Plenary Lecture 12

Title: Applying biosynthesis and microbial model for drug metabolism
in Medicinal Chemistry.

Professor Valeria de Oliveira

Federal University of Goias, Brazil


Lecture Summary: One of the major current challenges of medicinal chemistry is not only the discovery of new biologically active compounds, but is obtaining them by simple or friendly synthetic processes. Hydroxylation reactions in non activated carbon and glycosylation reactions with regiosselectivity are always a big challenge. No less important is the early performance of metabolism studies without the use of large number of laboratory animals. Filamentous fungi possess catalytic enzymes that perform such reactions, and can be very useful. Phase I and II metabolic reactions similar to those carried out with human enzymes can be mimicked for the production of new biologically active metabolites or derivatives. Fungal enzymes may also catalyze glycosylation reactions and modify chemical-physical characteristics such as solubility, improving bioavailability or even act as a carrier to a specific location. The hydroxylation reactions similar to mammalian phase I reactions can modify the parent compound, modifying its activity and making it more selective for a particular receptor1 type or wholly modifying the pharmacophoric moiety. Microorganisms, especially filamentous fungi of international collections or wild strains, cultivated freely or fixed in stainless2 steel springs are the most used. The reaction takes place in traditional culture media in microplates, flasks or bioreactors and are monitored by high performance liquid chromatography-TLC or High performance liquid chromatography-HPLC and purified at the end by column or preparative HPLC. These reactions are carried out in aqueous medium at pH around neutrality and without addition of cofactors, since the microorganism remains whole during the entire process. Income can be scaled and miniaturized screening processes in high-throughput screening -HTS can help to choose the right strain for each reaction. Chemoselectivity induced by new strategies such as immobilization in bioreactors can facilitate the extraction and purification, one of the few difficulties to be overcome. Here will be present glycosylation products of: zidovudine, entacapone, cardanol, 4 catechol nerolidil, curcumin, tannins and flavonoids. In flavonoids3, for example, glycosylations in certain positions may favor vasorelaxation or cytotoxic activity. The alternative method of in vitro metabolism study will be discussed for drugs already in the market such as olanzapine, diazepam4, stavudine and diacerein, or for drug candidates such as derivatives of N- phenyl piperazines and N-acyl hydrazones. N-phenyl piperazines hydroxylation can make them more selective for dopamine receptors and human or mammalian metabolites can be produced in sufficient quantities for pharmacological and toxicological tests, in the case of N-acyl hydrazones.


Acknowledgments: The author would like to thank INCT–INOFAR/CNPq (573.564/ 2008-6) – Brazil.


References: 1T.F. Gomes,T. F. et al. European Journal of Medicinal Chemistry 2013, 62, 214.

2Souza P. L. M . et al. Bioorg. Med. Chem. Lett. 2016, 26 3177.

3Penso J. et al. European Journal of Pharmacology 2014,733, 75.

4 Arruda, E.L. et al. Tetrahedron Letters2016, 57, 4392.