Aeruginosine: Chemie und Biologie der Serinprotease‐Inhibitoren

Abstract

Die Aeruginusine wurden aus Meeresschwämmen und cyanobakteriellen Wasserblüten isoliert, die in phylogenetisch sehr unterschiedlichen und geographisch weit voneinander entfernten Gewässern vorkommen. Gemeinsam ist den Aeruginosinen eine zentrale Hydroxy‐ (oder Dihydroxy‐)octahydroindolcarboxamid‐Kerneinheit, an deren Carboxy‐ und Aminoende ungewöhnliche Aminosäuren zu einem linearen Peptid aufgereiht sind. Einige der Aeruginosine entfalten ausgezeichnete Serinprotease‐Inhibitoraktivität in vitro, wofür drei wichtige pharmakophore Untereinheiten verantwortlich sind, die exakt angeordnet sein müssen: eine argininmimetische Untereinheit (P1) und zwei hydrophobe Reste an den Positionen P2 und P3, die bestimmte Wechselwirkungen eingehen können. In diesem Aufsatz bieten wir den ersten umfassenden Überblick über das chemische und biologische Verhalten der Aeruginosine. Besondere Aufmerksamkeit gilt dabei den Herkunftsorten der Substanzen, Strukturrevisionen und Totalsynthesen.

Synthesis of Hexahydroindoles by Intramolecular CH Alkenylation: Application to the Synthesis of the Core of Aeruginosins

“…In particular, octahydroindoles are found as the core of the aeruginosin family of marine natural products (see Scheme 1 for the structure of aeruginosin 298A), which show interesting biological properties as inhibitors of serine proteases. [12] We first examined the reactivity of bromoalkene 4 a (Scheme 2), which was synthesized as a racemic single diastereoisomer in four steps from cyclopentene. [13] Compound 4 a is a particularly challenging substrate because the nitrogen substituent contains several types of C À H bonds that could potentially be activated: primary C sp 3 ÀH a bonds, a tertiary C sp 3 ÀH b bond adjacent to a nitrogen atom, two types of secondary C sp 3 ÀH c, d bonds including more-acidic benzylic protons (H d ), and arylic C sp 2 ÀH e bonds.…”

Total Synthesis of Nominal Banyaside B: Structural Revision of the Glycosylation Site

“…The natural products that comprise the aeruginosin family of serine protease inhibitors1 represent one of the seven main classes of cyanobacterial peptides 2. They include the four glycopeptides, banyasides A3a ( 1 ) and B3a ( 2 ), suomilide,3b and spumigin HKVV,3c which incorporate a common, densely functionalized tricyclic azabicyclononane (Abn) core.…”

Construction of Chiral 2‐Substituted Octahydroindoles from Cyclic Ketones and Nitroolefins Bearing only One α‐Substituent

“…Nitroolefins bearing a variety of different electron-donating and electron-withdrawing substituents on their phenyl ring behaved as suitable substrates for the asymmetric Michael addition with cyclohexanone. High enantioselectivities (94 to > 99% ee) were achieved in all cases with good diastereoselectivities (84:16-94:6 dr) and yields (67-93%) ( Table 2, entries [1][2][3][4][5][6][7][8]. The position of the substituent appeared to have a significant influence on the yield (73-85%) and diastereoselectivity (88:12-94:6 dr) of the transformation, although the effect of the substituent on the enantioselectivity was only minor (94 to > 99% ee) ( Table 2, entries 4-6).…”

“…[1][2][3][4] For example, chiral 6-hydroxyoctahydroindole-2-carboxylic acid is an important component of aeruginosins, [1] and trans-octahydroindole-2-carboxylic acid is a key intermediate in the synthesis of the cardiovascular drug trandolapril. [2] Several other octahydroindole-containing compounds have also been reported in the literature, including those isolated from plants belonging to the Amaryllidaceae family.…”