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Aurones and their role in colouring flowers
There are many beautiful flowers in nature in a variety of shapes and colours. Such diversity is acquired through evolutionary processes to ensure successful reproduction by attracting pollinators or by promotion of wind pollination [38]. The colour is especially important to attract pollinators, such as insects and birds. For plant breeders, the colour of flowers is one of their most important targets. Such breeders have come up with many different-coloured hybrids and cultivars using natural mutants or genetically related species. Recent advances in genetic modification techniques enable the production of desirable and novel flower colours [39]. Many researchers exploit the knowledge of flavonoid biosynthesis effectively to obtain unique flower colours. Transgenic blue-violet flowers, for instance, are already on the market today and transgenic blue roses have been reported [40].
For creating transgenic plants with yellow colours, aurones are often used as pigments of choice. Ono and Fukuchi-Mizutani revealed that regulation of aurone biosynthesis led to production of yellow flowers in a Torenia hybrid [15].
Interestingly, the biosynthetic avenue leading to aurones differs somewhat from the chemical synthetic pathways discussed earlier. In transgenic flowers, the coexpression of Antirrhinum majus chalcone 4’-O-glucosyltransferase (Am4’CGT) in the cytoplasm and A. majus aureusidin synthase (AmAS1) in the vacuole combined with down-regulation of anthocyanin biosynthesis by RNA interference (RNAi) resulted in yellow flowers. These two enzymes will produce aureusidin 6-O-glucoside (21) via a 2’,4’,6’,4-tetrahydroxychalcone 4’-O-glucoside 20. The authors suggested that the chalcones (19) are 4’-O-glucosylated in the cytoplasm, their 4’-O-glucosides transported to the vacuole, and therein enzymatically converted to aurone 6-O-glucosides (Scheme 7).
Since chalcones are common throughout the plant kingdom, the strategy to generate yellow flowers by production of aureusidin 6-O-glucoside is widely applicable to most plant species producing chalcones. Furthermore, this genetic “trick” opens the door to molecular breeding strategies, which generate monotonous yellow flowers that dominantly produce aurone 6-O-glucoside [15].
Aurones as fluorescent probes with potential applications
Organic molecules that fluoresce in the visible region of the electromagnetic spectrum might be useful as probes in biological systems [42]. Such probes should cause minimal perturbation of the biological macro-molecule, they possess background fluorescence and are easy to use. There are three general types of fluorophores of interest here: xanthenes (fluorescein, rhodamine), boron dipyrromethenes and cyanines. Some of them already absorb and fluoresce in the visible region, but most of these molecules are relatively bulky with small Stokes’ shifts [1, 2]. Shanker and Dilek recently published aurone derivatives as potential fluorescent probes for biomolecules that can be observed with visible light [42]. Even the largest molecule they prepared for this study is smaller than the xanthene dyes. The UV–Vis absorption characteristics of naturally occurring aurones have been well documented [14, 15]. An amine substituent at the 4-position of aurone 22 leads to the largest red shift in the absorption maximum compared with that of the parent molecule. Acetylation of the amine (aurone 23) shifts the absorption and emission maxima to shorter wavelengths, while restricting the rotation of the amine nitrogen in 24 shifts the absorption and emission maxima to longer wavelengths.
On one hand, xanthenes have high quantum yields in polar environments, while on the other hand the aminoaurones investigated need to have a hydrophobic environment to be useful fluorescent probes. The molecules investigated can also be observed using common microscopy excitation sources. The authors further speculated that Z- and E-isomers can be interconverted photochemically and, therefore, may have applications as photoactivated switches. As a proof of the concept, they showed that the absorption and emission maxima of aurones may be varied to suit a particular application through functional group selection [42].
Aurones as chemosensors
Chen et al. developed novel aurones as chemosensors for cyanide anions like 25. These compounds exhibit remarkable response to cyanide anions with obvious changes , colour and fluorescence change owing to a hydrogen bonding reaction between cyanide anions and the O–H moiety of the sensors, which allows to use the naked eye to detect cyanide anions [43].
