In this study, we synthesized a series of phenylpropanoic acid derivatives based on modifications at four selected points of the molecular scaffold. The in vitro antiproliferative activities of the compounds were examined in representative human solid tumor cell lines. A SAR was established pointing out the relevance of the substituents. The best activity profiles were obtained for the derivatives bearing more lipophilic esters (GI50 3.1-21 μM).
BatovskaDI, KishimotoT, BankovaVS, KamenarskaZG, UbukataM. (2005) Synthesis of some phenylpropanoid monoglycerides via the Mitsunobu protocol. Molecules, 10, 552–558;
RaoCV, DesaiD, SimiB, KulkarniN, AminA, ReddyBS. (1993) Inhibitory effect of caffeic acid esters on azoxymethane-induced biochemical changes and aberrant crypt foci formation in rat colon. Cancer Research, 53, 4182–4188.
5.
MirzoevaOK, Sud'inaGF, PushkarevaMA, KorshunovaGA, SumbatianNV, VarfolomeevSD. (1995) Lipophilic derivatives of caffeic acid as lipoxygenase inhibitors with antioxidant properties. Bioorganicheskaia khimiia, 21, 143–151.
6.
RaoCV, DesaiD, RivensonA, SimiB, AminS, ReddyBS. (1995) Chemoprevention of colon carcinogenesis by phenylethyl-3-methylcaffeate. Cancer Research, 55, 2310–2315;
SuZZ, LinJ, GrunbergerD, FisherPB. (1994) Growth suppression and toxicity induced by caffeic acid phenethyl ester (CAPE) in Type 5 adenovirus-transformed rat embryo cells correlate directly with transformation progression. Cancer Research, 54, 1865–1870.
9.
LeeYJ, KuoHC, ChuCY, WangCJ, LinWC, TsengTH. (2003) Involvement of tumor suppressor protein p53 and p38 MAPK in caffeic acid phenethyl ester-induced apoptosis of C6 glioma cells. Biochemical Pharmacology, 66, 2281–2289.
JonesBC, McGuiganC, RileyPA. (1989) Synthesis and biological evaluation of some phosphate triester derivatives of the anti-cancer drug araC. Nucleic Acids Research, 17, 7195–7201.
12.
BergmanAM, KuiperCM, MyhrenF, SandvoldML, HendriksHR, PetersGJ. (2004) Antiproliferative activity and mechanism of action of fatty acid derivatives of arabinosylcytosine (ara-C) in leukemia and solid tumor cell lines. Nucleosides, Nucleotides and Nucleic Acids, 23, 1523–1526.;
13.
BergmanAM, KuiperCM, VoornDA, ComijnEM, MyhrenF, SandvoldML, HendriksHR, PetersGJ. (2004) Antiproliferative activity and mechanism of action of fatty acid derivatives of arabinofuranosylcytosine in leukemia and solid tumor cell lines. Biochemical Pharmacology, 67, 503–511.
14.
DonadelOJ, MartínT, MartínVS, VillarJ, PadrónJM. (2005) The tert-butyl dimethyl silyl group as an enhancer of drug cytotoxicity against human tumor cells. Bioorganic Medicinal Chemistry Letters, 15, 3536–3539.;
15.
PadrónJM, DonadelOJ, LeónLG, MartínT, MartínVS. (2006) Enhancement of drug cytotoxicity by silicon containing groups. Letters in Drug Design Discovery, 3, 625–630.
16.
BrookMA, ChanTH. (1983) A simple procedure for the esterification of carboxylic acids. Synthesis, 201–203.
17.
VyasGN, ShahNM. (1963) Organic Synthesis Collection, Wiley, New York. Vol. IV, 836.
18.
HassnerA, AlexanianV. (1978) Direct room temperature esterification of carboxylic acids. Tetrahedron Letters, 46, 4475–4478.
19.
LipinskiCA, LombardoF, DominyBW, FeeneyPJ. (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 46, 3–26.
20.
HanschC, LeoA. (1979) Substituent constants for correlation analysis in chemistry and biology, John Wiley & Sons Ltd., New York, USA, 1–329.
21.
MoriguchiI, HironoS, LiuQ, NakagomeY, MatsushitaY. (1992) Simple method of calculating octanol/water partition coefficient. Chemical & Pharmaceutical Bulletin, 40, 127–130;
22.
MoriguchiI, HironoS, NakagomeI, HiranoH. (1994) Comparison of reliability of log P values for drugs calculated by several methods. Chemical & Pharmaceutical Bulletin, 42, 976–978.
23.
MachathaSG., YalkowskySH. (2005) Comparison of the octanol/water partition coefficients calculated by ClogP®, ACDlogP and KowWin® to experimentally determined values. International Journal of Pharmaceutics, 294, 185–192.
SkehanP, StorengP, ScudeiroD, MonksA, McMahonJ, VisticaD, WarrenJT, BokeschH, KenneyS, BoydMR. (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. Journal of the National Cancer Institute, 82, 1107–1112.
26.
MirandaPO, PadrónJM, PadrónJI, VillarJ, MartínVS. (2006) Prins-type synthesis and SAR study of cytotoxic alkyl chloro dihydropyrans. ChemMedChem, 1, 323–329.
27.
EtzenhouserB, HanschC, KapurS, Dias SelassieC. (2001) Mechanism of toxicity of esters of caffeic and dihydrocaffeic acids. Bioorganic Medicinal Chemistry, 9, 199–209.
28.
HillT, OdellLR, EdwardsJK, GrahamME, McGeachieAB, RusakJ, QuanA, AbagyanR., ScottJL, RobinsonPJ, McCluskeyA. (2005) Small molecule inhibitors of dynamin I GTPase activity: Development of dimeric tyrphostins. Journal of Medicinal Chemistry, 48, 7781–7788.
29.
MonksA, ScudieroD, SkehanP, ShoemakerR, PaullK, VisticaD, HoseC, LangleyJ, CroniseP, Vaigro-WolffA, Gray-GoodrichM, CampbellH, MayoJ, BoydM. (1991) Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. Journal of the National Cancer Institute, 83, 757–766.