Vybrané deriváty pyridinu imobilizované na koloidních nanosystémech určených pro asymetrickou katalýzu a pro transport léčiv

MSc. Dattatry Shivajirao Bhosale

Doctoral thesis

Selected pyridine derivatives immobilized on colloidal nanosystems for asymetric catalysis and drug delivery application

Abstract:

The first part of dissertation work was focus on the preparation and characterization of recoverable catalysts for a Henry reaction. First have been prepared and characterized catalysts based on a Cu(II) complexes of block copolymer ?ż-methoxypoly(ethylene glycol)-b-poly(L-glutamic acid) with (2R, 5S)- or (2S, 5S)-5-isopropyl-5-methyl-2-(pyridine-2-yl)- imidazolidine-4-one. The reaction of substituted aldehydes with nitromethane catalyzed by these prepared semi-soluble catalysts gives corresponding 2-nitroalcohols with high chemical yields (70.98%) and high enantioselectivity (61.92% ee). The polymer catalyst can be easily isolated from the reaction mixture by adding diethyl ether, catalyst was precipitate, recycled by centrifugation, and reused up to 10 cycles. Next have been prepared and characterized recoverable catalyst based on Cu(II) complex of magnetic nanoparticles Fe3O4@SiO2 with (2R, 5S)-5-isopropyl-5-methyl-2-(pyridine-2-yl)imidazolidine-4-one ligand. The prepared catalyst was characterized using DLS, FT-IR spectroscopy, SEM, and microanalysis. The reaction of substituted aldehydes with nitromethane catalyzed by this heterogeneous catalyst gives corresponding 2-nitroalcohols with high chemical yields (88.92%) and high enantioselectivity (68.94% ee). The reaction rate decreased due to the formation of aggregated form of catalyst nanoparticles whose size (115.834 nm) depends up on their content in the reaction medium. The MNPs supported catalyst can be easily isolated from the reaction mixture by external magnetic field and reused up to 10 cycles. After a tenfold recycling of the catalyst, the catalytic activity slightly decreases (~10%); however, no change in enantioselectivity was observed (~94% ee). The efficiency of the catalyst was also verified in the preparation of an intermediate of synthesis of the medical drug (R)-Salmeterol (72%, 91% ee). The second part of dissertation work was oriented to preparation and characterization conjugate of isoniazid with magnetic nanoparticles Fe3O4@SiO2 (189 ?} 3 nm) as a drug delivery system. The molecules of isoniazid were attached to the surface of nanoparticles by a covalent pH-sensitive imine bond. The conjugate was characterized by X-ray diffraction, SEM, dynamic light scattering, IR spectroscopy and microanalysis. The conjugate released isoniazid under in vitro conditions (pH = 4; 37 ??C; t. . 115 s). In addition, the cytotoxicity of the Fe3O4@SiO2-isoniazid was evaluated in SK-BR-3 cell using the xCELLigence system.

Abstract:

Prvni .ast diserta.ni prace byla zam..ena na p.ipravu a charakterizaci recyklovatelnych katalyzator. ur.enych pro Henryho reakci. Nejprve byly p.ipraveny a charakterizovany katalyzatory zalo.ene a m..natych komplexech blokoveho kopolymeru ?ż-methoxy- poly(ethylenglykol)-b-poly(L-glutamova kyselina) s (2R, 5S)- nebo s (2S, 5S)-5-isopropyl-5-methyl-2-(pyridin-2-yl)imidazolidin-4-onem. Reakce substituovanych aldehyd. s nitromethanem katalyzovana p.ipravenymi semi-rozpustnymi katalyzatory poskytovala odpovidajici 2-nitroalkoholy s vysokymi chemickymi vyt..ky (70.98%) a vysokou enantioselektivitou (61.92% ee). Polymerni katalyzator byl jednodu.e izolovan vysra.enim z reak.ni sm.si p.idavkem diethyletheru. Vysra.eny katalyzator izolovan pomoci centrifugy a recyklovan do 10 cykl.. Dale byl p.ipraven a charakterizovan recyklovatelny katalyzator zalo.eny na m..natem komplexu magnetickych nano.astic Fe3O4@SiO2 s (2R, 5S)-5-isopropyl-5-methyl-2-(pyridin-2-yl)imidazolidin-4-onem. Katalyzator byl charakterizovan pomoci DLS, FT-IR spektroskopie, SEM a mikroanalyzou. Reakce substituovanych aldehyd. s nitromethanem katalyzovana timto heterogennim katalyzatorem poskytovala odpovidajici 2-nitroalkoholy s vysokymi chemickymi vyt..ky (88.92%) a vysokou enantioselektivitou (68.94% ee). Reak.ni rychlost byla zpomalovana v d.sledku tvorby agregovanych forem nano.astic katalyzatoru (115.834 nm), a to v zavislosti na jejich hmotnostnim obsahu v reak.nim prost.edi. Katalyzator zalo.eny na magnetickych .asticich byl jednodu.e separovan z reak.ni sm.si aplikaci externiho magnetickeho pole a recyklovan do 10 cykl.. Po desetinasobne recyklaci katalyzatoru, byl pozorovan pokles vyt..ku (~10%), zatimco enantioselektivita byla stale vysoka (~94% ee). Vhodnost pou.iti katalyzatoru byla ov..ena p.i p.iprav. meziproduktu ur.eneho pro syntezu le.iva (R)-Salmeterolu (72%, 91% ee). Druha .ast diserta.ni prace byla zam..ena na p.ipravu a charakterizaci cileneho konjugatu isoniazidu s magnetickymi nano.asticemi Fe3O4@SiO2 (189 ?} 3 nm). Molekuly isoniazidu byly na povrch magnetickych nano.astic navazany prost.ednictvim kovalentni pH-sensitivni imino vazby. P.ipraveny konjugat byl charakterizovan pomoci rentgenove difrakce, SEM, dynamickeho rozptylu sv.tla, infra.ervene spektroskopie a mikroanalyzy. Konjugat uvol.oval isoniazid za podminek in vitro (pH = 4; 37 ??C; t. . 115 s). Dale byla studovana toxicita konjugatu Fe3O4@SiO2-isoniazid pomoci bun.k SK-BR-3 pou.itim systemu xCELLigence.

Keywords

Blokový kopolymer, magnetické nanočástice, chirální ligandy, Henryho reakce, recyklace katalyzátoru, pH senzitivní konjugáty léčiv, cytotoxicita

Language used: English

Date on which the thesis was submitted / produced: 3. 7. 2017

Accessible from:: 31. 12. 2999

Thesis defence

University of Pardubice

Faculty of Chemical Technology

Doctoral programme / field:
Organic Chemistry / Organic Chemistry