Synthesis and Biological Evaluation of Imines Structurally Related to Resveratrol as Dual Inhibitors of VEGF Protein Secretion and hTERT Gene Expression 1
Free accessResearch articleFirst published online May, 2017
Synthesis and Biological Evaluation of Imines Structurally Related to Resveratrol as Dual Inhibitors of VEGF Protein Secretion and hTERT Gene Expression 1
A group of 28 N-benzylidene aniline derivatives structurally related to the natural stilbene resveratrol has been prepared through condensation of anilines with the corresponding aldehydes. The ability of these imines to inhibit proliferation of two tumor cell lines (HT-29 and MCF-7) and one non-tumor cell line (HEK-293) was first determined. Subsequently, we determined the ability of some of the most cytotoxic compounds to inhibit the secretion of the VEGF-A factor in HT-29 cells and to downregulate the expression of the VEGF and hTERT genes, the latter one being involved in the activation of telomerase.
JangM, CaiL, UdeaniGO, SlowingKV, ThomasCF, BeecherCWW, FongHHS, FarnsworthNR, KinghornAD, MehtaRG, MoonRC, PezzutoJM. (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275, 218–220
2.
Diaz-GereviniGT, RepossiG, DainA, TarresMC, DasUN, EynardAR. (2016) Beneficial action of resveratrol: how and why?Nutrition, 32, 174–178.
3.
DelmasD, SolaryE, LatruffeN. (2011) Resveratrol, a phytochemical inducer of multiple cell death pathways: apoptosis, autophagy and mitotic catastrophe. Current Medicinal Chemistry, 18, 1100–1121
4.
EmplMT, AlbersM, WangS, SteinbergP. (2015) The resveratrol tetramer r-viniferin induces a cell cycle arrest followed by apoptosis in the prostate cancer cell line LNCaP. Phytotherapy Research, 29, 1640–1645.
5.
BrakenhielmE, CaoR, CaoY. (2001) Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. The FASEB Journal, 15, 1798–1800
6.
WongJC, FiscusRR. (2015) Resveratrol at anti-angiogenesis/anticancer concentrations suppresses protein kinase G signaling and decreases IAPs expression in HUVECs. Anticancer Research, 35, 273–282.
7.
IguraK, OhtaT, KurodaY, KajiK. (2001) Resveratrol and quercetin inhibit angiogenesis in vitro. Cancer Letters, 171, 11–16.
8.
ZecchinA, BorgersG, CarmelietP. (2015) Endothelial cells and cancer cells: metabolic partners in crime?Current Opinion in Hematology, 22, 234–242.
9.
MoghaddamSM, AminiA, MorrisDL, PourgholamiMH. (2012) Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer. Cancer Metastasis Reviews, 31, 143–162.
10.
VasudevNS, ReynoldsAR. (2014) Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis, 17, 471–494.
11.
PotenteM, GerhardtH, CarmelietP. (2011) Basic and therapeutic aspects of angiogenesis. Cell, 146, 873–887
ShayJW, WrightWE. (2011) Role of telomeres and telomerase in cancer. Seminars in Cancer Biology, 21, 349–353.
14.
ZakianVA. (2012) Telomeres: the beginnings and ends of eukaryotic chromosomes. Experimental Cell Research, 318, 1456–1460.
15.
SaretzkiG. (2014) Extra-telomeric functions of human telomerase: cancer, mitochondria and oxidative stress. Current Pharmaceutical Design, 20, 6386–6403.
16.
SmiraldoPG, TangJ, ShayJW, WrightWE. (2012) Cellular senescence, telomerase, and cancer in human cells. In Telomerases. LueNF, AutexierC. (Eds). John Wiley & Sons, Inc., Hoboken, NJ, 243–263
BusemanCM, WrightWE, ShayJW. (2012) Is telomerase a viable target in cancer?Mutation Research, 730, 90–97
19.
AkincilarSC, UnalB, TergaonkarV. (2016) Reactivation of telomerase in cancer. Cellular and Molecular Life Sciences, 73, 1659–1670.
20.
BlackburnEH, EpelES, LinJ. (2015) Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science, 350, 1193–1198
21.
ShayJW. (2016) Role of telomeres and telomerase in aging and cancer. Cancer Discovery, 6, 584–593.
22.
LanzilliG, FuggettaMP, TricaricoM, CottarelliA, SerafinoA, FalchettiR, RavagnaG, TurrizianiM, AdamoR, FranzeseO, BonmassarE. (2006) Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro. International Journal of Oncology, 28, 641–648.
