Newly Synthesized Imino-Derivatives Analogues of Resveratrol Exert Inhibitory Effects in Breast Tumor Cells
Abstract
:1. Introduction
- (1)
- Nitrogen mustards, such as cyclophosphamide whose action depends on the alkylating ability of the active metabolite on the nitrogenous bases of DNA, in particular guanine;
- (2)
- Platinum coordination complexes, such as Cisplatin (I), which can bind the nitrogenous bases of DNA forming cross-link bonds;
- (3)
- Taxanes as Paclitaxel (II) and Docetaxel (III);
- (4)
- Anthracycline like Doxorubicin (IV) and Epirubicin (V);
- (5)
- Folic acid analogues as Methotrexate, which reversibly and competitively inhibits the dihydrofolate reductase (DHFR); and
- (6)
- Pyrimidine analogues, in particular 5–fluorouracile [2].
2. Results
2.1. Chemistry
2.2. Bioavailability
2.3. Inhibitory Activity
2.4. Docking Studies
2.5. In Vitro hTopoI and II Inhibition Assays
3. Discussion and Conclusions
4. Materials and Methods
4.1. Chemistry
4.2. In Vitro Bioavailability Studies
4.3. Docking Studies
4.4. Biological Assays
4.4.1. Cell Cultures
4.4.2. Cell Viability Assay
4.4.3. TUNEL Assay
4.4.4. Human Topoisomerase I (hTopoI) Relaxation Assay
4.4.5. Human Topoisomerase II (hTopoII) Decatenation Assay
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
13C NMR | carbon nuclear magnetic resonance |
1H NMR | proton nuclear magnetic resonance |
ANOVA | analysis of variance |
BSA | bovine serum albumin |
d | doublet |
DAPI | 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride |
DHFR | dihydrofolate reductase |
DMEM | Dulbecco’s modified Eagle’s medium |
DMSO | dimethyl sulfoxide |
DMSO-d6 | deuterated dimethyl sulfoxide |
DNA | deoxyribonucleic acid |
dUTP | 2′-deoxyuridine 5′-triphosphate |
EB | ethidium bromide |
EDTA | ethylenediaminetetraacetic acid |
ER | estrogen receptor |
ESI-MS | electrospray ionization mass spectrometry |
FBS | fetal bovine serum |
HEK-293 | human embryonic kidney 293 |
hTopo | human topoisomerase |
Hz | hertz |
IC50 | half maximal inhibitory concentration |
IR | infrared |
kDNA | kinetoplast DNA |
m/z | mass/charge |
MCF-7 | michigan cancer foundation-7 |
MDA-MB-231 | M.D. Anderson metastatic breast-231 |
MS (EI) | electron ionization mass spectrometry |
MTT | 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide |
PBS | phosphate-buffered saline |
PDB | protein data bank |
s | singlet |
SCDNA | supercoiled DNA |
SD | standard deviation |
SkBr-3 | Sloan–Kettering breast-3 |
TAE | tris-acetic acid-EDTA |
TE | tris-EDTA |
TUNEL | terminal deoxynucleotidyl transferase dUTP nick end labeling |
U | units |
UV | ultraviolet |
Vis | visible |
δ | chemical shift |
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2 h pH 1.0 | 4 h pH 7.0 | Total 6 h | |
---|---|---|---|
resveratrol | 12 ± 0.6 | 23 ± 0.8 | 35 ± 1.1 |
3 | 16 ± 0.7 | 31 ± 1.1 | 47 ± 1.6 |
4 | 17 ± 0.8 | 28 ± 0.9 | 45 ± 1.3 |
IC50 (µM) ± S.D. | |||
---|---|---|---|
Compound | MCF-7 | SkBr3 | HEK293 |
3 | 12 (±1) | 15 (±1) | >90 |
6 | >90 | >90 | >90 |
7 | >90 | >90 | >90 |
resveratrol | >90 | >90 | >90 |
Compound | Binding Energy (Kcal/mol) | Calculated Ki (μM) * | Topo II Alpha Residues Involved in Ligand Binding § | |
---|---|---|---|---|
resveratrol | −6.73 | 11.7 | Gln726, Asn770, Asn779, Glu854, Arg929 | Pro716 |
3 | −6.8 | 10.4 | Lys723, Gln726, Asn770, Glu773, Arg929 | Pro716 |
4 | −7.25 | 4.8 | Lys723, Gln726, Asn770, Glu773, Arg929 | Pro716 |
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Iacopetta, D.; Lappano, R.; Mariconda, A.; Ceramella, J.; Sinicropi, M.S.; Saturnino, C.; Talia, M.; Cirillo, F.; Martinelli, F.; Puoci, F.; et al. Newly Synthesized Imino-Derivatives Analogues of Resveratrol Exert Inhibitory Effects in Breast Tumor Cells. Int. J. Mol. Sci. 2020, 21, 7797. https://doi.org/10.3390/ijms21207797
Iacopetta D, Lappano R, Mariconda A, Ceramella J, Sinicropi MS, Saturnino C, Talia M, Cirillo F, Martinelli F, Puoci F, et al. Newly Synthesized Imino-Derivatives Analogues of Resveratrol Exert Inhibitory Effects in Breast Tumor Cells. International Journal of Molecular Sciences. 2020; 21(20):7797. https://doi.org/10.3390/ijms21207797
Chicago/Turabian StyleIacopetta, Domenico, Rosamaria Lappano, Annaluisa Mariconda, Jessica Ceramella, Maria Stefania Sinicropi, Carmela Saturnino, Marianna Talia, Francesca Cirillo, Fabio Martinelli, Francesco Puoci, and et al. 2020. "Newly Synthesized Imino-Derivatives Analogues of Resveratrol Exert Inhibitory Effects in Breast Tumor Cells" International Journal of Molecular Sciences 21, no. 20: 7797. https://doi.org/10.3390/ijms21207797