The cannabinoid substances group can be subdivided into three subgroups called: phytocannabinoids, endogen cannabinoids and synthetic cannabinoids. All of these have the ability of modulate the activity of the receptors CB1 and CB2, which are part of the physiological endocannabinoid system. Research on synthetic cannabinoids has had different scopes, focusing primarily on the understanding of the physiological function of the CB1 receptor. However, some of these compounds have started to be used as psychoactive substances, so the focus of their study has been channeled towards their toxic effects, their pharmacokinetics and how they can be detected in users. In this study, we present an approach to phase I-biotransformation of the compound JWH-007, which is a strong agonist of the CB1 receptors and it is reported by its use as a psychoactive substance due to the effects caused by its administration. In that sense, we first synthesized the compound with an alkylation reaction SN2 followed by an acylation reaction Friedel-Crafts. Once purified and chemically characterized, an in vitro biotransformation study was carried out in a controlled system that includes CYP2C9, and the subsequent determination of the chemical structures of the products generated by Mass Spectroscopy. Our data suggests that some of these Phase I-metabolites retain their biological activity, since they have an important affinity for the CB1 receptor. In that way, the determination of the kinetic parameters of the enzymatic process allows to conclude the chemical structures of the main Phase I-metabolites and their catalysis speed. The chosen in vitro biotransformation system is ideal for the initial study of the metabolism of compounds of biological interest. This, in turn, opens can lead to later research in more complex system such as cell lines or animals. The knowledge of the key points in the biotransformation of the compound is essential in the pharmacological study of CB receptors, which are still being explored as a therapeutically alternative and more recently because of their value as molecular targets of new drugs.

Tricycle Phenyl-Pyrroloquinolinones (PPyQs) are a class of compounds that have showed interesting in vitro and in vivo anti-proliferative activity acting as tubulin polymerization inhibitors by binding at the colchicine site into β-tubulin. The major initial focus on introducing fluorine into biologically active compounds is to improve their metabolic stability by blocking potential reactive positions with fluorine. In an attempt to reduce the oxidative metabolism of 7-PPyQs and at the same time to possibly maintain the excellent pharmacodynamic, we designed the synthesis of some compounds 12-15 and 19, monofluoro-phenyl derivatives of the earlier 3-ethyl-7-PPyQ 20 and 3-benzoyl-7-PPyQ 21. Of the new compounds synthesized, potent cytotoxicity (low and sub-nanomolar GI50 values) was observed with 12 and 13, both more potent than 20, in both leukemic and solid tumor cell lines. Neither compound 12 nor 13 induced significant cell death in normal human lymphocytes, suggesting that the compounds may be selectively active against cancer cells. In particular, 13 was a potent inducer of apoptosis in the A549 and HeLa cell lines. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, indicating that cells followed the intrinsic pathway of apoptosis. Experiments carried out in a mouse syngeneic model demonstrated high antitumor activity of 13, which significantly reduced the tumor mass at doses four-ten times lower than that required for the CA-4P used as reference compound. Finally, molecular docking and metabolic stability studies of the newly synthesized compounds will be reported

The traditional Turkish medicine includes many compounds with variations in their chemical and physical properties. In this work, compounds present in the leaves and flower of Kitaibelia balansae extracted with solvents of different polarities were screened out and their structures were characterized by liquid chromatography/electrospray ionization mass spectrometry in negative ion mode. 67 compounds were observed in the leaves extract, 35 of which were recognized and identified as flavonoids. The naphthodianthrones, hiperforin and hypericin were almost the major compounds in the leave extract. Catechin, epicatechin, myricetin, quercitrin, isoquercetin, kaempferol, apigenin, and chlorogenic acid were also present in these extracts together with other compounds. However, up to date to our knowledge there is no research on Kitaibelia balansae species has been conducted.

