Sinteza 3-cianopiridinskih zaviralcev monoamin oksidaze B in ligaz Mur

Urbančič, Tilen (author), Frlan, Rok (mentor)

Monoamin oksidaza (MAO) je encim, ki katalizira oksidativno deaminacijo aminov, in ki se nahaja na zunanji membrani mitohondrijev. Poznamo dve izoformni obliki encima, MAO A in MAO B, ki se razlikujeta predvsem v substratih. Obe obliki sta pomembni tarči pri zdravljenju nevrodegenerativnih bolezni, kot sta Alzheimerjeva in Parkinsonova bolezen. Pri zdravljenju le teh se uporabljajo večinoma ireverzibilni zaviralci encima. V zadnjih letih je trend raziskovanja reverzibilnih MAO zaviralcev, saj ti povzročajo manj nezaželenih učinkov. Ligaza MurD je od ATP odvisen encim v družini encimov ligaz Mur. Gre za bakterijske encime, ki katalizirajo dodajanje peptidov na peptidno verigo prekurzorja peptidoglikana. Gre za že uveljavljeno protibakterijsko tarčo, s katero želimo sintetizirati nove protibakterijske učinkovine. V zadnjih raziskavah navajajo kot eno od možnosti za nastanek Alzheimerjevo bolezen tudi bakterije. V sklopu naloge smo načrtovali in sintetizirali derivate spojine (E)-5-stirilnikotinonitrila, ki so potencialni zaviralci encima MAO oz. MurD. Spojine smo načrtovali na osnovi že znanih aktivnih spojin sintetiziranih na Katedri za farmacevtsko kemijo, Fakultete za farmacijo, Univerze v Ljubljani. Glavni poudarek kemijske sinteze je na Heckovi reakciji in izboljšanje nizkih izkoristkov le-te. Sintetizirali smo 11 novih spojin. Biokemijsko smo testirali sedem spojin na izoliranih rekombinantih človeških encimih MAO-A in MAO-B, ter štiri na izoliranem encimu ligazi MurD. Najbolj se je izkazala spojina (E)-5-(4-metoksi-2-nitrostiril)nikotinnitril (11) z IC50 vrednostjo 0.42 µM na encimu MAO-B. Zaključimo lahko, da je spojina (E)-5-(4-metoksi-2-nitrostiril)nikotinnitril (11) odlična smernica za nadaljnje raziskovanje reverzibilnih zaviralcev MAO-B in zdravljenje nevrodegenerativnih bolezni.

• Language: Slovenian
• Keywords: MAO, ligaze Mur, zaviralec, protibakterijske učinkovine, nevrodegenerativne bolezni
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-111103
• Publication date in RUL: 24.09.2019

Secondary language

• Language: English
• Title: Synthesis of 3-cyanopyridine inhibitors of monoamine oxidase B and Mur ligases

Abstract

Monoamine oxidase is an enzyme that catalyses oxidative deamination of amines. It is located in the outer mitochondrial membrane. There are two known isoforms of MAO enzyme: MAO-A and MAO-B. The main difference between them is the substrate they catalyse. Both isoforms have an important role in the treatment of neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease. The main focus of research in recent years has been directed towards the development of reversible MAO inhibitors because they usually have lower degree of side effects. MurD ligase is an ATP dependent enzyme of the Mur ligases family. It is a well-documented bacterial enzyme responsible for catalysing the addition of peptides to peptidoglycan precursor. The goal of our thesis has been to synthesise new antibacterial compounds using well documented antibacterial targets such as MurD ligases. In our research we set out to design and synthesise analogues of the compound (E)-5-styrylnicotinonitrile which are potential inhibitors of either enzyme MAO or MurD ligases. Compounds were designed based on well documented active compounds synthesised in the Department of Pharmaceutical chemistry, Faculty of Pharmacy, University of Ljubljana. Heck’s reaction has been chosen as the main chemical reaction of our work as it has the tendency to increase low yields. In total eleven new compounds were synthesised. Seven of them were biochemically tested on isolated recombinants human enzyme MAO-A and MAO-B, and four compounds on isolated enzyme MurD ligases. Best inhibitory properties showed (E)-5-(4-methoxy-2-nitrostyryl) nicotinonitrile (11) with IC50 level of 0.42 µM on enzyme MAO-B To conclude (E)-5-(4-methoxy-2-nitrostyryl)nicotinonitrile (11) is an excellent guideline to further research new reversible MAO-B inhibitors and the treatment of neurodegenerative diseases.

• Keywords: MAO, ligases Mur, inhibitor, antibacterial drugs, neurodegenerative diseases