Pharmaceutics & Novel Drug Delivery Systems

Dr Ivan A Yaremenko has completed his PhD in Organic Chemistry by N D Zelinsky Institute of Organic Chemistry RAS in 2013. At present he is researcher N D Zelinsky Institute of Organic Chemistry RAS. He published 21 research papers, and 11 patents.

Organic peroxides have significant potential for creating on their basis new medicinal agents. In recent decades, the chemistry of organic peroxides has been intensively developing due to the detection of antimalarial, anthelmintic, antitumor, growth regulation, and antitubercular activity. The greatest progress in the development of medicinal agents on the base of synthetic peroxides is associated with compounds that contain an ozonide (1, 2, 4-trioxolane) moiety. In our studies, a general approach to the preparation of bicyclic ozonides is developed via reaction of 1,5-diketones with H2O2, promoted by such acids as BF3 Et2O, H2SO4, p-TsOH and HBF4. This process leads to the stereoisomeric bridged ozonides and provides a rare example of selective synthesis of ozonides without the use of ozone. Synthesized ozonides from 1,5-diketones and H2O2 have high cytotoxicity in vitro and selectivity against HepG2, A549, PC3, and DU145 cancer cell lines, which in some cases is higher than that of paclitaxel, doxorubicin, cisplatin, artemisinin, artesunic acid. This work was supported by RFBR according to the research project № 18-53-15010 and Projets de Recherche Conjoints (PRC) – CNRS, PRC Russie 2017 CNRS

Vera A Vil has completed her PhD in Organic Chemistry by N D Zelinsky Institute of Organic Chemistry RAS in 2017. She has worked as researcher of N D Zelinsky Institute of Organic Chemistry RAS. Her interests are organic chemistry, medical and agricultural chemistry, chemical technology. She has published 24 papers in reputed journals and 5 patents.

Peroxides are widely used in various areas of life. Traditional and the most developed field is the application of peroxides as radical initiators in industrial processes in the manufacture of polymers from unsaturated monomers, as well as in crosslinking of silicone rubbers, acrylonitrile-butadiene rubbers, fluororubbers, polyethylene, ethylene-propylene copolymer, etc. The biological activity of organic peroxides is usually associated with the antimalarial properties of artemisinin and its derivatives. However, the analysis of published data indicates that organic peroxides exhibit a variety of biological activity-anthelmintic, antifungal, antiviral, etc.- which is still being given insufficient attention. The modern trend in medicinal chemistry of peroxides is the search of effective anticancer drugs. The natural and synthetic peroxides exhibiting a cytotoxic effect on cancer cells already include hundreds of compounds. In view of very dynamic development of these areas of medical chemistry, in the near future, one should expect a breakthrough in the synthesis of biologically active peroxides and in understanding of its action with respect to a wide range of bio-targets. Rapid development of medicinal chemistry stimulates the development of new methods for the synthesis of organic peroxides. Focus on the selectivity and high yields revives previously non-selective chemistry of peroxides.This work was supported by RFBR according to the research project â„– 18-33- 00651.

Stanislav A Paveliev received his master’s degree in 2015 and is now working on his PhD thesis. The field of scientific interests is the new classes of stable N-oxyl radicals, new approaches to their generation and the study of their properties. The recent results are presented in the following article: Beilstein J. Org. Chem., 2018, 14, 2146-2155.

