epoxides are versatile intermediates in organic synthesis; and a large variety of reagents are known for the ring opening of these compounds to yield products with important biological activities and pharmacological properties [1,2]. On the other hand, hydrazine derivatives are nowadays of considerable technical and commercial importance [3].…”

Bi(OTf)3 or Bi(TFA)3 catalyzed efficient, regio- and chemoselectively synthesis of beta-hydroxy thioethers from aryl disulfides in the presence of zinc powder

“…Among them thiolyzation of epoxides has attracted much attention because it produces -hydroxy thioethers as valuable intermediates for the synthesis of important compounds such as -thioketones, 1 -hydroxy sulfoxides, 2,3 benzothiazepines 4 or benzoxathiepines 5 that are used as building blocks for preparation of some natural products [6][7][8][9][10] or pharmaceuticals. 11,12 The classical synthesis of -hydroxy thioethers consists of heating an epoxide with an excess of unpleasant odor thiol. A number of different Lewis acids have been used for this transformation.…”