Biological roles, targets and activities
Aurones and others sub-classes of flavonoids, such as flavones and chalcones, have been studied for their numerous biological activities. Aurones, however, are only studied sparingly compared with the others sub-classes [44, 45]. Nevertheless, recent studies have revealed promising biological properties of this group of natural molecules. We described the most relevant biological properties of aurones discovered so far in our recently published review too [46].
Aurones as antiparasitic agents
Recently, Souard et al. synthesized and analysed 35 aurones for their potential as antimalarial drugs. All of these compounds were found to be non- cytotoxic in human cell lines and among them, seven had an IC50 below 5 μM in the antiplasmodial assay. The most active compound was tested in vivo on mice and was not toxic to the mouse itself, but the antiplasmodial effect appeared to be less efficient compared with the in vitro studies due to its low solubility. The structure– activity relationship analysis revealed that dimethoxylation at positions C4 and C6, a halogen atom at position 4’, and the substitution of the intracyclic oxygen atom with an N-H group increased the activity of the compounds. However, a long chain had an adverse effect. Concerning the azaaurones, an ethyl moiety at C4’ rather than C2’, substitution of the ethyl group by an ethynyl group, methoxylation at the 4’-position, and a dimethylamino moiety improve the efficiency of the molecules (26) [47].
Aurones as antimicrobial agents
Aurones also exert antibacterial and antifungal properties. A recent article published in 2010 reported that a series of synthetic aurone analogues are efficient antibacterial and antifungal molecules. All of these compounds exhibited moderate to good antibacterial activity against E.coli, B. subtilis, S. aureus, K. pneumoniae and P. vulgaris. Concerning their antifungal activity, all of these compounds were able to inhibit different fungal strains, including A. fumigatus, A. niger, T. virdie, C. albicans and P. chrysogenum at a concentration of 25 μg/mL and with different efficiency (27) [48].
Tiwari et al. synthesised ferrocene-substituted aurones and tested them against antibiotic- sensitive and antibiotic-resistant strains of S. aureus and a resist- ant strain of S. epidermidis as well as human breast cancer cells. The most active compound 28 showed not only a bactericidal effect from time-kill assays but it is also active in human breast carcinoma, with IC50 value in the low micromolar range [49].
Aurones as anti-viral agents
A series of different flavonoids has been analysed for neuraminidase inhibition potency, a glycoprotein involved in the infection process of the influenza virus. Among this list of 25 flavonoids, most of the aurones tested were described as good neuraminidase inhibitors. The structure–activity relationship revealed that a glycosyl group at any position, and a hetero-function at C3 or C4 decrease this effect, and an OH group at C6 or C4’, a double bond between C-2 and the phenylidene, and a hetero-function at C3 are essential for the activity (29) [50].
Several aurone derivatives synthesized by Haudecoeur and Belkacem were analysed to target the hepatitis C virus RNA-dependent RNA polymerase. The authors identified the aurone target site by site–directed mutagenesis as the thumb pocket I of the polymerase. They identified seven aurone derivatives as potent inhibitor molecules with an IC50 below 5 μM. Interestingly, all of these compounds are non-cytotoxic towards cultured human Huh7 and HEK293 cells. This data permitted the authors to identify important substituents for biological activity: on the A ring, a hydroxy group at position C4 or a dihydroxy substitution at positions C4 and C6; on the B ring, hydroxy groups at positions C2’, C4’ – or C3’, C4’ or a hydrophobic and a bulky substituent or an alternative core (30) [51].
Aurones as anti-inflammatory agents
The aurone derivatives synthesized by Bandgar and Patil, described as antibacterial and antifungal molecules, also show anti-inflammatory properties. They are able to inhibit the production of TNF-α (tumour necrosis factor-alpha) and IL-6 (interleukin-6), two cytokines that are often involved in diseases, such as autoimmune diseases, diabetes, arthrosclerosis and cancer [48].
