Návrh a syntéza nových potenciálně cytotoxicky aktivních salicylamidů

Ing. Jan Dušek

Doctoral thesis

Design and synthesis of novel potentially cytotoxically active salicylamides

Abstract:

Byla provedena rozsahla literarni re.er.e zam..ena na metody syntezy a popsane biologicke aktivity salicylamid., na mo.nosti syntezy peptid. v.etn. pou.itych .inidel, aditiv a aspekt. racemizace substratu, a na molekuly schopne inhibice proteasomu. Bylo navr.eno a experimentaln. ov..eno n.kolik mo.nych p.istup. ke konstrukci salicylamid. s peptidovym .et.zcem, ktere navazuji a roz.i.uji sou.asne znalosti v teto oblasti. Byla vybrana nejvhodn.j.i synteticka metoda, ktera byla dale optimalizovana zejmena za u.elem omezeni racemizace. Byla provedena synteza serie slou.enin odvozenych od substituovane kyseliny salicylove a dipeptid., ktere byly vhodnym zp.sobem charakterizovany (1H a 13C NMR, I., HRMS v uspo.adani MALDI-TOF, CHN analyza). Dale bylo provedeno testovani jejich biologickych aktivit (antiproliferativni aktivita v..i kmen.m leukemie K562 a CEM a mnoho.etneho myelomu U266, proteasomalni inhibice U266 v.etn. selektivity v..i jednotlivym podjednotkam ?Ŕ kruhu proteasomu 20S U266 a .asovemuho pr.b.hu inhibice v r.znych koncentracich p.ipravenych salicylamid.).

Abstract:

Extensive literary review describing biological activities and methods of salicylamide synthesis, describing peptide synthesis including used reagents, aditives and aspects of substrate racemization, and describing molecules able of proteasomal inhibition was carried out and is presented. Several synthetical strategies for salicylamide containing a peptide chain was designed and experimentaly verified. Proposed samlicylamides are extending current state of knowledge about said topic. The most suitable synthetic method was chosen and further optimized with the aim of resolve the peptide racemisation issue which occured during the synthesis. Series of salicylamides with peptide sidechain was synthesized and characterized (1H a 13C NMR, IR, HRMS in the MALDI-TOF setting, CHN analysis). Furthermore, prepared compounds were tested for their biological activities (antiproliferative activity against leukemia cell lines K562 and CEM and multiple myeloma cell line U266, proteasomal inhibition of U266 including the selectivity towards proteolytic subunits of â ring of 20S proteasome U266, time progress of proteasomal inhibition at various salicylamide concentration levels).

Keywords

Alifatické salicylamidy, inhibice proteasomu, syntéza peptidů, amidační činidla, racemizace

Language used: Czech

Date on which the thesis was submitted / produced: 28. 5. 2020

Thesis defence

• Date of defence: 29. 6. 2020
• Supervisor: doc. Ing. Aleš Imramovský, Ph.D.

University of Pardubice

Faculty of Chemical Technology

Doctoral programme / field:
Organic Chemistry / Organic Chemistry