Cyclopenta[ b]indole Derivative Inhibits Aurora B in Primary Cells

The Aurora family of kinases is closely involved in regulating cell division. Inhibition of Aurora A and B with small molecules is currently being investigated in clinical trials for the treatment of different cancers. It has also been evaluated as a treatment option against different autoimmune diseases in preclinical studies. Here, we present a cyclopenta[b]indole derivative capable of inhibiting Aurora B selectively in kinase assays. To evaluate the Aurora B inhibition capacity of the compound, we used a kinase IC50 assay as well as a suppression assay of proliferating primary cells. In addition, we examined if the cells had gained a phenotype characteristic for Aurora B inhibition after treatment with the compound. We found that the compound selectively inhibited Aurora B (IC50 = 1.4 μM) over Aurora A (IC50 > 30 μM). Moreover, the compound inhibited proliferating PBMCs with an IC50 = 4.2 μM, and the cells displayed reduced phosphorylation of histone H3 as well as tetraploidy, consistent with Aurora B inhibition

Ruthenium-Catalyzed E-Selective Alkyne Semihydrogenation with Alcohols as Hydrogen Donors

Selective direct ruthenium-catalyzed semihydrogenation of diaryl alkynes to the corresponding E-alkenes has been achieved using alcohols as the hydrogen source. The method employs a simple ruthenium catalyst, does not require external ligands, and affords the desired products in > 99% NMR yield in most cases (up to 93% isolated yield). Best results were obtained using benzyl alcohol as the hydrogen donor, although biorenewable alcohols such as furfuryl alcohol could also be applied. In addition, tandem semihydrogenation-alkylation reactions were demonstrated, with potential applications in the synthesis of resveratrol derivatives

Exceptionally rapid oxime and hydrazone formation promoted by catalytic amine buffers with low toxicity

Hydrazone and oxime bond formation between α-nucleophiles (e.g. hydrazines, alkoxy-amines) and carbonyl compounds (aldehydes and ketones) is convenient and is widely applied in multiple fields of research. While the reactants are simple, a substantial drawback is the relatively slow reaction at neutral pH. Here we describe a novel molecular strategy for accelerating these reactions, using bifunctional buffer compounds that not only control pH but also catalyze the reaction. The buffers can be employed at pH 5-9 (5-50 mM) and accelerate reactions by several orders of magnitude, yielding second-order rate constants of >10 M-1s-1. Effective bifunctional amines include 2-(aminomethyl)imidazoles and N,N-dimethylethylenediamine. Unlike previous diaminobenzene catalysts, the new buffer amines are found to have low toxicity to human cells, and can be used to promote reactions in cellular applications

Oxidative Coupling as a Biomimetic Approach to the Synthesis of Scytonemin

The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations In Its synthesis from 3-indole acetic acid are a Heck carbocyclization and a Suzuki-Miyaura cross-coupling, orchestrated In a stereospecific tandem fashion, followed by a biosynthetically inspired oxidative dimerization. The tandem sequence generates a tetracyclic (E)-3-(arylidene)-3,4-dihydrocyclopenta[b]indol-2(1H)-one that is subsequently dimerized into the unique homodimeric core structure of scytonemin

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

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\u27 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

Strategies and Methods for Synthesizing Scytonemin Analogues

Natural product synthesis is an exciting field of organic chemistry, directed toward constructing naturally occurring compounds, which often are both chemically complex and biologically intriguing. Scytonemin is a unique, dimeric natural product found in cyanobacteria. It is the active compound of the cyanobacterial photoprotective mechanism and is biosynthesized when the bacteria are exposed to solar radiation. Scytonemin has furthermore been proposed to have an ancient history, stretching back to the early photosynthetic life. The natural product is composed of two identical 3-benzylidene cyclopenta[b]indole-2-one moieties connected to each other at position one. Nostodione A, the little brother of scytonemin, is another natural product found in cyanobacteria. It also contains the 3-benzylidene cyclopenta[b]indole-2-one skeleton, but is not symmetrically substituted in C-1. Instead it appears as a 1,2-dione. Nostodione A has been proposed to be a biosynthetic precursor to scytonemin. Both scytonemin and nostodione A have shown anti-proliferative properties.In this project, flexible synthetic routes leading to the core skeleton of scytonemin and nostodione A have been developed. The syntheses are based on different ring closing strategies for the annulation of indoles. The commercially available indole-3-acetic acid was used to prepare a number of 3-alkynyl indoles, which thereafter were used to investigate gold- and palladium-catalyzed ring-closing reactions. Using gold in catalytic amounts gave the symmetrical, and undesired, carbazole skeleton exclusively. However, palladium catalysis could successfully be used to construct a number of derivatives containing the 3-benzylidene cyclopenta[b]indole-2-one skeleton. In paper I, we utilized the developed route for the first total synthesis of scytonemin. The dimeric structure was obtained by coupling two monomeric structures oxidatively in a biomimetic approach. In paper II, we presented the first total synthesis of nostodione A. Here, the C-1 position was functionalized by a DDQ mediated oxidation under aqueous conditions