Nitroxide radicals are small redox-sensitive molecules, characterized by EPR and MRI contrast. Paramagnetic nitroxide radicals participate in electron-transfer reactions with oxidative and reductive equivalents with formation of noncontrast intermediates – hydroxylamine and/or oxoammonium. The interaction of these intermediates with superoxide radicals at physiological pH (7.4) leads to recovery of nitroxide in its initial radical form and appearance of MRI/EPR contrast. The rate constants of the electron-transfer reactions determine the dynamics of a nitroxide-enhanced MRI signal in living cells and tissues. Carcinogenesis is one of the most versatile models, characterized by a big difference in the redox signaling in comparison with healthy organisms. The cells and tissues of healthy mammals are characterized by low levels of reactive oxygen species (ROS) and some constant (reference) level of reducing equivalents. It is widely accepted that increasing ROS above the critical level provokes genomic instability and triggers uncontrolled proliferation. The normal cells become malignant. There are number of reports about MR imaging of cancer using N-oxyl radicals derivatives. All these studies give a preference to pyrrolidine-type nitroxide radicals (e.g. carboxy-PROXYL and carbamoyl-PROXYL), because of their greater resistance to reduction and a long-lived MRI signal in biological specimens in comparison with piperidine-type (TEMPO-type) nitroxide radicals. For cancer imaging in vivo, based on tissue redox activity, the nitroxide must be cell penetrating. The redox-sensitive nitroxide has to be delivered into the cells to interact with oxidizers and reducers substances and to serve as a redox sensor. The present research is devoted to obtaining new types of N-oxyl radicals - potential molecular sensors for imaging of cancer in vivo, and studying their physicochemical properties. This work was supported by the Russian Foundation for Basic Research (18-33-00613).

Olga Mikhailovna Mulina was born in 1993. She graduated from D. Mendeleev University of Chemical Technology of Russia in 2015. At this time she is a postgraduate student in N.D. Zelinsky Institute of Organic Chemistry RAS and has already published 1 patent and 5 papers in reputed journals. Her research interests concern with oxidative coupling processes, S-centered radicals and electrosynthesis.

Sulfonamides play an important role in modern organic and medicinal chemistry. Sulfonamide moiety is widespread in natural and biologically active compounds. Substances of this class possess antibacterial, anticancer, antiviral, anticonvulsant, antiinflammatory, and anti HIV protease activity. Sulfonamide group is applied for the protection of amines due to its easy removing. Therefore wide application fields of these compounds have been stimulating the development of new methods for their synthesis. In recent decades, in order to obtain structures with sulfur-nitrogen bonds oxidative strategies are finding ever-widening application. The main reasons for the rapid development of this area are mild reaction conditions of such processes and a wide scope of substrates used. We for the first time have found electrochemical synthesis of sulfonamides from arylsulfonyl hydrazides or sodium p-methylbenzenesulfinate and amines. The reaction goes in undivided electrochemical cell with the use of graphite anode and iron cathode. The yield of target products is 56-98%. This work was supported by RFBR according to the research project â„– 18- 53-15010 and Projets de Recherche Conjoints (PRC) - CNRS, PRC Russie 2017 CNRS.

Grinberg Igor is currently pursuing Postdoctoral research under the supervision of Professor Shlomo Margel, at the Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Israel. He received his BSc (2002), MSc (2007), and his PhD (2011) in Biology and Life Sciences, at Bar-Ilan University. His work involves the development of the chicken embryo model as well as in vivo (small animal) models for investigating various types of nanoparticles for various medical applications.

Bone has a poor blood supply, which generally consequences in low uptake of therapeutic agents thus necessitating the use of high drug dosage. Bisphosphonates (BPs) have a high affinity to hydroxyapatite and hence are widely used in the treatment of bone disorders. Biodegradable nanoparticles (NPs) due to their submicron size and biocompatibility have great potential to be used for therapeutic purposes. Thus, we hypothesize that a targeted delivery mechanism based on BP NPs conjugated to the therapeutic agent will lead to enhance bone uptake. We have engineered a unique biodegradable PEG based bisphosphonate nanoparticle (NPs) bearing two functional surface groups: (1) primary amine groups for covalent attachment of a dye/drug (e.g. NIR dye Cy 7 or doxorubicin); (2) bisphosphonate groups for targeting and chelation to bone hydroxyapatite. We have shown the ability of these novel BP NPs to target primary and secondary bone cancer and have demonstrated the potential use of doxorubicin conjugated BP NPs in the treatment of OS. These doxorubicin-conjugated BP NPs, due to their high affinity to Ca+2 ions, enable the delivery of doxorubicin directly to the tumor. In addition, their potential use in the treatment of other bone disorders is demonstrated.