title: Synthetic remodeling of the chartreusin pathway to tune antiproliferative and antibacterial activities.
abstract: Natural products of the benzonaphthopyranone class, such as chartreusin, elsamicin A, gilvocarcin, and polycarcin, represent potent leads for urgently needed anticancer therapeutics and antibiotics. Since synthetic protocols for altering their architectures are limited, we harnessed enzymatic promiscuity to generate a focused library of chartreusin derivatives. Pathway engineering of the chartreusin polyketide synthase, mutational synthesis, and molecular modeling were employed to successfully tailor the structure of chartreusin. For the synthesis of the aglycones, improved synthetic avenues to substituted coumarin building blocks were established. Using an engineered mutant, in total 11 new chartreusin analogs (desmethyl, methyl, ethyl, vinyl, ethynyl, bromo, hydroxy, methoxy, and corresponding (1→2) abeo-chartreusins) were generated and fully characterized. Their biological evaluation revealed an unexpected impact of the ring substituents on antiproliferative and antibacterial activities. Irradiation of vinyl- and ethynyl-substituted derivatives with blue light resulted in an improved antiproliferative potency against a colorectal cancer cell line. In contrast, the replacement of a methyl group by hydrogen caused a drastically decreased cytotoxicity but markedly enhanced antimycobacterial activity. Furthermore, mutasynthesis of bromochartreusin led to the first crystal structure of a chartreusin derivative that is not modified in the glycoside residue. Beyond showcasing the possibility of converting diverse, fully synthetic polyphenolic aglycones into the corresponding glycosides in a whole-cell approach, this work identified new chartreusins with fine-tuned properties as promising candidates for further development as therapeutics.
authors.affiliation: Department of Biomolecular Chemistry and §Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, HKI , 07745 Jena, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Ueberschaar
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Xu
authors.forename: Kirstin
authors.initials: K
authors.lastname: Scherlach
authors.forename: Mikko
authors.initials: M
authors.lastname: Metsä-Ketelä
authors.forename: Tom
authors.initials: T
authors.lastname: Bretschneider
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Dahse
authors.forename: Helmar
authors.initials: H
authors.lastname: Görls
authors.forename: Christian
authors.initials: C
authors.lastname: Hertweck
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016983:Enterococcus / Q000187:drug effects*; D006027:Glycosides / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001578:Benzopyrans; D006027:Glycosides; C002185:chartreusin