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Synthesis, structural characterization, DFT calculations and antiproliferative evaluation of novel spirohydantoin derivatives containing a substituted benzyl moiety

Authorized Users Only
2019
Authors
Lazić, Anita M.
Radovanović, Lidija D.
Božić, Bojan
Božić, Nedeljković B.
Vitnik, Vesna
Vitnik, Željko
Rogan, Jelena R.
Valentić, Nataša V.
Ušćumlić, Gordana
Trišović, Nemanja
Article (Published version)
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Abstract
Two series of cycloalkanespiro-5-hydantoins, namely cyclohexanespiro-5-hydantoins and cycloheptanespiro-5-hydantoins with a 4-substituted benzyl or a 2-(4-substituted phenyl)-2-oxoethyl group at N3 position, were synthesized and their effects on proliferation of human colon (HCT-116), leukemia (K562) and breast (MDA-MB-231) cancer cell lines were tested. For comparison, we also described the 5,5-diphenylhydantoin analogues. The structural features of the investigated compounds were characterized by elemental analysis, FT-IR, UV–Vis, 1H and 13C NMR spectroscopy and X-ray crystallography. Regarding their structure–activity relationships, it was shown that the substitution on the benzyl moiety with the methoxy, chloro or bromo group potentiated the antiproliferative activity relative to the parent compounds, while an increase in the size of the cycloalkyl group resulted mostly in a decrease of the antiproliferative activity. The single crystal X-ray analysis revealed the existence of dime...rs and chains formed by the N–H⋯O hydrogen bonds. The analysis of the molecular descriptors of Lipinski demonstrated that all investigated compounds obeyed the rule of five. To further understand their geometry and electronic structure, DFT calculations with B3LYP method using 6-311++G(d,p) basic set were performed. In this context, the UV–Vis spectra of the investigated compounds were analyzed in detail, whereby the predicted absorption spectra from DFT calculation matched the experimentally obtained ones, with a good correlation. The interesting physico-chemical and pharmacologically relevant properties of the investigated compounds warrant their further investigation.

Keywords:
Antiproliferative activity / DFT calculation / Spirohydantoin / X-ray structure determination
Source:
Journal of Molecular Structure, 2019, 1180, 48-62
Publisher:
  • Elsevier B.V.
Projects:
  • Study of the Synthesis, Structure and Activity of Natural and Synthetic Organic Compounds (RS-172013)
  • Rational design and synthesis of biologically active and coordination compounds and functional materials, relevant for (bio)nanotechnology (RS-172035)
  • Bioinformatic promoter predictions and theoretical modeling of gene circuits in bacteria (RS-173052)
  • Zero- to Three-Dimensional Nanostructures for Application in Electronics and Renewable Energy Sources: Synthesis, Characterization and Processing (RS-45007)

