Antonio ElÃas Kuri Pineda
Mexico
Title: Biotransformation study of the synthetic cannabinoid JWH-007
Biography
Abstract
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.
Matteo Dal PrÃ
University of Padua, Italy
Title: Fluorinated anti-tubulin phenyl-pyrroloquinolinones: In vitro and in vivo anticancer properties
Biography
Abstract
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