Sinteza, spektroskopska karakterizacija i biološka aktivnost N-1-sulfonilcitozinskih derivata

Large scale preparation of N-1-sulfonylcytosine derivatives has been optimized. The best method was the condensation reaction of silylated cytosine (1) with p-toluenesulfonyl chloride in acetonitrile. Depending on the isolation procedure, 1-(p-toluenesulfonyl)cytosine 2 and 1-(p- -toluenesulfonyl)cytosine hydrochloride 3 were isolated in 80 % and 75 % yields, respectively. The NMR evidence presented shows that 2 appears as a common keto-amino tautomer in DMSO-d6 solution while its hydrochloride 3 forms exclusively the rare keto imino tautomer. N-1-Sulfonylcytosine derivatives 2 and 3 were investigated for possible cytotoxic activity on human normal fibroblasts (WI38), human pancreatic adenocarcinoma cells (MIAPaCa2), poorly differentiated cells from lymph node metastases of colon carcinoma (SW-620), and human Burkitt lymphoma cells (Raji). MTT-cytotoxicity screens in human tissue culture cell lines showed that both investigated compounds demonstrated antiproliferative activity in different histological types of tumors. In comparison with 5-fluorouracil, some of N-1-sulfonylcytosine derivatives showed 10 times stronger activity, with respect IC50. The inhibitory effect of the investigated derivatives on normal human cells was lower compared to their antitumor effects. In addition to antitumor effects, hematological findings following the parenteral administration of substances were also investigated.Optimizirana je priprava većih količina N-1-sulfonilcitozinskih derivata, kondenzacijom sililiranoga citozina i p-toluensulfonil klorida u acetonitrilu. Ovisno o načinu izolacije dobiveni su 1-(p-toluensulfonil)citozin 2 (80 %) i 1-(p-toluensulfonil)citozin hidroklorid 3 (75 %). NMR eksperimenti pokazuju isključivo nastajanje keto-imino tautomera 3 u DMSO-d6 otopini, dok se 2 pojavljuje u uobičajenome keto-amino obliku. Ispitivani su potencijalni citotoksični učinci N-1-sulfonilcitozinskih derivata 2 i 3 na fibroblastima čovjeka (WI38), stanicama adenokarcinoma gušterače (MIAPaCa2), slabo diferenciranim metastazama adenokarcinoma debelog crijeva (SW-620) i stanicama Burkitt-ovog limfoma (Raji). Rezultati dobiveni MTT-testom pokazuju da ispitivani spojevi djeluju antiproliferativno na različite histološke tipove tumora. U usporedbi s 5-fluorouracilom, N-1-sulfonilcitozinski derivati pokazuju 10 puta jaču inhibiciju rasta izloženih tumorskih stanica. Inhibicijski učinci ispitivanih spojeva na normalne stanice značajno su slabiji u odnosu na protutumorske učinke. Osim antitumorskoga učinka, ispitivani su i hematološki parametri poslije parenteralne primjene ispitivanih tvari