Table of contents :
1. General introduction
References
2. Aurones
2.1 General introduction
2.2 Synthesis of aurone derivatives
2.3 Aurones and their role in colouring flowers
2.4 Aurones as fluorescent probes with potential applications
2.5 Aurones as chemosensors
2.6 Biological roles, targets and activities
i. Aurones as antiparasitic agents
ii. Aurones as antimicrobial agents
iii. Aurones as anti-viral agents
iv. Aurones as anti-inflammatory agents
v. Aurones as anti-cancer agents
vi. Aurones to treat skin diseases
vii. Aurones in Alzheimer’s disease
viii. Aurones as SIRT1 inhibitors
ix. Aurones as potential biological herbicides
x. Aurones as radical scavenger
2.7 Summary of the literature survey
2.8 Novel benzopyran-2- and 4-one-containing aurones
2.8.1 Chemistry
2.8.2 Biology
2.9 Conclusion and Outlook
2.10 Experimental part
2.10.1 Chemistry
2.10.1.1 General introduction
2.10.1.2 Synthesis of the aurone derivatives
2.10.2 Biology
2.10.2.1 General
2.10.2.2 Cell culture
2.10.2.3 Cell Cycle Analysis on K562 Cells
2.11 References
3. DNMT Inhibitors
3.1 Introduction to Epigenetics
3.2 DNA methyltransferases
3.2.1 General introduction
3.2.1 Catalytic mechanism of DNMTs
3.3 Known DNMT inhibitors
3.3.1 Nucleoside-like inhibitors
3.3.2 Non-nucleoside inhibitors
3.4 Summary of the literature survey
3.5 Optimisation study SGI 1027
3.5.1 Chemical synthesis of compounds 84-96
3.5.2 Biochemical and biological results
3.5.2.1 DNMT1, DNMT3A2/3L, PRMT1 and GLP assays
3.5.2.2 Docking studies of compound 84 and 88 as well as mechanism of action of 88
3.5.2.3 Effects of quinoline-based DNMTi in a panel of cancer cell lines.
3.5.2.4 Effects of 85 and 88 in medulloblastoma stem cells (MbSCs)
3.6 Conclusion and outlook
3.7 Experimental part
3.7.1 Chemistry
3.7.1.1 General introduction
3.7.1.2 Synthesis of selective non-nucleosidic human DNMTi
3.7.2 Biology
3.7.2.1 General introduction
3.7.2.2 Nanoscale DNMT1 pre-screen. HotSpot DNMT assay
3.7.2.3 DNMT1, DNMT3A2/3L, PRMT1, and GLP inhibition assays
3.7.2.4 DNMT1 inhibition assay
3.7.2.5 DNMT3A inhibition assay
3.7.2.6 PRMT1 and GLP inhibition assays
3.7.2.7 Competition studies
3.7.2.8 Molecular modelling
3.7.2.9 U-937, RAJI, PC-3, MDA-MB-231 and PBM cellular assays
3.7.2.10 Medulloblastoma cancer stem cell (MbSC) assays
3.7.2.11 RNA isolation and Real-Time qPCR
3.7.2.12 Western blot assay
3.7.2.13 MTT assay
3.8 References
4. Coumarin based chalcones as potential NF-κB inhibitors
4.1. General introduction
4.2. Chemistry
4.3. Effect of synthetic coumarin-based molecules on the TNF-alpha induced NF-κB pathway
4.4. Conclusion and outlook
4.5. Experimental part
4.5.1 Chemistry
4.5.1.1 General introduction
4.5.1.2 Synthesis of potential NF-κB inhibitors
4.5.2 Biology
4.5.1.3 General introduction
4.5.1.4 Cell culture
4.5.1.5 Assay to test the TNF-alpha induced NF-κB pathway
4.6. References
5. Conclusion and perspectives
6. French summary
6.1. Introduction
6.2. Les aurones
6.3. Les inhibiteurs de la méthyltransférase de l’ADN
6.4. Chalcones à base de coumarine comme des inhibiteurs potentiels de NF-κB
6.5. Conclusion et perspectives
6.6. References