Statement of the Problem: Chronic wounds represent an important issue in medical practice taking into account their impact on patient’s quality of life, the difficulty of their care and the costs involved. Based on their specific characteristics and biological properties, chitosan and hyaluronic acid have attracted the researchers’ interest in developing new systems with medical applications. The purpose of this study was the development of some new polymeric systems, hydrogel type, with potential use in chronic wounds treatment. Materials & Methods: The developed systems were obtained using chitosan hydrogel 5%, bentonite 5% and hyaluronic acid solution 1%. The proportion of chitosan-bentonite hydrogel and hyaluronic acid solution ranged between 95%-5% and 40%- 60%. In these formulations the arginine 2% was included. The obtained hybrid hydrogels were characterized in terms of pH and morphology using Scanning Electron Microscopy (SEM). The presence of arginine in the polymer matrix was proved by Fourier-Transformed Infrared Spectroscopy (FT-IR). Findings: There were obtained seven new hybrid hydrogels based chitosan-bentonite-hyaluronic acid-arginine, whose pH varied between 4.72 and 5.33. The presence of the active substance was proved by IR spectroscopy and the morphology was analyzed by SEM. Conclusion & Significance: The systems developed represent a step in the attempt to improve chronic wound management, targeting the tissue regeneration and the risk of local infections. Recent Publications 1. Giri T K, Thakur A, Ajazuddin A A, Badwaik H and Tripathi D K (2012) Modified chitosan hydrogels as drug delivery and tissue engineering systems: present status and applications, Acta Pharmaceutica Sinica B, 2 (5):439-449. 2. Debats I B J G, Wolfs T G A M, Gotoh T, Cleutjens J P M, Peutz-Kootstra CJ and Van der Hulst R (2009) Role of arginine in superficial wound healing. Nitric Oxide 15:147-156. 3. Mogoşanu GD and Grumezescu (2014) AM Natural and synthetic polymers for wounds and burns dressing, International Journal of Pharmaceutics, 463 (2):127-136. 4. Stern R and Maibach H I (2008) Hyaluronan in skin: aspects of aging and its pharmacologic modulation, Clinics in Dermatology, 26: 106-122. 5. Mayet N, Choonara Y E, Kumar P, Tomar L K, Tyagi C, Du Toit LC and Pillay V (2014) A Comprehensive Review of Advanced Biopolymeric Wound Healing Systems, Journal of Pharmaceutical Sciences, 103 (8): 2211-2230.

Statement of the Problem: Recent data indicate that chronic wounds account for almost 4% of total health system costs, and that this proportion is increasing. The common chronic skin and soft tissue wounds include the diabetic food ulcer, the pressure ulcer and the venous and arterial leg ulcers. Prevention of bacterial infection is important in severe cases because it is associated with septic shock, the major cause of death. Materials & Methods: New hybrid hydrogels based on chitosan-hyaluronic acid-bentonite which have incorporated arginine (2%) as active substance, have been developed. The proportion of chitosan-bentonite hydrogel and hyaluronic acid solution ranged between 95%-5% and 40%-60%. Arginine is a basic alpha-amino acid which is known that enhances wound collagen synthesis and wound breaking strength during normal and impaired healing. The hybrid hydrogels have been studied in terms of swelling degrees and porosity. The antimicrobial study using Gram positive and Gram negative bacterial strains and in vitro antioxidant assays were performed. In order to correlate the intensity of the biological effect with arginine concentration, in vitro kinetic release of active agent was also performed. Findings: The swelling degree is depending on concentration of chitosan and hyaluronic acid as well as on concentration of arginine and is ranged between 200% and 300% after 60 min. The presence of arginine in the polymeric matrix has as result increasing of the porosity degree. The porosity degree is an important characteristic of polymeric membranes used in the treatment of wounds, since it influences the exudate absorption, the rate of colonization and the angiogenesis process. Arginine improved also the biological effects of the polymeric matrix based on chitosan-hyaluronic acid-bentonite. Conclusion & Significance: The features and biological effects of the developed hybrid hydrogels recommended them as new therapeutic alternatives in the treatment of chronic wounds. Recent Publications 1. Cervini-Silva J, Ramírez-Apan MT, Kaufhold S, Ufer K, Palacios E and Montoya A (2016) Role of bentonite clays on cell growth, Chemosphere, 149: 57-61. 2. Giri TK, Thakur A, Ajazuddin AA, Badwaik H and Tripathi DK (2012). Modified chitosan hydrogels as drug delivery and tissue engineering systems: present status and applications, Acta Pharmaceutica Sinica B, 2 (5): 439-449. 3. Mogoşanu GD and Grumezescu AM (2014) Natural and synthetic polymers for wounds and burns dressing, International Journal of Pharmaceutics, 463 (2): 127-136. 4. Morton LM and Phillips TJ (2016) Wound healing and treating wounds: Differential diagnosis and evaluation of chronic wounds, Journal of the American Academy of Dermatology, 74 (4): 589-605. 5. Smith R G (2008) Enzymatic debriding agents: an evaluation of the medical literature. Ostomy/wound management, 54.8: 16-34.

