In the European chemical industry, there is a strong drive to shift from fossil to renewable resources in the pursuit of sustainability. Sophorolipids, a class of biosurfactants, are interesting renewable resources, since they combine a complex structure with divergent biological and physico-chemical properties. The microbially produced lactonic sophorolipids were used for the production of a broad range of innovative sophorolipid amines 1 and sophorolipid quaternary ammonium salts 2. These sophorolipid quaternary ammonium salts were evaluated for their antimicrobial activity against Gram-negative and Gram-positive bacterial test strains. Minimum inhibitory concentration (MIC) values were determined for the active compounds. Values of 5-8 µM results were obtained for the derivatives containing an octadecyl chain attached to the nitrogen atom, compared to values of 10-52 µM for the antibiotic gentamicin sulfate. These results shows great promise for modified sophorolipids in the medical sector, for example for the inhibition of biofilm formation.

Transdermal delivery of drugs is a novel method of pharmacotherapy for many diseases. The main advantages of this method of administration are

• prolongation of the drug action;
• absence of the drug concentration hopping;
• decrease of the side effect risk.

This method of administration has to be viewed for preventive actions and therapy of viral respiratory infections. The aim of this work was studying the possibility of transdermal rimantadine delivery for influenza A prophylaxis and treatment in experimental animals. Rimantadine was administrated in the hydrogel matrix (formed from 1.2-propylene glycol and polyvinyl alcohol) in the doses 1 or 2 mg/mouse applied on the shaved back of mice 1 day before infection. Mice of experimental and control groups were infected intranasally with highly pathogenic influenza virus A/PR/8/34 (H1N1). Challenge was carried out using 4 animals for each virus dilution within the range of 10-1 to 10-7. Deaths of animals were recorded for 14 days. The results of our investigations had shown high anti-influenza efficacy of rimantadine under transdermal delivery. Differences of LD50 between control and experimental groups consist 1.7-1.75 log10 when dose of rimantadine was 1 mg/mouse and 2.25 log10 when preparation was administrated in dose 2mg/mouse. In this study the anti-influenza efficacy of rimantadine after its transdermal administration was established for the first time.

Cancer causes about 13% of all human deaths and at least one fifth of all deaths in Europe and North America.¹ Although chemotherapy is increasingly prescribed, it is not without side effects and so new, more selective remedies for cancer sufferers must be found.

Since the discovery of the anticancer properties of the indolocarbazole staurosporine, many analogues have been synthesised in order to obtain compounds that have a higher potency with respect to anticancer mechanisms.^{2, 3} The overall objective of this project is to produce selective and highly potent novel anticancer agents through modification of the indolocarbazole structure and a focus of this work is the replacement of the lactam/maleimide heretocycle to form a series of novel indolocarbazole derivatives including the first reported synthesis of a series of novel substituted indolocarbazole uracils. Biological evaluation via the NCI 60 cell line screen has been completed for a number of these compounds with some showing significant selectivity towards individual leukaemia and melanoma cell lines.

References

1. GLOBOCAN 2008, database (version 1.2) http://globocan.iarc.fr
2. C. Peifer, T. Stoiber, E. Unger, F. Totzke, C. Schächtele, D. Marmé, R. Brenk, G. Klebe, D. Schollmeyer and G. Dannhardt, J. Med. Chem., Design, Synthesis, and Biological Evaluation of 3,4-Diarylmaleimides as Angiogenesis Inhibitors, 2006, 49, 1271.
3. L. T. Pierce, M. C. Cahill, H. J. Winfield and F. O. McCarthy, Eur. J. Med. Chem., Synthesis and Identification of Novel Indolo[2,3-a]pyrimido[5,4-c]carbazoles as a New Class of Anti-cancer Agents 2012, 56, 292.

Ellipticine is a natural product possessing multimodal cytotoxic activity including DNA intercalation, topoisomerase II inhibition, c-Kit kinase inhibition and restoration of function to mutant p53 protein.¹ While ellipticine itself is not a suitable candidate for therapeutic use, derivatives including 2-methyl-9-hydroxyellipticinium acetate and 2-(2-(diethylamino)ethyl)-9-hydroxyellipticinium chloride, have progressed to clinical trials.² 

The effect of derivatisation on the isoellipticine is uncharted and structural diversification of isoellipticine could lead to drug candidates with a better clinical profile due to enhanced target specificity. Our initial approach to this uses substitutent modification at positions 10, 7 and 2 (salt formation at the N2 position represents a favourable attribute for cytotoxic activity as illustrated by the two most successful ellipticines). A number of novel derivatives of isoellipticine have been synthesised and further derivatised. Preliminary biological testing of novel compounds was performed using a topoisomerase II decatenation assay and via assessment of the anticancer profile using the National Cancer Institute 60 cell line screen for cellular activity.³

We will present here the design, synthesis and  anticancer properties and significant cell line selectivity of a series of novel ellipticine derivatives devised in our laboratory.

