The efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases.
An antibody raised against acridinium hapten 1 is shown
to catalyze the retro Diels−Alder reaction of the
anthracene−HNO cycloadduct 2 to release anthracene
4 and nitroxyl (HNO). Nitroxyl is oxidized to nitric
oxide
(NO) in the presence of superoxide dismutase. Since the enzyme
superoxide dismutase is ubiquitous in vivo, this
catalytic antibody system may be equivalent to NO-synthase.
Antibody catalysis is triggered by recognition of the
phenyl rings in hapten 1 at an angle near that of the
transition state of the retro Diels−Alder reaction of 2.
Acridinium
hapten 1 is in chemical equilibrium with its conjugate Lewis
base 9-hydroxyacridane 1-OH (pK ∼ 8.2).
Catalytic
antibody 9D9 (K
M(2) = 100
μM, k
cat = 0.07
min-1, k
uncat = 3
× 10-4 min-1) is
the result of an heterologous
immunization and binds both 1
(K
i
= 16.6 μM at pH 6.1) and
1-OH (K
i
= 0.9 μM at
pH 9.0). The more tightly
bound neutral conjugate base 1-OH probably represents a more
accurate mimic of the transition state of the retro
Diels−Alder process.
The oxidative transformation of (+)‐aristoteline ((+)‐5) into its metabolites, the recently synthesized indole alkaloids (−)‐serratoline ((−)‐6), (+)‐aristotelone ((+)‐2), and (−)‐alloaristoteline ((−)‐22), was investigated in more detail. It was demonstrated that the diastereoface selectivity of the reaction of (+)‐5 with 3‐chloroperbenzoic acid can be altered by variation of the solvent as well as by addition of CF3COOH. The chemoselectivity of the 1,2‐rearrangement of the intermediate 3H‐indol‐3‐ol derivatives could be controlled as follows: treatment of 3H‐indol‐3‐ols with aqueous polyphosphoric acid led to the pseudoindoxyl ( = 1,2‐dihydro‐3H‐indol‐3‐one) derivatives, whereas an analogous treatment of the corresponding O‐benzoates furnished exclusively the corresponding, constitutionally isomeric 2‐oxindole ( = 1,3‐dihydro‐2H‐indol‐2‐one) products. Exploitation of these and related findings led to efficient total syntheses of the Aristotelia alkaloid (−)‐tasmanine ((−)‐1) and of the corresponding unnatural epimer (+)‐12, as well as of the two pseudoindoxyls (+)‐aristotelone ((+)‐2) and (−)‐2‐epiaristotelone ((−)‐11). All these transformations were carried out with synthetic (+)‐aristoteline ((+)‐5) as the single indole alkaloid precursor.
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