DOI: 10.1016/j.molstruc.2018.11.071

ISSN: 0022-2860

WoS: 000457660300007

Scopus: 2-s2.0-85059311562
[ Google Scholar ]
1
1
URI
http://cer.ihtm.bg.ac.rs/handle/123456789/2489
Collections
  • Radovi istraživača / Researchers' publications
Institution
IHTM
TY  - JOUR
AU  - Lazić, Anita M.
AU  - Radovanović, Lidija D.
AU  - Božić, Bojan
AU  - Božić, Nedeljković B.
AU  - Vitnik, Vesna
AU  - Vitnik, Željko
AU  - Rogan, Jelena R.
AU  - Valentić, Nataša V.
AU  - Ušćumlić, Gordana
AU  - Trišović, Nemanja
PY  - 2019
UR  - http://cer.ihtm.bg.ac.rs/handle/123456789/2489
AB  - Two series of cycloalkanespiro-5-hydantoins, namely cyclohexanespiro-5-hydantoins and cycloheptanespiro-5-hydantoins with a 4-substituted benzyl or a 2-(4-substituted phenyl)-2-oxoethyl group at N3 position, were synthesized and their effects on proliferation of human colon (HCT-116), leukemia (K562) and breast (MDA-MB-231) cancer cell lines were tested. For comparison, we also described the 5,5-diphenylhydantoin analogues. The structural features of the investigated compounds were characterized by elemental analysis, FT-IR, UV–Vis, 1H and 13C NMR spectroscopy and X-ray crystallography. Regarding their structure–activity relationships, it was shown that the substitution on the benzyl moiety with the methoxy, chloro or bromo group potentiated the antiproliferative activity relative to the parent compounds, while an increase in the size of the cycloalkyl group resulted mostly in a decrease of the antiproliferative activity. The single crystal X-ray analysis revealed the existence of dimers and chains formed by the N–H⋯O hydrogen bonds. The analysis of the molecular descriptors of Lipinski demonstrated that all investigated compounds obeyed the rule of five. To further understand their geometry and electronic structure, DFT calculations with B3LYP method using 6-311++G(d,p) basic set were performed. In this context, the UV–Vis spectra of the investigated compounds were analyzed in detail, whereby the predicted absorption spectra from DFT calculation matched the experimentally obtained ones, with a good correlation. The interesting physico-chemical and pharmacologically relevant properties of the investigated compounds warrant their further investigation.
PB  - Elsevier B.V.
T2  - Journal of Molecular Structure
T1  - Synthesis, structural characterization, DFT calculations and antiproliferative evaluation of novel spirohydantoin derivatives containing a substituted benzyl moiety
VL  - 1180
SP  - 48
EP  - 62
DO  - 10.1016/j.molstruc.2018.11.071
ER  - 
@article{
author = "Lazić, Anita M. and Radovanović, Lidija D. and Božić, Bojan and Božić, Nedeljković B. and Vitnik, Vesna and Vitnik, Željko and Rogan, Jelena R. and Valentić, Nataša V. and Ušćumlić, Gordana and Trišović, Nemanja",
year = "2019",
url = "http://cer.ihtm.bg.ac.rs/handle/123456789/2489",
abstract = "Two series of cycloalkanespiro-5-hydantoins, namely cyclohexanespiro-5-hydantoins and cycloheptanespiro-5-hydantoins with a 4-substituted benzyl or a 2-(4-substituted phenyl)-2-oxoethyl group at N3 position, were synthesized and their effects on proliferation of human colon (HCT-116), leukemia (K562) and breast (MDA-MB-231) cancer cell lines were tested. For comparison, we also described the 5,5-diphenylhydantoin analogues. The structural features of the investigated compounds were characterized by elemental analysis, FT-IR, UV–Vis, 1H and 13C NMR spectroscopy and X-ray crystallography. Regarding their structure–activity relationships, it was shown that the substitution on the benzyl moiety with the methoxy, chloro or bromo group potentiated the antiproliferative activity relative to the parent compounds, while an increase in the size of the cycloalkyl group resulted mostly in a decrease of the antiproliferative activity. The single crystal X-ray analysis revealed the existence of dimers and chains formed by the N–H⋯O hydrogen bonds. The analysis of the molecular descriptors of Lipinski demonstrated that all investigated compounds obeyed the rule of five. To further understand their geometry and electronic structure, DFT calculations with B3LYP method using 6-311++G(d,p) basic set were performed. In this context, the UV–Vis spectra of the investigated compounds were analyzed in detail, whereby the predicted absorption spectra from DFT calculation matched the experimentally obtained ones, with a good correlation. The interesting physico-chemical and pharmacologically relevant properties of the investigated compounds warrant their further investigation.",
publisher = "Elsevier B.V.",
journal = "Journal of Molecular Structure",
title = "Synthesis, structural characterization, DFT calculations and antiproliferative evaluation of novel spirohydantoin derivatives containing a substituted benzyl moiety",
volume = "1180",
pages = "48-62",
doi = "10.1016/j.molstruc.2018.11.071"
}
Lazić AM, Radovanović LD, Božić B, Božić NB, Vitnik V, Vitnik Ž, Rogan JR, Valentić NV, Ušćumlić G, Trišović N. Synthesis, structural characterization, DFT calculations and antiproliferative evaluation of novel spirohydantoin derivatives containing a substituted benzyl moiety. Journal of Molecular Structure. 2019;1180:48-62
Lazić, A. M., Radovanović, L. D., Božić, B., Božić, N. B., Vitnik, V., Vitnik, Ž., Rogan, J. R., Valentić, N. V., Ušćumlić, G.,& Trišović, N. (2019). Synthesis, structural characterization, DFT calculations and antiproliferative evaluation of novel spirohydantoin derivatives containing a substituted benzyl moiety.
Journal of Molecular StructureElsevier B.V.., 1180, 48-62.
https://doi.org/10.1016/j.molstruc.2018.11.071
Lazić Anita M., Radovanović Lidija D., Božić Bojan, Božić Nedeljković B., Vitnik Vesna, Vitnik Željko, Rogan Jelena R., Valentić Nataša V., Ušćumlić Gordana, Trišović Nemanja, "Synthesis, structural characterization, DFT calculations and antiproliferative evaluation of novel spirohydantoin derivatives containing a substituted benzyl moiety" 1180 (2019):48-62,
https://doi.org/10.1016/j.molstruc.2018.11.071 .

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