Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides.
The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho-quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates.
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai, Japan.
Teigo
T
Asai
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai, Japan.
Kento
K
Tsukada
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai, Japan.
Satomi
S
Ise
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai, Japan.
Naoki
N
Shirata
School of Pharmacy, Iwate Medical University, Nishitokuta, Yahaba, Iwate, Japan.
Makoto
M
Hashimoto
School of Pharmacy, Iwate Medical University, Nishitokuta, Yahaba, Iwate, Japan.
Isao
I
Fujii
Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
Katsuya
K
Gomi
Graduate School of Medicine and Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
Kosuke
K
Nakagawara
Graduate School of Medicine and Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
Eiichi N
EN
Kodama
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai, Japan.
Yoshiteru
Y
Oshima
D001236:Aspergillus oryzae / Q000201:enzymology; D001578:Benzopyrans / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism; D002597:Chaetomium / Q000378:metabolism; D005658:Fungi / Q000378:metabolism*; D045563:Indolequinones / Q000096:biosynthesis / Q000737:chemistry; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D010860:Pigments, Biological / Q000737:chemistry; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D061065:Polyketides / Q000737:chemistry* / Q000378:metabolism
D001578:Benzopyrans; D001688:Biological Products; D045563:Indolequinones; D007211:Indoles; D010860:Pigments, Biological; D061065:Polyketides; C494154:azaphilone; C068040:quinone methide; D048630:Polyketide Synthases