Tamas Lorincz has an MSc. degree in biochemical engineering and is a PhD candidate in the group lead by Professor Dr. Andras Szarka at Budapest University of Technology and Economics. Tamás Lőrincz received a Gedeon Richter Plc. Talentum PhD. scholarship in 2014 and the New National Excellence Program scholarship of the Hungarian Ministry of Human Capacities in 2017.

Pharmacologic (mM) concentration of ascorbate induces oxidative stress through the Fenton reaction. Cancer cells are known to show higher sensitivity towards ROS as normal cells. The mechanism of the induced cytotoxicity is still to be elucidated and involves oxidative stress, glutathione depletion, lipid peroxidation, the elevation of labile iron pool and caspase independency. In the frame of a large scale screening experiment to explore chemical compounds with killing effect on tumor cells a new chemical compound, erastin was identified which could induce cell death (ferroptosis) of RASmutant tumor cells. The morphology, biochemistry and genetics of ferroptosis differs considerably from other cell death types, such as apoptosis, necrosis, and autophagy and show high similarity as listed above which lead us to hypothesize that ferroptosis (at least partly) is responsible for ascorbate induced cytotoxicity in cancer cells. Recent Publications 1. Tamás Lőrincz, Katalin Jemnitz, Tamás Kardon, József Mandl, András Szarka 2. Ferroptosis is Involved in Acetaminophen Induced Cell Death 3. Pathology Oncology Research 21:(4) pp. 1115-21. (2015) 4. Tamás Lőrincz, András Szarka 5. The determination of hepatic glutathione at tissue and subcellular level 6. Journal of Pharmacological and Toxicological Methods 88: pp. 32-39. (2017) 7. Szilvia Z Tóth, Tamás Lőrincz, András Szarka 8. Concentration Does Matter: The Beneficial and Potentially Harmful Effects of 9. Ascorbate in Humans and Plants 10. Antioxidants and Redox Signaling [Epub ahead of print] (2017) 11. Area of research interest: cell death, in vitro toxicology, antitumor pharmacology

Katarzyna Gach-Janczak has been working in the Department of Biomolecular Chemistry at Medical University of Lodz since 2006, first as a PhD student, then as an Assistant and now as an Assistant Professor. In May 2010, she defended her Doctoral thesis. She completed her Post-doctoral training in the Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, University of Rouen (France). Her area of scientific interests is bidirectional. She is searching for new analgesics based on the structure of the endogenous opioid peptides and studying synthetic heterocyclic compounds as potential anticancer agents. She has published 43 research papers in international journals.

Centrally acting opioid agonists, such as morphine, are the most widely used analgesics for the treatment of severe pain. Among the three types of classic opioid receptors, mu, delta and kappa, the mu receptor was identified as primarily responsible for the pain-relieving effects but also responsible for a number of undesired side effects, including sedation, respiratory depression, inhibition of gastrointestinal transit, tolerance and physical dependence. In the previous decades, chemists and pharmacologists focused on obtaining analogs with high selectivity for one opioid receptor type. More recently, the development of compounds with mixed opioid profile is gaining a lot of interest eg. synergistic antinociceptive effects in response to the mu and delta receptor activation were observed in several in vivo studies. In this study we have shown that the replacement of the tyrosine residue in the mu-selective opioid ligand Tyr-c[D-Lys-Phe-Asp]NH2 with 2',6'-dimethyltyrosine (Dmt) produced a cyclopeptide Dmt-c[D-Lys-Phe-Asp]NH2 with mu-delta opioid receptor profile. This new analog showed improved antinociception in the hot-plate test as compared to the parent peptide but also significantly inhibited the gastrointestinal transit. Using the bioluminescence resonance energy transfer (BRET) assay it was shown that this analog was biased toward β-arrestin. To the best of our knowledge, it is the first reported β-arrestin biased opioid analog of a peptide structure. Our data are in accordance with earlier reports indicating that various in vivo activities of opioid agonists arise not only from the activation of one or more opioid receptors, but also from promoting G-protein or β-arrestin pathways.