23.
Martí-CentellesR, Cejudo-MarínR, FalomirE, MurgaJ, CardaM, MarcoJA. (2013) Inhibition of VEGF expression in cancer cells and endothelial cell differentiation by synthetic stilbene derivatives. Bioorganic & Medicinal Chemistry, 21, 3010–3015.
24.
For recent reviews on imines, also called Schiff's bases, see, for example: (a) BelowichME, StoddartJF. (2012) Dynamic imine chemistry. Chemical Society Reviews, 41, 2003–2024
25.
QinW, LongS, PanunzioP, BiondiS. (2013) Schiff bases: a short survey on an evergreen chemistry tool. Molecules, 18, 12264–12289.
26.
For various types of pharmacological studies on imines, see, for example: (a) GrozingerCM, ChaoED, BlackwelHE, MoazedD, SchreiberSL. (2001) Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. Journal of Biological Chemistry, 276, 38837–38843
27.
CholSY, KimS, KimH, SukK, HwangJS, LeeBG, KimAJ, KimSY. (2002) (4-Methoxy-benzylidene)-(3-methoxy-phenyl)-amine, a nitrogen analog of stilbene as a potent inhibitor of melanin production. Chemical and Pharmaceutical Bulletin, 50, 450–452
LuJ, LiC, ChaiYF, YangDY, SunCR. (2012) The antioxidant effect of imine resveratrol analogues. Bioorganic & Medicinal Chemistry Letters, 22, 5744–5747
30.
FujitaY, IslamR, SakaiK, KanedaH, KudoK, TamuraD, AomatsuK, NagaiT, KimuraH, MatsumotoK, de VelascoMA, AraoT, OkawaraT, NishioK. (2012) Aza-derivatives of resveratrol are potent macrophage migration inhibitory factor inhibitors. Investigational New Drugs, 30, 1878–1886; (1979)
31.
BaeSJ, HaM, ParkYJ, ParkJY, SongYM, HaTK, ChunP, MoonHR, ChungHY. (2012) Design, synthesis, and evaluation of (E)-N-substituted benzylidene-aniline derivatives as tyrosinase inhibitors. European Journal of Medicinal Chemistry, 57, 383–390
32.
SiddiquiA, DandawateP, RubR, PadhyeS, AphaleS, MogheA, JagyasiA, SwamyKV, SinghB, ChatterjeeA, RongheA, BhatHK. (2013) Novel aza-resveratrol analogs: synthesis, characterization and anticancer activity against breast cancer cell lines. Bioorganic & Medicinal Chemistry Letters, 23, 635–640
33.
LiSY, WangXB, KongLY (2014) Design, synthesis and biological evaluation of imine resveratrol derivatives as multi-targeted agents against Alzheimer's disease. European Journal of Medicinal Chemistry, 71, 36–45.
34.
ArdenN, BetenbaughMJ. (2004) Life and death in mammalian cell culture: strategies for apoptosis inhibition. Trends in Biotechnology, 22, 174–180.
35.
Van WeemenBK, SchuursAHWM. (1971) Immunoassay using antigen-enzyme conjugates. FEBS Letters, 15, 232–236
36.
EngvallE, PerlmannPJ. (1972) Enzyme-linked immunosorbent assay, Elisa: III. Quantitation of specific antibodies by enzyme-labeled antiimmunoglobulin in antigen-coated tubes. Journal of Immunology, 109, 129–135
37.
O'BeirneAJ, CooperHR. (1979) Heterogeneous enzyme immunoassay. Journal of Hystochemistry and Cytochemistry, 27, 1148–1162.
38.
NakamuraM, AbeY, TokunagaT. (2002) Pathological significance of vascular endothelial growth factor A isoform expression in human cancer. Pathology International, 52, 331–339
39.
EllrichmannM, RitterPR, SchraderH, SchmidtWE, MeierJJ, SchmitzF. (2010) Gastrin stimulates the VEGF-A promotor in a human colon cancer cell line. Regulatory Peptides, 165, 146–150.
40.
Rodríguez-NietoS, MedinaMA, QuesadaAR. (2001) A re-evaluation of fumagillin selectivity towards endothelial cells. Anticancer Research, 21, 3457–3460.
41.
HahmER, GhoYS, ParkS, ParkC, KimKW, YangCH. (2004) Synthetic curcumin analogs inhibit activator protein-1 transcription and tumor-induced angiogenesis. Biochemical and Biophysical Research Communications, 321, 337–344.
