Griseorhodins D–F, Neuroactive Intermediates and End Products of Post-PKS Tailoring Modification in Griseorhodin Biosynthesis

Abstract

The griseorhodins belong to a family of extensively modified aromatic polyketides that exhibit activities such as inhibition of HIV reverse transcriptase and human telomerase. The vast structural diversity of this group of polyketides is largely introduced by enzymatic oxidations, which can significantly influence the bioactivity profile. Four new compounds, griseorhodins D–F, were isolated from a griseorhodin producer, Streptomyces sp. CN48+, based upon their enhancement of calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, griseorhodins D1 and D2, were shown to be identical to the major, previously uncharacterized products of a grhM mutant in an earlier griseorhodin biosynthesis study. Their structures enabled the establishment of a more complete hypothesis for the biosynthesis of griseorhodins and related compounds. The other two compounds, griseorhodins E and F, represent new products of post-polyketide synthase tailoring in griseorhodin biosynthesis and showed significant binding activity in a human dopamine active transporter assay.

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

“…Many fungal spirobenzofuranones contain the grisane ( 191 ) moiety as the central structural motif ( Scheme 26 ). The spiro linkage between the B and C rings is installed by oxidative phenol coupling starting from type II-PKS-derived anthraquinone precursors [ 155 ].…”

Synergistic anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and absolute stereochemistry of 7,8-dideoxygriseorhodin C

“…Marine gastropod mollusks that are defended by thick shells harbor diverse culturable bacteria, many of which produce biologically active compounds [1][2][3][4]. Our continuing efforts to screen extracts from mollusk-associated bacteria against methicillin-resistant Staphylococcus aureus (MRSA) led us to the isolation of 7,8-dideoxygriseorhodin C (1) from Streptomyces sp.…”

“…In addition, some members of this structural family are known to be inhibitors of HIV reverse transcriptase and human telomerases [9]. The most recently isolated griseorhodins D, E, and F are intermediates and end products of post-PKS tailoring modification during biosynthesis [1].…”

Oxidative Catalytic Spiroketalization Leading to Diastereoselective Synthesis of Spiro[benzofuran‐2,1′‐isochromene]s

“…Spiroketal is a privileged structural unit that exists widely in a range of natural products that exhibit interesting biological activity . Among the family of spiroketals, benzannulated 5,6‐spiroketals behave as a key pharmacophore in many bioactive natural products, such as β ‐rubromycin, heliquinomycin, griseorhodin A (Figure ). General strategies to access this key motif are through oxidative spiroketalization, gold‐catalyzed intramolecular alkyne hydroalkoxylation, Pd‐catalyzed reductive coupling, copper(I)‐catalyzed spiroketalization of propargyl alcohols, Sc(OTf) 3 ‐catalyzd epoxide‐opening spiroketalizations, multi ‐ step spiroketalization of aryl acetylenes or ketones, hetero‐Diels‐Alder reaction of o ‐quinone methide precursors .…”