Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives
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2017
Authors
Milošević, Nataša P.Kojić, Vesna

Curcić, Jelena
Jakimov, Dimitar
Milić, Nataša
Banjac, Nebojša

Ušćumlić, Gordana

Kaliszan, Roman
Article (Published version)

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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.
Keywords:
Antiproliferative effect / Lipophilicity / Pharmacokinetics / Toxicology / QSA(P)RSource:
Journal of Pharmaceutical and Biomedical Analysis, 2017, 137, 252-257Publisher:
- Elsevier Science Bv, Amsterdam
Funding / projects:
- Study of the Synthesis, Structure and Activity of Natural and Synthetic Organic Compounds (RS-172013)
DOI: 10.1016/j.jpba.2017.01.042
ISSN: 0731-7085
PubMed: 28167418
WoS: 000395357100033
Scopus: 2-s2.0-85012283810
Institution/Community
Tehnološko-metalurški fakultetTY - JOUR AU - Milošević, Nataša P. AU - Kojić, Vesna AU - Curcić, Jelena AU - Jakimov, Dimitar AU - Milić, Nataša AU - Banjac, Nebojša AU - Ušćumlić, Gordana AU - Kaliszan, Roman PY - 2017 UR - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/5819 AB - 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. PB - Elsevier Science Bv, Amsterdam T2 - Journal of Pharmaceutical and Biomedical Analysis T1 - Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives EP - 257 SP - 252 VL - 137 DO - 10.1016/j.jpba.2017.01.042 ER -
@article{ author = "Milošević, Nataša P. and Kojić, Vesna and Curcić, Jelena and Jakimov, Dimitar and Milić, Nataša and Banjac, Nebojša and Ušćumlić, Gordana and Kaliszan, Roman", year = "2017", abstract = "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.", publisher = "Elsevier Science Bv, Amsterdam", journal = "Journal of Pharmaceutical and Biomedical Analysis", title = "Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives", pages = "257-252", volume = "137", doi = "10.1016/j.jpba.2017.01.042" }
Milošević, N. P., Kojić, V., Curcić, J., Jakimov, D., Milić, N., Banjac, N., Ušćumlić, G.,& Kaliszan, R.. (2017). Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives. in Journal of Pharmaceutical and Biomedical Analysis Elsevier Science Bv, Amsterdam., 137, 252-257. https://doi.org/10.1016/j.jpba.2017.01.042
Milošević NP, Kojić V, Curcić J, Jakimov D, Milić N, Banjac N, Ušćumlić G, Kaliszan R. Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives. in Journal of Pharmaceutical and Biomedical Analysis. 2017;137:252-257. doi:10.1016/j.jpba.2017.01.042 .
Milošević, Nataša P., Kojić, Vesna, Curcić, Jelena, Jakimov, Dimitar, Milić, Nataša, Banjac, Nebojša, Ušćumlić, Gordana, Kaliszan, Roman, "Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives" in Journal of Pharmaceutical and Biomedical Analysis, 137 (2017):252-257, https://doi.org/10.1016/j.jpba.2017.01.042 . .