New oseltamivir analogues were designed and synthesized, starting from shikimic acid. Biological evaluation against three human cancer cell lines (KB, MCF7 and Lu-1) showed that many of them exhibited cytotoxic activity. Azides 5 are more active than the corresponding amines 6. Thus, the reduction of the azide group into amine led to the loss of cytotoxicity. The compounds with a cyclohexanemethyloxy group at C-3 were more active than the other investigated compounds belonging to the same series. This cyclohexanemethyloxy group seems to be critical for the cytotoxic activity of this class of compounds. The synthetic oseltamivir analogues 6a-e had no inhibition activity, even at the concentration of 50 μM when they were evaluated for their in vitro influenza A neuraminidase inhibitory activity by an enzymatic assay.
AbrechtS., HarringtonP., IdingH., KarpfM., TrussadiR., WirzB., ZutterU. (2004) The synthetic development of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu®): a challenge for synthesis & process research. Chimia, 58, 621–629.
2.
DewickP.M. (2002) Medicinal Natural Products: A Biosynthetic Approach, 2nd Edition. John Wiley & Sons, Ltd, UK, 121–166.
3.
(a) KishoreG.M., ShahD.M. (1988) Amino acid biosynthesis inhibitors as herbicides. Annual Review of Biochemistry, 57, 627–663; (b) Jiang S, Singh G, Boam DJ, Coggins JR. (1999) Synthesis of 3-deoxy-3,3-difluoroshikimic acid and its 4-epimer from quinic acid. Tetrahedron: Asymmetry, 10, 4087–4090; (c) Song C, Jiang S, Singh G. (2001) Syntheses of (6S)–6-fluoro- and (6R)–6-hydroxyshikimic acids. Tetrahedron Letters, 42, 9069 –9071.
4.
(a) ZhangY., LiuA., YeZ.G., LinJ., XuL.Z., YangS.L. (2006) New approach to the total synthesis of (-)-zeylenone from shikimic acid. Chemical & Pharmaceutical Bulletin, 54, 1459–1461; (b) Liu A, Liu ZZ, Zou ZM, Chen SZ, Xu LZ, Yang SL. (2004) Synthesis of (+)-zeylenone from shikimic acid. Tetrahedron, 60, 3689–3694.
5.
SutherlandJ.K., WatkinsW.J., BaileyJ.P., ChapmanA.K., DaviesG.M. (1989) The synthesis of 6a- and 6p-fluoroshikimic acids. Journal of the Chemical Society, Chemical Communications, 1386–1387.
6.
(a) RohloffJ.C., KentK.M., PostichM.J., BeckerM.W., ChapmanH.H., KellyD.E., LewW., LouieM.S., McGeeL.R., PrisbeE.J., SchultzeL.M., YuR.H., ZhangL. (1998) Practical total synthesis of the anti-influenza drug GS-4104. Journal of Organic Chemistry, 63, 4545–4550; (b) Federspiel M, Fischer R, Hennig M, Mair HJ, Oberhauser T, Rimmler G, Albiez T, Bruhin J, Estermann H, Gandert C, Gockel V, Gotzo S, Hoffmann U, Huber G, Janatsch G, Lauper S, Rockel-Stabler O, Trussardi R, Zwahlen AG. (1999) Industrial synthesis of the key precursor in the synthesis of the anti-influenza drug oseltamivir phosphate (Ro 64-0796/002, GS-4104-02): Ethyl (3R,4S,5S)–4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate. Organic Process Research & Development, 3, 266–274; (c) Karpf M, Trussardi R. (2001) New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu). Journal of Organic Chemistry, 66, 2044–2051; (d) Harrington PJ, Brown JD, Foderaro T, Hughes RC. (2004) Research and development of a second-generation process for oseltamivir phosphate, prodrug for a neuraminidase inhibitor. Organic Process Research & Development, 8, 86–91; (e) Nie LD, Shi XX, Ko KH, Lu WD. (2009) A short and practical synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid. Journal of Organic Chemistry, 74, 3970–3973; (f) Nie LD, Shi XX. (2009) A novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid. Tetrahedron: Asymmetry, 20, 124–129.
7.
UsamiY., IchikawaH., ArimotoM. (2008) Synthetic efforts for stereo structure determination of cytotoxic marine natural product pericosines as metabolites of Periconia sp. from sea hare. International Journal of Molecular Sciences, 9, 401–421.
8.
NguyenQ.C., DoanT.M.H., LeA.T., PhamX.V., TranT.T.T., PhamV.C., NguyenV.H. (2006) Isolation of shikimic acid from Vietnamese star anise. Tap Chi Hoa Hoc, 44, 745–748.
9.
KimC.U., LewW., WilliamsM.A., LiuH., ZhangL., SwaminathanS., BischofbergerN., StevensR.C. (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. Journal of the American Chemical Society, 119, 681–690.
10.
WuX.Y., SheX., ShiY. (2002) Highly enantioselective epoxidation of α,β-unsaturated esters by chiral dioxirane. Journal of the American Chemical Society, 124, 8792–8793.
11.
MosmannT. (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65, 55–63.