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.

Monoterpenoid indole alkaloids (MIAs) comprise an important class of molecules for drug discovery, and they have variant carbon skeletons with prominent bioactivities. For instance, in spite of limitations to their use, camptothecins are the only clinically approved topoisomerase I (Top1) inhibitors. The enzyme strictosidine synthase, which is key for MIA biosynthesis, was applied to the enantioselective preparation of three N-substituted (S)-3,14,18,19-tetrahydroangustine (THA) derivatives. These non-camptothecin MIAs were shown to have moderate in vitro HepG2 cytotoxicity and Top1 inhibition activities. The (S)-configured MIAs had stronger cytotoxicity and Top1 inhibition than their chemically synthesized (R)-enantiomers, which aligned with the results of molecular dynamics simulations. A series of N-substituted (S)-THAs were then chemoenzymatically synthesized to investigate structure-activity relationships. The most active analogue observed was the N-(2-Cl benzoyl)-substituted derivative (7i). Insight into the binding mode of 7i and a Top1-DNA covalent complex was investigated by molecular dynamics simulations, which will facilitate future efforts to optimize the Top1 inhibitory activities of non-camptothecin MIAs.

Aminophenoxazinone core is widely prevalent in natural products, dye and pharmaceutical molecules. We report here a TEMPO-catalyzed electrosynthetic method allowing the dehydrogenative cyclocondensation of o-aminophenols. This mild and sustainable method...

Pictet-Spengler reaction is an important strategy for the chemical or biosynthetic construction of alkaloids. Various suitable catalysts have thus been developed to drive the reaction. We herein report for the first time that water could directly catalyze the Pictet-Spengler reactions of 2-(1H-indol-4yl)ethanamines with aldehydes or ketones to generate azepino [3,4,5-cd]indoles. Notably, this protocol is environmentally benign and highly practical with a wide substrate scope and promising gram-scale applications. A plausible mechanism for this catalytic reaction is proposed to provide insights and potentially open a new avenue for organic synthesis.

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