Antioksidativno djelovanje NSAID hidroksamskih kiselina

In the present study, seven hydroxamic acid derivatives of nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, fenoprofen, ketoprofen, indomethacin and diclofenac) were found to possess significant antioxidant, radical scavenging and metal chelating activities. The most active antioxidant and radical scavenger was N-methylhydroxamic acid of diclofenac (ANT = 88.0 % and EC50 = 60.1 microg mL-1). The activity of the standard substance, butylated hydroxyanisole, in the two assays was ANT = 86.9 % and EC50 = 18.8 microg mL-1, respectively. Ibuproxam was the strongest iron chelator among investigated hydroxamic acids (EC50 = 255.6 microg mL-1), yet significantly weaker than the standard substance, EDTA (EC50 = 29.1 microg mL-1). It seems that different mechanism is involved in metal chelating activity than in antioxidant and radical scavenging activity. Antioxidant and radical scavenging activities may be connected with conjugation of the nitrogen lone electron pair with the carbonyl group. On the other hand, more hydrophilic substances tend to be better iron chelators.U radu je opisano antioksidativno djelovanje te sposobnost hvatanja slobodnih radikala i stvaranja kelata sedam hidroksamskih kiselina, derivata nesteroidnih protuupalnih lijekova ibuprofena, fenoprofena, ketoprofena, indometacina i diklofenaka. Najjače antioksidativno djelovanje i najjaču sposobnost hvatanja slobodnih radikala imala je N-metilhidroksamska kiselina diklofenaka (ANT = 88,0 % i EC50 = 60,1 g mL1). Vrijednosti za standardnu supstanciju, butilirani hidroksianisol, bile su: ANT = 86,9 % i EC50 = 18,8 g mL1. Derivat ibuprofena bio je najjači kelator među ispitivanim hidroksamskim kiselinama (EC50 = 255,6 g mL1), ali značajno slabiji od standardne supstancije, EDTA (EC50 = 29,1 g mL1). Pretpostavlja se da su različiti mehanizmi uključeni u keliranje metala i antioksidativno djelovanje, odnosno hvatanje slobodnih radikala. Antioksidativno djelovanje i sposobnost hvatanja slobodnih radikala moglo bi biti povezano s konjugacijom slobodnog para elektrona na dušiku s karbonilnom skupinom. S druge strane, hidrofilnije supstancije pokazale su se kao jači kelatori iona željeza

Makromolekulski prolijekovi. XIII. Vodotopljivi konjugati 17β-estradiola i estradiol-17β-valerata s poliaspartamidnim polimerom

Two hydrosoluble conjugates of 17β-estradiol (ED) and estradiol-17β-valerate (EV) with polyaspartamide polymer were prepared and characterized. ED and EV were first chemically modified and bound to poly,-(N-2-hydroxyethyl-DL-aspartamide)-poly,-(N-2-aminoethyl-DL-aspartamide) (PAHA), a hydrosoluble polyaspartamide-type copolymer bearing both hydroxyl and amino groups. ED was first converted to 17-hemisuccinate (EDS) and then bound to PAHA. In the resulting conjugate PAHA-EDS, the estradiol moiety was linked to the polymer through a 2-aminoethylhemisuccinamide spacer. On the other hand, EV was first converted to estradiol-17-valerate-3-(benzotriazole-1-carboxylate), which readily reacted with amino groups in PAHA affording the polymer-drug conjugate PAHA-EV. In the prepared conjugate PAHA-EV, the estradiol moiety was covalently bound to the polyaspartamide backbone by carbamate linkage, through an ethylenediamine spacer. The polymer-drug conjugates were designed and prepared with the aim to increase water-solubility, bioavailability and to improve drug delivery of the lipophilic estrogen hormone.U radu je opisana priprava i karakterizacija dvaju vodotopljivih polimer-lijek konjugata 17β-estradiola (ED) i estradiol-17β-valerata (EV) s poliaspartamidnim polimerom. ED i EV su prvo kemijski modificirani i vezani na poli,-(N-2-hidroksietil-DL-aspartamid)-poli,-(N-2-aminoetil-DL-aspartamid) (PAHA), vodotopljivi poliaspartamidni kopolimer s hidroksi i amino skupinama. ED je prvo preveden u 17-hemisukcinat (EDS), a zatim vezan na PAHA. U nastalom konjugatu PAHA-EDS estradiolska komponenta vezana je na polimer preko 2-aminoetilhemisukcinatne razmaknice. S druge strane, EV je prvo preveden u estradiol-17-valerat-3-(benzotriazol-1-karboksilat), koji reagira s amino skupinama u PAHA dajući polimer-lijek konjugat PAHA-EV. U tom je konjugatu estradiolska komponenta kovalentno vezana na poliaspartamidnu okosnicu karbamatnom vezom, preko etilenediaminske razmaknice. Polimer-lijek konjugati estradiola dizajnirani su i pripravljeni sa ciljem da se poveća topljivost i bioraspoloživost te isporuka tog lipofilnog estrogenog hormona