References

1. E.C. O’Sullivan, C.M. Miller, F.M. Deane and F.O. McCarthy. Stud. Nat. Prod. Chem. Emerging targets in the bioactivity of Ellipticines and derivatives, 2013, 39(6), 189.
2. C.M. Miller and F.O. McCarthy, RSC Adv. Isolation, biological activity and synthesis of the natural product ellipticine and related pyridocarbazoles, 2012, 2(24), 8883.
3. C.M. Miller, E.C. O'Sullivan, K.J. Devine and F.O. McCarthy, Org. Biomol. Chem. Synthesis and Biological Evaluation of Novel Isoellipticine Derivatives and Salts, 2012, 10(39), 7912.

Identification and development of new protein kinase inhibitors became these last two decades the key point for the search of new therapeutic agents because, the disorder of these enzymes in cellular environment is often the cause of pathologies as cancer and Alzheimer's disease (AD). In our laboratory, it was highlighted that N,N'-bis(5-arylidene-4-oxo-4,5-dihydrothiazolin-2-yl)aminopropylpiperazine (IC₅₀ 40 nM) presented selective inhibition towards the protein kinase DYRK1A [1,2] (dual specificity, tyrosine phosphorylation regulated kinases), enzyme suspected to have an impact on neurodegenerative diseases [3-5] and cancer [6]. To understand the mechanism of action towards DYRK1A and GSK3alpha/beta, we developed a route in 6 steps for a series of 5-arylidene-3-(arylmethyl)aminobutyl-2-thioxo-1,3-thiazolidine-4-ones. This methodology involved the construction of the 2-thioxo-1,3-thiazolidine-4-one platform under microwave irradiation from commercial bis(carboxymethyl)trithiocarbonate. The results of this multi-steps synthesis as well as the biological evaluations will be presented and discussed in this poster.

References
1. Coulibaly W-K., Paquin L., Bénie A., Bekro Y-A., Durieux E., Rucheau S., Meijer L., Le Guével R., Corlu A., Bazureau J-P., Scienta Pharm. 2012, 80, 825-836.
2. Coulibaly W-K, Paquin L., Bénie A., Bekro Y-A., Durieu E., Meijer L., Bazureau J-P. Eur. J. Med. Chem. 2012, 58, 581-590.
3. Debdab M., Carreaux F., Renault S., Meijer L., Bazureau J.-P. et al. J. Med. Chem. 2011, 54, 4172-4186.
4. Tahtouh T., Burgy G., Carreaux F., Bazureau J-P., Meijer L. et al. J. Med. Chem. 2012, 55, 9312-9330.
5. Burgy G., Limanton E., Meijer L., Carreaux F., Bazureau J-P. Eur. J. Med. Chem. 2013, 62, 728-737.
6. Ionescu A., Dufrasne F., Gelbcke M., Jabin I., Kiss R., Lamoral-Theys D. Mini-Rev. Med. Chem. 2012, 12, 1315-1329.

Protein kinases are enzymes assuring the transfer of a phosphate group of molecule donors of high energy, such as ATP, in specific substrates. The disorder of these enzymes in cellular environment are involved in some pathologies such as cancer and Alzheimer's disease [1]. So the discovery of inhibitors became the key point for the research of new therapeutic agents. In our team, N,N'-bis(5-arylidene-4-oxo-4,5-dihydrothiazolin-2-yl)aminopropylpiperazine (IC₅₀=40 nM) was identified as promising and selective inhibitor [2, 3] of DYRK1A (dual specificity, tyrosine phosphorylation regulated kinases), a protein kinase of interest for neurodegenerative diseases [4, 5] and also for cancer [6]. In order to understand the mechanism of action of this inhibitor towards DYRK1A but also towards GSK3a/b (who also plays an important role in malaria), we have developed a 4-steps synthesis from the commercial reagents N,N'-bis(3-aminopropyl)piperazine. The key step of this process is the construction of the 2-thioxo-1,3-thiazolidine-4-one platform under microwave irradiation from commercial bis(carboxymethyl)trithiocarbonate. Results for the synthesis will be presented and discussed in this presentation .

References
1. Debdab M., Carreaux F., Renault S., Meijer L., Bazureau J.-P. et al. J. Med. Chem. 2011, 54, 4172.
2. Coulibaly W-K, Paquin L., Bénie A., Bekro Y-A., Durieu E., Meijer L., Bazureau J-P. Eur. J. Med. Chem. 2012, 58, 581.
3. Coulibaly W-K., Paquin L., Bénie A., Bekro Y-A., Durieux E., Rucheau S., Meijer L., Le Guével R., Corlu A., Bazureau J-P., Scienta Pharm. 2012, 80, 825.
4. Tahtouh T., Burgy G., Carreaux F., Bazureau J-P., Meijer L. et al. J. Med. Chem. 2012, 55, 9312-9330.
5. Burgy G., Limanton E., Meijer L., Carreaux F., Bazureau J-P. Eur. J. Med. Chem. 2013, 62, 728.
6. Ionescu A., Dufrasne F., Gelbcke M., Jabin I., Kiss R., Lamoral-Theys D. Mini-Rev. Med. Chem. 2012, 12, 1315.