Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives.
Design of a new drug entity is usually preceded by analysis of quantitative structure activity (properties) relationships, QSA(P)R. Six newly synthesized succinimide derivatives have been determined for (i) in silico physico-chemical descriptors, pharmacokinetic and toxicity predictors, (ii) in vitro biological activity on four different carcinoma cell lines and on normal fetal lung cells and (iii) lipophilicity on liquid chromatography. All compounds observed were predicted for good permeability and solubility, good oral absorption rate and moderate volume of distribution as well as for modest blood brain permeation, followed by acceptable observed toxicity. In silico determined lipophilicity, permeability through jejunum and aqueous solubility were correlated with experimentally obtained lipophilic constants (by use of high pressure liquid chromatography) and linear correlations were obtained. Absorption rate and volume of distribution were predicted by chromatographic lipophilicity measurements while permeation through blood bran barrier was predicted dominantly by molecular size defined with molecular weight. Five compounds have demonstrated antiproliferative activity toward cervix carcinoma HeLa cell lines; three were cytotoxic against breast carcinoma MCF-7 cells, while one inhibited proliferation of colon carcinoma HT-29 cell lines. Only one compound was cytotoxic toward normal cell lines, while other compounds were proven as safe. Antiproliferative potential against HeLa cells was described as exponential function of lipophilicity. Based on obtained results, lead compounds were selected.
University of Novi Sad, Faculty of Medicine, Department of Pharmacy, Hajduk Veljkova 1-3, 21000 Novi Sad, Serbia. Electronic address: natasa.milosevic@mf.uns.ac.rs.
Natasa P
NP
Milosevic
University of Novi Sad, Faculty of Medicine, Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia.
Vesna
V
Kojic
University of Novi Sad, Faculty of Medicine, Department of Pharmacy, Hajduk Veljkova 1-3, 21000 Novi Sad, Serbia.
Jelena
J
Curcic
University of Novi Sad, Faculty of Medicine, Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia.
Dimitar
D
Jakimov
University of Novi Sad, Faculty of Medicine, Department of Pharmacy, Hajduk Veljkova 1-3, 21000 Novi Sad, Serbia.
Natasa
N
Milic
University of Belgrade, Faculty of Agriculture, Food Technology and Biochemistry, Nemanjina 6, 11080 Belgrade-Zemun, Serbia.
Nebojsa
N
Banjac
University of Belgrade, Faculty of Technology and Metallurgy, Karnegijeva 4, 11000 Belgrade, Serbia.
Gordana
G
Uscumlic
Medical University of Gdansk, Department of Biopharmaceutics and Pharmacodynamics, Al. Gen. Hallera 107, 80-416 Gdansk, Poland.
Roman
R
Kaliszan
D000072283:A549 Cells; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D010539:Permeability; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility; D013388:Succinimides / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology
D013388:Succinimides
Antiproliferative effect; Lipophilicity; Pharmacokinetics; QSA(P)R; Toxicology