Huajian Zhu

One-pot multicomponent approach to indolizines and pyrido[1,2-a]indoles.

A new synthetic protocol for efficient and regiospecifc assembly of indolizines and pyrido[1,2-a]indoles by coupling of substituted methyl bromides and alkynes with corresponding pyrrole-2-carboxaldehyde and 1H-indole-2-carboxaldehyde has been developed. Additionally, a possible mechanism for the reaction is proposed.

Scaffold Tailoring by a Newly Detected Pictet–Spenglerase Activity of Strictosidine Synthase: From the Common Tryptoline Skeleton to the Rare Piperazino-indole Framework

The Pictet-Spenglerase strictosidine synthase (STR1) has been recognized as a key enzyme in the biosynthesis of some 2000 indole alkaloids in plants, some with high therapeutic value. In this study, a novel function of STR1 has been detected which allows for the first time a simple enzymatic synthesis of the strictosidine analogue 3 harboring the piperazino[1,2-a]indole (PI) scaffold and to switch from the common tryptoline (hydrogenated carboline) to the rare PI skeleton. Insight into the reaction is provided by X-ray crystal analysis and modeling of STR1 ligand complexes. STR1 presently provides exclusively access to 3 and can act as a source to generate by chemoenzymatic approaches libraries of this novel class of alkaloids which may have new biological activities. Synthetic or natural monoterpenoid alkaloids with the PI core have not been reported before.

A facile chemoenzymatic approach: one-step syntheses of monoterpenoid indole alkaloids.

Facile chemoenzymatic syntheses of cytotoxic monoterpenoid indole alkaloids with novel skeletons and multiple chiral centers are described. Synthesis of these alkaloids was achieved by a simple one-step reaction using strictosidine and 12-aza-strictosidine as the key intermediates. Strictosidines were prepared by coupling of secologanin with tryptamine and 7-aza-tryptamine, respectively, using the immobilized recombinant Rauvolfia strictosidine synthase. A detailed stereochemical analysis is presented herein. The results provide an opportunity for a chemoenzymatic approach that leads to an increased diversification of complex alkaloids with improved structures and activities.

Improved Expression of His6‐Tagged Strictosidine Synthase cDNA for Chemo‐Enzymatic Alkaloid Diversification

Strictosidine synthase (STR1) catalyzes the stereoselective formation of 3α(S)‐strictosidine from tryptamine and secologanin. Strictosidine is the key intermediate in the biosynthesis of 2,000 plant monoterpenoid indole alkaloids, and it is a key precursor of enzyme‐mediated synthesis of alkaloids. An improved expression system is described which leads to optimized His6‐STR1 synthesis in Escherichia coli. Optimal production of STR1 was achieved by determining the impact of co‐expression of chaperones pG‐Tf2 and pG‐LJE8. The amount and activity of STR1 was doubled in the presence of chaperone pG‐Tf2 alone. His6‐STR1 immobilized on Ni‐NTA can be used for enzymatic synthesis of strictosidines on a preparative scale. With the newly co‐expressed His6‐STR1, novel 3α(S)‐12‐azastrictosidine was obtained by enzymatic catalysis of 7‐azatryptamine and secologanin. The results obtained are of significant importance for application to chemo‐enzymatic approaches leading to diversification of alkaloids with novel improved structures.

Strictosidine Synthase Triggered Enantioselective Synthesis of N-Substituted (S)-3,14,18,19-Tetrahydroangustines as Novel Topoisomerase I Inhibitors

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.