The cyanobacterial pigments scytonemin and nostodione A - Synthesis, photophysicochemical behavior and biological studies
Doktorsavhandling, 2014

The natural UV-screener scytonemin is found in a plethora of cyanobacterial species. Its UV-protective ability allows the bacteria to thrive in inhospitable locations exposed to intense solar radiation. Scytonemin has a dimeric structure consisting of two 1-1' linked 3-(4-hydroxybenzylidene)cyclopenta[b]indole-2-one moieties. The cyanobacterial pigment nostodione A consists of the same skeleton, but is not symmetrically appended at C-1. Instead it appears as a 1,2-dione. Both natural products have displayed attractive bioactivity, e.g. inhibition of cancer cell mitosis and in vitro reduction of kinase activity. In this study, flexible synthetic strategies leading to the 3-alkenyl-cyclopenta[b]indole-2-one skeleton have been investigated, with focus on different ring-closing methods for the annulation of indoles. In particular, statistical experimental design has been utilized to successfully optimize a cascade Heck-Suzuki reaction. Here, the cyclopentanone is fused onto the indole with the concurrent assembly of the exocyclic alkenyl moiety. The route has been employed to construct a number of 3-alkenyl-cyclopenta[b]indole-2-one containing compounds with various substituents around the exocyclic double bond. Both the total synthesis of scytonemin and of nostodione A could be completed from suitable 3-alkenyl-cyclopenta[b]indole-2-one fragments, the former via an oxidative enolate coupling of two monomers and the latter via a selective oxidation. A number of relevant derivatives were synthesized via the developed synthetic route and used to investigate the photophysicochemical properties of scytonemin. Scytonemin demonstrated a low photo-stability in organic solvents, contradictory to its reported behavior in vivo. In cyanobacterial colonies, scytonemin is located in the extra cellular polysaccharide matrix, which likely has a stabilizing effect on scytonemin. Lastly, elaboration of the 3-alkenyl-cyclopenta[b]indole-2-one skeleton into kinase inhibitors relevant for combating melanoma was pursued. The kinase inhibiting properties of 17 substances, including scytonemin and nostodione A, were studied. Activity against the clinically proven melanoma target BRAF V600E was found and the most promising compound also displayed favorable properties in cell studies.

UV-screeners

design of experiments

cascade reactions

palladium catalysis

nostodione A

ligand effect

gold catalysis

kinase inhibitor

Scytonemin

photo-stability

KB
Opponent: Ulf Ellervik

Författare

Andreas Ekebergh

Chalmers, Kemi- och bioteknik, Organisk kemi

Oxidative Coupling as a Biomimetic Approach to the Synthesis of Scytonemin

Organic Letters,; Vol. 13(2011)p. 4458-4461

Artikel i vetenskaplig tidskrift

Total Synthesis of Nostodione A, a Cyanobacterial Metabolite

Organic Letters,; Vol. 14(2012)p. 6274-6277

Artikel i vetenskaplig tidskrift

Ämneskategorier

Fysikalisk kemi

Organisk kemi

Fundament

Grundläggande vetenskaper

ISBN

978-91-7597-125-4

Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 3806

KB

Opponent: Ulf Ellervik