Total synthesis of griseusins and elucidation of the griseusin mechanism of action

Abstract

An efficient divergent synthesis of griseusins enabled SAR studies, mechanistic elucidation and evaluation in an axolotl tail regeneration model.

Palladium-Catalyzed Regiospecific peri- and ortho-C–H Oxygenations of Polyaromatic Rings Mediated by Tunable Directing Groups

“…In stark contrast, the ortho -hydroxylation of naphthalene has not been focused independently and examples pertained to the ortho- C–H oxygenation studies of benzene ring also suffered from adverse assembly/disassembly of directing groups . As a conceptual extension of synthesizing natural naphthoquinones, we envisioned the selectivity control of peri- C–H and ortho -C–H oxygenation of the same polyaromatic substrates by simply changing directing groups might serve as enabling strategy for the divergent synthesis of sets of uniquely polyaromatic natural products (Figure c). In the context of step-economies, the directing group strategy described herein offers the potential to circumvent redundant functional group manipulations that often hamper C–H activation methods.…”

Himalaquinones A–G, Angucyclinone-Derived Metabolites Produced by the Himalayan Isolate Streptomyces sp. PU-MM59

“…1,29 Structurally similar cytotoxic natural products were recently determined to function via inhibition of peroxiredoxin 1 (Prx1), leading to an increase of reactive oxygen species (ROS), subsequent inhibition of mTORC1-mediated 4E-BP1 phosphorylation (4E-BP1p), apoptosis induction, and tumor suppression. 34,37,64 Given the positive correlation between inhibition of 4E-BP1 (B) Dose−response of compound 7 against A549 (non-small-cell lung) and PC3 (prostate) human cancer cell lines (72 h). See also Supporting Information, Figure S4 and Table S1.…”

“…Western blot analysis was performed as previously described. 34,64 Specifically, after treatment with test agent, cells were lysed in NP-40 lysis buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 10% glycerol, protease and phosphatase inhibitor cocktail). Equal amounts of lysate were…”

Activation and Identification of a Griseusin Cluster in Streptomyces sp. CA-256286 by Employing Transcriptional Regulators and Multi-Omics Methods

“…Although pyranonaphtoquinones, including griseusins, may exist in two enantiomeric versions [15,[23][24][25], the 3 -O-α-(D)-forosaminyl derivative (3) has only been found associated with (+)-griseusin A [19], which in turned was shown to be the enantiomer of the formerly isolated griseusin A [26,27]. Considering the compound 2 as an N-AcCys adduct of 3, the absolute configuration of the pyranonaphtoquinone core of 2 was judged to be the same as that reported for 3 (i.e., (+)-griseusin A).…”

“…5 and 0.39 µg/mL for Bacillus subtilis PCI 219 [19]. Recently, the chemical synthesis of griseusin A has been determined and cytotoxicity of griseusin compounds against cancer cells and in axolotl embryo tail inhibition studies has been elucidated, with promising results [25].…”