Dimethyl-5-acetyl-4-methyl-6-(4-methylphenylimino)-6H-thiopyran-2,3-dicarboxylate (4) has been synthesized and its antiproliferative activity is reported here. Compound 4 inhibited the growth of human colon cancer cell line HCT-15 with an IC50 value of 3.5 μM and of breast cancer cell line MCF-7 with an IC50 value of 1.5 μM in a dose/time-dependent manner using a sulforhodamine B assay. Moreover, suppression of clonogenic activity occurred after exposure to 4 at a concentration of 4 μM for HCT-15 and 1.7 μM for MCF-7. The results also showed tumor cell invasion through matrigel and cell adhesion. The effect of ligand complexation on DNA structure led to overall affinity constant of K4-DNA=9.8×104 M−1.
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References
1.
BoultonS., KyleS., DurkaczW.2000. Mechanisms of enhancement of cytotoxicity in etoposide and ionising radiation-treated cells by the protein kinase inhibitor wortmannin. Eur J Cancer, 36:535–541.
2.
BrownM.J., CarterP.S., FenwickA.E., FosberryA.P., HamprechtD.W., HibbsM.J., ArvestR.L., MensahL., MilnerP.H., O'HanlonP.J., PopeA.J., RichardsonC.M., WestA., WittyD.R.2002. The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase. Bioorg Med Chem Lett, 12:3171–3174.
3.
CasyG., LaneS., TalorR.J.K.1986. The preparation of thiathromboxane analogues and a formal total synthesis of dithiathromboxane A2 based on conjugate addition reactions of thiin-4-ones. J Chem Soc Perkin Trans, 1:1397–1404.
4.
CasyG., TaylorR.J.K.1988. Facile Ramberg-Bäcklund reactions for the synthesis of 2,3-disubstituted cyclopentenones; A short synthetic route to tetrahydrodicranenone B. J Chem Soc Chem Commun, 454–455. 10.1039/C39880000454. http://pubs.rsc.org/en/content/articlelanding/1988/C39880000454
5.
CasyG., TaylorR.J.K.1989. The synthesis of 2,3-disubstituted cyclopentenones using Ramberg-Bäcklund reaction in conjunction with organocopper chemistry. Tetrahedron, 45:455–466.
6.
DennyW.A., AtwellG.J., BaguleyB.C.1983. Potential antitumor agents. 39. Anilino ring geometry of amsacrine and derivatives: relationship to DNA binding and antitumor activity. J Med Chem, 26:1625–1630.
7.
FroehlichE., MandevilleJ.S., WeinertC.M., KreplakL., Tajmir-RiahiH.A.2011. Bundling and aggregation of DNA by cationic endrimers. Biomacromolecules, 12:511–517.
8.
HamadiH., KhoobiM., HossainiZ., ShafieeA.2011. Facile and efficient synthesis of functionalized iminothiopyran and isothiochromen via one-pot multicomponent reactions. Mol Divers, 15:35–40.
9.
HollickJ.J., GoldingB.T., HardcastleI.R., MartinN., RichardsonC., RigoreauL.J., SmithG.C., GriffinR.J.2003. 2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-dependent protein kinase (DNA-PK)Bioorg Med Chem Lett, 13:3083–3086.
10.
HollickJ.J., RigoreauL.J., Cano-SoumillacC., CockcroftX., CurtinN.J., FrigerioM., GoldingB.T., GuiardS., HardcastleI.R., HicksonI., HummersoneM.G., MenearK.A., MartinN.M., MatthewsI., NewellD.R., OrdR., RichardsonC.J., SmithG.C., GriffinR.J.2007. Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase related kinases. Structure-activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase. J Med Chem, 19:1958–1972.
11.
HuangR., WallqvistA., CovellD.G.2006. Assessment of in vitro and in vivo activities in the National Cancer Institute's anticancer screen with respect to chemical structure, target specificity, and mechanism of action. J Med Chem, 49:1964–1979.
12.
HurleyL.H.2002. DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer, 2:188–200.
13.
KimC.H., ParkS.J., LeeS.H.2002. A targeted inhibition of DNA-dependent protein kinase sensitizes breast cancer cells following ionizing radiation. J Pharmacol Exp Ther, 303:753–759.
14.
LesykR., ZimenkovskyB., AtamanyukD., JensenF., Kieć-KononowiczK., GzellaA.2006. Anticancer thiopyrano[2,3-d][1,3]thiazol-2-ones with norbornane moiety. Synthesis, cytotoxicity, physico-chemical properties, and computational studies. Bioorg Med Chem, 14:5230–5240.
15.
LindenmeyerF., LiH., MenashiS., SoriaC., LuH.2001. Apigenin acts on the tumor cell invasion process and regulates protease production. Nutr Cancer, 39:139–147.
16.
MandevilleJ.S., N'soukpoé-KossiC.N., NeaultJ.F., Tajmir-RiahiH.A.2010. Structural analysis of DNA interaction with retinol and retinoic acid. Biochem Cell Biol, 88:469–77.
17.
McAllisterG.D., TaylorR.J.K.2001. The synthesis of polyoxygenated, enantiopure cyclopentene derivatives using Ramberg-Bäcklund rearrangement. Tetrahedron Lett, 42:1197–1200.
18.
