TY - JOUR
T1 - Stereocomplementary Chemoenzymatic Pictet-Spengler Reactions for Formation of Rare Azepino-indole Frameworks
T2 - Discovery of Antimalarial Compounds
AU - Cai, Yunrui
AU - Shao, Nana
AU - Xie, Hujun
AU - Futamura, Yushi
AU - Panjikar, Santosh
AU - Liu, Haicheng
AU - Zhu, Huajian
AU - Osada, Hiroyuki
AU - Zou, Hongbin
N1 - Funding Information:
When taking into account the crystal structures of the active site of STR1 together with the three complexed amine ligands, the natural tryptamine ( 1 - 1 ), unnatural indole-ethanamines ( 1 - 2 , IEA), and ( 1 , 4-IEA) respectively, the mechanism that leads to 3a catalysis by STR1 may be similar to that for 3α-( S )-strictosidine ( 3 - 1 ) formation, as outlined in references (3b,5c) . Their densities are closely colocated when overlaid to the catalytic center of the enzyme ( Figure 1 B). These X-ray results support the reaction of the Pictet–Spengler based formation of the novel 4α-( S )-azepino[3,4,5- cd ]indolyl-strictosidine ( 3a , de > 98%). Compared to KPi-mediated chemical synthesis of the epimer 3b , the phosphate ion H 2 PO 4 – may in principle take on the role of Glu309 and mimic the enzyme catalyzed reaction under formation of the imine. The schiff base (iminium ion) would cyclize to the seven-membered 4β ( R ) C-ring intermediate (see Scheme 3 ). The intermediate is transformed under simultaneous regeneration of the indole system and admission of the C-4 hydrogen releasing finally the catalytic H 2 PO 4 – anion. Whereas X-ray data support the enzyme reaction mechanism illustrated, the KPi-dependent reaction is also partially supported by the computational calculations.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/8/2
Y1 - 2019/8/2
N2 - 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.
AB - 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.
KW - Pictet-Spengler reactions
KW - antimalarial activity
KW - azepino-indole alkaloids
KW - complementary stereoselectivity
KW - phosphate
KW - strictosidine synthase
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U2 - 10.1021/acscatal.9b01628
DO - 10.1021/acscatal.9b01628
M3 - Article
AN - SCOPUS:85071056730
SN - 2155-5435
VL - 9
SP - 7443
EP - 7448
JO - ACS Catalysis
JF - ACS Catalysis
IS - 8
ER -