Stereocomplementary Chemoenzymatic Pictet–Spengler Reactions for Formation of Rare Azepino-indole Frameworks: Discovery of Antimalarial Compounds

Abstract

Strictosidine synthase (STR1) catalyzes a Pictet–Spengler reaction (PSR) forming strictosidine, a likely biosynthetic key to all higher plant monoterpenoid indole alkaloids. Increasing the biocatalytic capacity of the enzyme may make it a powerful tool for generation of compound libraries with enhanced structural diversity and pharmaceutical activity. Herein two production routes of a rare class of azepino­[3,4,5-cd]-indoles are developed: a complementary STR1-dependent chemoenzymatic and stereoselectively chemical route to an epimeric 1H-azepino­[3,4,5-cd]­indolyl strictosidine or vincoside, respectively. Mechanisms of the asymmetric catalysis are proposed based on computational calculations and X-ray analysis of STR1-ligand complexes. Further chemoenzymatic manipulation of the complementary PSR products resulted in several diverse and complex azepino-indole alkaloids, in which two alkaloids with the epimeric center directs the discovered antimalaria activity: 4α­(S) with IC50 ≈ 3.4 μM, 4β­(R) with IC50 ≈ 6.1 μM. The chemoenzymatic synthesis may significantly extend the applications of the enantiospecific STR1-based PSR in the future.

The antimalarial activity of indole alkaloids and hybrids

“…falciparum, implying the configuration of C-4 position could influence the activity. [69] The β-carboline derivatives 29a,b exhibited 71.79%…”

“…The antiplasmodial activity of 4α( S )‐configurated azepino[3,4,5‐ cd ]indole 28a (IC 50 : 3.4 µM) was superior to that of its 4β( R )‐configurated epimer 28b (IC 50 : 6.1 µM) against CQS 3D7 strain of P. falciparum , implying the configuration of C‐4 position could influence the activity. [ 69 ] The β‐carboline derivatives 29a , b exhibited 71.79% and 86.17% inhibition of P. berghei schizont maturation respectively at a concentration of 5 µg/ml, whereas the reference chloroquine exhibited 90.66% inhibition at 10 µg/ml. [ 70 ] These two hybrids did not cause any deaths and behavioral changes at a dose of >2.5 g/kg in the in vivo acute toxicity evaluation, suggesting their excellent safety profile.…”

Water‐Promoted Synthesis of Azepino[3,4,5‐cd]indole Analogues via Pictet‐Spengler Reaction

“…Inspired by the previously reported phosphate‐mediated PSRs,− we embarked on the investigation of azepino‐indole formation by treating 2‐(1 H ‐indol‐4‐yl)ethanamine ( 1 a ) with benzaldehyde ( 2 a ) in potassium phosphate buffer (KPi, pH=7.0) at 50 °C. The desired product 3 aa was obtained in a good yield of 72% (Table , entry 1).…”

“…− In addition, a special PSR was realized in toluene at reflux with tryptophan methyl ester derivatives as the amine source, without the aid of any catalyst . Very recently, we disclosed a strictosidine synthase (STR1)‐catalyzed and potassium phosphate (KPi)‐mediated stereocomplementary PSR of 2‐(1 H ‐indol‐4‐yl)ethanamine and secologanin to give complex indole alkaloids with aezpino‐indole frameworks . These observations demonstrated that the PSR conditions could be continuingly improved for more sustainable performance.…”

Asymmetric Biocatalytic Synthesis of 1‐Aryltetrahydro‐β‐carbolines Enabled by “Substrate Walking”

“…[5,7] In nature this condensation reactioni sc atalysed by enzymes called Pictet-Spenglerases, [8] which are sub-categorised according to their substrates. For instance, norcoclaurine synthases( NCSs) [9] prefer dopamine as amine substrate,w hile strictosidine synthases (STRs) [10] acceptt ryptamine and its derivatives, leadingt ob-carbolines as products. While for norcoclaurine synthases ab road scope of carbonyl substratesh as been reported, [9] it has only recently been shown that STRs accepts mall aliphatic aldehydes besides the natural, highly functionalized aldehyde secologanin (4c, Figure1)and itsa nalogues.…”