McDonaldB.P., SteeleR.W., SutherlandJ.K.1988. Synthetic approaches to thiathromboxanes. Part 2. Synthesis of structural isomers of thiathromoxane A2. J Chem Soc Perkin Trans, 1:675–679.
19.
MehrzadJ., RajabiM., KhalilzadehM.A.2010. Design and antiproliferative activity of 2-(3,5-Dihydroxyphenyl)-6-hydroxybenzothiazole (DHB) on PC-3 prostate cancer cell line. Iran J Org Chem, 2:498–500.
20.
MignattiP., RifkinD.B.1996. Plasminogen activators and angiogenesis. Curr Top Microbiol Immunol, 213:33–50.
21.
MinottiG., MennaP., SalvatorelliE., CairoG., GianniL.2004. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev, 56:185–229.
22.
NafisiS., HashemiM., RajabiM., Tajmir-RiahiH.A.2008. DNA adducts with antioxidant flavonoids apigenin, morin and naringin. DNA Cell Biol, 27:433–442.
23.
NedolyaN.A., BrandsmaL., VerkruijsseH., TrofimovB.A.1998. 2-Iminothiopyrans from methylthiobutadiene and isothiocyanates. Chem Heterocycl Comp, 34:550–553.
24.
PortugalJ.2009. Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity. BMC Pharmacol, 9:11.
25.
PortugalJ., CashmanD.J., TrentJ.O., Ferrer-MirallesN., PrzewlokaT., FoktI., PriebeW., ChairesJ.B.2005. A new bisintercalating anthracycline with picomolar DNA binding affinity. J Med Chem, 48:8209–8219.
26.
QuagliaW., PiginiM., PiergentiliA., GiannellaM., GentiliF., MarucciG., CarrieriA., CarottiA., PoggesiE., LeonardiA., MelchiorreC.2002. Structure-activity relationships in 1,4-benzodioxan-related compounds. 7. Selectivity of 4-phenylchroman analogues for alpha(1)-adrenoreceptor subtypes. J Med Chem, 45:1633–1643.
27.
RajabiM., SignorelliP., GorincioiE., GhidoniR., SantanielloE.2010. Antiproliferative activity of N6-isopentenyladenosine on MCF-7 breast cancer cells: cell cycle analysis and DNA-binding study. DNA Cell Biol, 29:687–691.
28.
ShaoZ.M., WuJ., ShenZ.Z., BarskySH.1998. Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res, 58:4851–4857.
29.
SmithG.C.M., JacksonS.P.1999. The DNA-dependent protein kinase. Genes Dev, 13:916–934.
30.
SugitaY., HosoyaH., TerasawaK., YokoeI., FujisawaS., SakagamiH.2001. Cytotoxic activity of benzothiepins against human oral tumor cell lines. Anticancer Res, 21:2629–2632.
31.
Tajmir-RiahiH.A., NeaultJ.F., NaouiM., DiamantoglouS.1995. The effects of HCl on the solution structure of calf thymus DNA: a comparative study of DNA denaturation by proton and metal cations using Fourier transform IR ifference spectroscopy. Biopolymers, 35:493–501.
32.
ValerioteF., Van PuttenL.1975. Proliferation-dependent cytotoxicity of anticancer agents: a review. Cancer Res, 35:2619–2630.
33.
Van VlietL.A., RodenhuisN., DijkstraD., WikstromH., PugsleyT.A., SerpaK.A., MeltzerL.T., HeffnerT.G., WiseL.D., LajinessM.E., HuffR.M., SvenssonK., SundellS., LundmarkM.2000. Synthesis and pharmacological evaluation of thiopyran analogues of the dopamine D3 receptor-selective agonist (4aR,10bR)-(+)-trans-3,4,4a,10b-tetrahydro-4-n-propyl-2H,5H [1]b enzopyrano[4,3-b]-1,4-oxazin-9-ol (PD 128907)J Med Chem, 43:2871–2882.
34.
VedejsE., KrafftG.A. 1982. Cyclic sulfides in organic synthesis. Tetrahedron, 38:2857–2881.
35.
WangW., LiH., WangJ., ZuL.S.2006. Enantioselective organocatalytic tandem Michael-Aldol reactions: one-pot synthesis of chiral thiochromenes. J Am Chem Soc, 128:10354–10355.
36.
WardD.E., JheengutV., BeyeG.E.2006. Thiopyran route to polypropionates: an efficient synthesis of serricornin. J Org Chem, 71:8989–8992.
37.
WeinsteinJ.N., MyersT.G., O’ ConnorP.M., FriendS.H., FornaceA.J., KohnK.W., FojoT., BatesS.E., RubinsteinL.V., AndersonN.L.1997. An information-intensive approach to the molecular pharmacology of cancer. Science, 275:343–349.
38.
YoshimuraY., YamazakiY., SaitoY., TakahataH.2009. Synthesis of 1-(5,6-dihydro-2H-thiopyran-2-yl)uracil by a Pummerer-type thioglycosylation reaction: the regioselectivity of allylic substitution. Tetrahedron, 65:9091–9102.
39.
ZhangX., LiX., FanX., WangX., LiD., QuG., WangJ.2009. Ionic liquid promoted preparation of 4H-thiopyran and pyrimidine nucleoside-thiopyran hybrids through one-pot multi-component reaction of thioamide. Mol Divers, 13:57–61.
