Synthesis, characterization and potential biological activity of the complexes of platinum(iv) and palladium(ii) ions with a derivative of ethylendiamine-n,n'-di-(s,s)-(2,2'-dibenzyl)acetate ligand

U ovoj Doktorskoj disertaciji je opisana sinteza i karakterizacija (2S)-2- -(2-okso-1,3-oksazinan-3-il)propanske kiseline kao i estara tipa O-alkil-N-(3-hloropropil)-(2S)-alaninata monohlorhidrata (R = propil-, butil-) u nameri da se dobiju 1,3-propandiamin-N,N′-di-(S,S)-2-propanska kiselina, (H2-(S,S)-rddp) i O,O′-dialkil estara tetradentatnog liganda 1,3- -propandiamin-N,N′-di-(S,S)-2-propanske kiseline, R2-(S,S)-rddp). Estri O-alkil-N-(3-hloro-propil)-(2S)-alaninata monohlorhidrata dobijeni su direktnom reakcijom između (2S)-2-(2-okso-1,3-oksazinan-3-il) propanske kiseline i odgovarajućeg apsolutnog alkohola( 1-propanol, 1-butanol) u molskom odnosu 1:2, uz uvođenje gasovitog hlorovodonika. Potom je sintetisana etilendiamin-N,N′-di-S,S-(2,2'-dibenzil)etanska kiselina trihidrat, N2-(S,S)-eddba·3N2O. Na prethodno opisan način sintetisani su O,O'-dialkil estri etilendiamin-N,N′-di-(S,S)-(2,2'-dibenzil) etanske kiseline kao dihlorhidrati, R2-(S,S)-eddba·2NSl (R =etil-, propil-, butil- i pentil-). Strukture i sastav izolovanih liganada pretpostavljene su primenom elementalne mikroanalize, infracrvene, 1H i 13C NMR spektroskopije, a potvrđene na bazi rezultata rendgenske strukturne analize u slučaju: (2S)-2-(2- -okso-1,3-oksazinan-3-il)propanske kiseline, O-propil-N-(3-hloropropil)-(2S)- -alaninata i O-butil-N-(3-hloropropil)-(2S)-alaninata kao monohlorhidrati, i O,O'-dipropil-etilendiamin-N,N'-di-(S,S)-(2,2'-dibenzil)etanoat kao trihidrata, N2-(S,S)eddba·3N2O. Dobijeni O,O'-dialkil estri etilendiamin-N,N′-di-(S,S)-(2,2'-dibenzil) etanske kiseline su upotrebljeni za sintezu odgovarajućih kompleksa platine(IV) i paladijuma(II). Sastav dobijenih kompleksa platine(IV), [PtCl4(R2- -(S,S)-eddba)] i paladijuma(II), [PdCl2(R2-S,S-eddba)] potvrđeni su elementalnom mikroanalizom. Struktura izolovanih kompleksa potvrđena je na osnovu infracrvene, 1H i 13C NMR spektroskopije. In vitro antitumorska aktivnost kompleksa platine(IV) sa tetradentatnim ligandima (sa navedenim O,O′-dialkil estrima N2-(S,S)-eddba) određivana je na ćelijama CCL u periodu od 72 sata korišćenjem MTT tehnike. Zaključak je da kompleksi pokazuju jak citotoksični efekat. Citotoksični efekti svih kompleksa su dozno-zavisni i svi ispitivani kompleksi su pokazali znatno veći citotoksični efekat na CLL ćelije od cisplatine. In vitro antimikrobna aktivnost sintetisanih liganada i odgovarajućih kompleksa paladijuma(II) testirana je određivanjem minimalnih inhibitorskih (MIK) i minimalnih baktericidnih koncentracija (MBC). Ove supstance u poređenju sa pozitivnim kontrolama, pokazale su nisko antibakterijsko delovanje Antibakterijsko delovanje kompleksa je bilo izraženije na gram pozitivne bakterije, a znatno manje na gram negativne bakterije. Najsenzitivnija bila je bakterija vrste Enterococcus faecalis, Ligandi su pokazali slabo delovanje na gram negativne bakterije posebno na vrstu Proteus vulgaris.In this Work, the synthesis and characterization of the compounds (2S)-2-(2-oxo- -1,3-oxazinan-3-yl)propionic acid nd esters of type O-alkyl-N-(3-chloro-propyl)-(2S)-- alaninate monohlorhydrate (R = propyl-, butyl-) in order to obtain 1,3-propanediamine--N,N′-ди-(S,S)-2-propanoic acid, (H2-(S,S)-рddp) and O,O'-dialkyl esters with tetradentate ligand of 1,3-propanediamine-N,N'-di-(S,S)-2-propanoicb acid, (R2-(S,S)--pddp). Esters of O-alkyl-N-(3-chloropropyl)-(2S)-alaninate monohlorhydrate obtained by the direct reaction between (2S)-2-(2-oxo-1,3-oxazinan-3-yl)propionic acid and the corresponding absolute alcohol (1-propanol, 1-butanol) in the molar ratio 1:2, with the addition of gaseous hydrogenchloride. Then, the synthesized ethylenediamine-N,N'-di-(S,S)-(2,2'-dibenzyl) ethanoic acid trihydrate, Н2-(S,S)-eddbа·3Н2О. As described above were synthesized by the O,O'--dialkyl esters of ethylenediamine-N,N'-di-(S,S)-(2,2'-dibenzyl)ethanoic acid as the dihydrochloride, R2-(S,S)-eddbа·2НСl (R = ethyl-, propyl-, butyl- and pentyl-). Structure and composition of the isolated ligands were assumed using by elemental microanalysis, IR, 1H and 13C NMR spectroscopy, and confirmed by X-ray diffraction analysis in the case (2S)-2-(2-okso-1,3-oksazynan-3-yl)propanoic acid, О-аlkyl-N-(3-chloropropyl)-(2S)-alaninate monocholorohydrate, and O,O'-dipropyl- -ethylen dianine-N,N'-di-(S,S)-(2,2'-dibenzyl)etanoate threehydrate, Н2-(S,S)eddbа·3Н2О. The obtained ligands О,О'-dialkyl estars of ethylendianine-N,N'-di-(S,S)-(2,2'--dibenzyl)etanoic acide were used for synthesis of the corresponding platinum(IV) and palladium(II) complexes. The composition of obtained platinum(IV), [PtCl4(R2-(S,S)--eddbа)] and palladium(II) complexes, [PdCl2(R2-S,S-eddbа)] was confirmed by elemental microanalysis. The structure of isolated complexes is assumed on basis of infrared, 1H and 13C NMR spectroscopy. In vitro antitumor activity of platinum complex (IV) with tetradentate ligands (with the above O,O'-dialkyl esters of Н2-(S,S)-eddbа) was determined on cells of CCL for a period of 72 hours by using the MTT techniques. The conclusion is that the complexes show strong cytotoxic effect. Cytotoxic effects of the complex are dose-depe- -ndent, and all tested complexes showed much higher cytotoxic effect on CLL cells by cisplatin. The in vitro antimicrobial activity of the synthesized ligands and the corresponding complexes of palladium (II) was tested by determination of minimal inhibitory (MIC) and minimum bactericidal concentration (MBC). These substances when compared to the positive controls, showed high antibacterial activity. The antibacterial activity of the complex was more pronounced in the gram-positive bacteria and much less of the gramnegative bacteria. Was the most sensitive species of bacteria Enterococcus faecalis. Ligands showed weak activity against gram-negative bacteria in particular of the type of Proteus vulgaris