Synthesis of novel heterocyclic hydrazine derivatives and their conjugates

Abstract

Hüdrasiin on lihtne keemiline ühend molekulvalemiga N2H4. Ilmselt teatakse seda kõige paremini filmist „Marslane“ (2015), milles astronaut Mark Watney (Matt Damon) kasutas võõral planeedil ellujäämiseks seda algselt raketikütusena kasutatavat ühendit, et lagundada see vesinikuks, millest seejärel valmistada vett. Hüdrasiin on iseenesest väga mürgine, kuid selle derivaate on eraldatud mitmetest elusorganismidest. Need derivaadid on tihti selektiivse toksilisusega kas viiruste, bakterite, seente või vähirakkude vastu. Selektiivsel toksilisusel põhineb paljude ravimite toime, mistõttu on need ühendid äratanud ka ravimiarendajate huvi. Heterotsüklilisteks nimetatakse keemilisi ühendeid, mis sisaldavad tsüklilist struktuurielementi ning mis omakorda koosneb vähemalt kahte eri tüüpi aatomitest. Heterotsüklilistel ühenditel on suur roll farmaatsiatööstuses, kuna enamus ravimeid on heterotsüklilised ning 90% nendest heterotsüklitest sisaldab lämmastiku aatomit. Näiteks 2012. aastal võis heterotsükleid leida kõigist kümnest enimmüüdud ravimist, millest 8 sisaldas seejuures ka lämmastiku aatomit. Sünteesimeetodid, mille abil saab sünteesida heterotsüklilisi ühendeid, mis sisaldavad ühtlasi ka lämmastik-lämmastik sidet olles seega samaaegselt ka hüdrasiini derivaadid, on üsna vähetuntud. Seetõttu oli antud doktoritöö eesmärk laiendada sünteetilisi võimalusi selliste uudsete ja perspektiivsete ühendite valmistamiseks.

Hydrazine, a simple compound with a molecular formula N2H4 is probably most well-known from the movie „The Martian“ (2015). Hydrazine – originally used as a rocket fuel – was decomposed to hydrogen, which was then oxidized to water by fictional astronaut Mark Watney (Matt Damon) to survive on a foreign planet. Hydrazine itself is very toxic, but its derivatives have been isolated from living organisms and often their toxicity is selective towards various biological targets, such as viruses, bacteria, fungi or cancer cells, which is highly desirable for drug developers. Heterocyclic compounds have at least one cyclic moiety in their molecular structure that contains at least two different types of atoms in the ring. These compounds have an essential role in drug industry, as majority of pharmaceuticals include at least one heterocyclic ring in their composition and more than 90% of these heterocyclic moieties comprise a nitrogen atom in their structure. In 2012, heterocycles could be found in each of top ten brand name small molecule drugs and 8 of them had a nitrogen atom present in the ring. Synthetic methods for the preparation of heterocyclic compounds that also include a hydrazine moiety (nitrogen-nitrogen bond) in their structure are rather scarce. Therefore, the aim of this theses was to expand possibilities for the synthesis of these novel and highly perspective compounds