Strategies and Methods for Synthesizing Scytonemin Analogues

Natural product synthesis is an exciting field of organic chemistry, directed toward constructing naturally occurring compounds, which often are both chemically complex and biologically intriguing. Scytonemin is a unique, dimeric natural product found in cyanobacteria. It is the active compound of the cyanobacterial photoprotective mechanism and is biosynthesized when the bacteria are exposed to solar radiation. Scytonemin has furthermore been proposed to have an ancient history, stretching back to the early photosynthetic life. The natural product is composed of two identical 3-benzylidene cyclopenta[b]indole-2-one moieties connected to each other at position one. Nostodione A, the little brother of scytonemin, is another natural product found in cyanobacteria. It also contains the 3-benzylidene cyclopenta[b]indole-2-one skeleton, but is not symmetrically substituted in C-1. Instead it appears as a 1,2-dione. Nostodione A has been proposed to be a biosynthetic precursor to scytonemin. Both scytonemin and nostodione A have shown anti-proliferative properties.In this project, flexible synthetic routes leading to the core skeleton of scytonemin and nostodione A have been developed. The syntheses are based on different ring closing strategies for the annulation of indoles. The commercially available indole-3-acetic acid was used to prepare a number of 3-alkynyl indoles, which thereafter were used to investigate gold- and palladium-catalyzed ring-closing reactions. Using gold in catalytic amounts gave the symmetrical, and undesired, carbazole skeleton exclusively. However, palladium catalysis could successfully be used to construct a number of derivatives containing the 3-benzylidene cyclopenta[b]indole-2-one skeleton. In paper I, we utilized the developed route for the first total synthesis of scytonemin. The dimeric structure was obtained by coupling two monomeric structures oxidatively in a biomimetic approach. In paper II, we presented the first total synthesis of nostodione A. Here, the C-1 position was functionalized by a DDQ mediated oxidation under aqueous conditions

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

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\u27 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

On the photostability of scytonemin, analogues thereof and their monomeric counterparts

As a part of their sun-protective strategy, cyanobacteria produce the natural UV-screener scytonemin. Its accumulation in the extracellular sheaths allows the bacteria to thrive in inhospitable locations highly exposed to solar radiation. Scytonemin is often referred to as photostable and has been reported to be non-fluorescent. Taken together, these properties indicate inherently fast non-radiative relaxation processes. Despite these interesting traits, the photophysics of scytonemin is as yet almost completely unexplored. In this study, we have compared the steady-state photophysics of scytonemin itself and four derivatives thereof. Furthermore, the in vitro photostability of scytonemin was studied in different solvents using a solar simulation system. Scytonemin and the investigated derivatives demonstrated a more rapid photoinduced decay in comparison with two commercial UV-screening agents. The photostability could be modulated by varying the solvent, with the protic solvent ethanol providing the most stabilizing environment

Total Synthesis of Nostodione A, a Cyanobacterial Metabolite

The first total synthesis of the mitotic spindle poison nostodione A is described. The inherent oxidative sensitivity of indoles is utilized for a late introduction of a second carbonyl to the cyclopent[b]indole-2-one system. The tricyclic system is prepared from indole-3-acetic acid and O-silylated 4-ethynylphenol, using a stereoselective intramolecular reductive Heck cyclization as the key transformation