Cytotoxicity on sonchifolinic acid (1) isolated from Samallunthus leaf and synthetic compounds related to compound 1 were comparatively studied for the first time. Derivatives of 1 such as propyl (1a), butyl (1b), pentyl (1c) and 2-methoxy ethyl (1d) sonchifolate were prepared and their cytotoxic activity on HeLa cells were compared with sonchifolin (2), a structurally related natural compound. Alkylation of the carboxylic acid group at C-14 position in 1 enhanced the cytotoxic activity 2–5 times (1a - 1d and 2, IC50 5.29 - 21.07 μM) compared with that of sonchifolinic acid (1) (IC50 47.12 μM). Higher lipophilicity and moderate bulkiness of the inserted alkyl group contributed to the increased SL cytotoxicity in vitro. This result shows sonchifolinic acid (1) could be a valuable leading compound for semi-synthetic derivatives in order to develop new potent anticancer drugs.
(a) MatejićJ., SaracZ., RandelovicV. (2010) Pharmacological Activity of Sesquiterpene Lactones. Biotechnology & Biotechnological Equipment, 24, 95–100; (b) Muschietti LV, Ulloa J. (2016) Natural sesquiterpene lactones as potential trypanocidal therapeutic agents: A review. Natural Product Communications, 11, 1569-1578; (c) Abood S, Eichelbaum S, Mustafi S, Veisaga ML, López LA, Barbieri M (2017) Biomedical properties and origins of sesquiterpene lactones, with a focus on dehydroleucodine. Natural Product Communications, 12, 995-1005.
2.
SchorrK., MerfortI., Da CostaF.B. (2007) A novel dimeric melampolide and further terpenoids from Smallanthus sonchifolius (Asteraceae) and the inhibition of the transcription factor NF-kappa B. Natural Product Communications, 2, 367–374.
3.
MercadoM.I., Coll AráozM.V., GrauA., CatalánC.A. (2010) New acyclic diterpenic acids from yacon (Smallanthus sonchifolius) leaves. Natural Product Communications, 5, 1721–1726.
4.
KitaiY., HayashiK., OtsukaM., NishiwakiH., SenooT., IshiiT., SakaneG., SugiuraM., TamuraH. (2015) New sesquiterpene lactone dimer, uvedafolin, extracted from eight yacon leaf varieties (Smallanthus sonchifolius): cytotoxicity in HeLa, HL-60, and Murine B16-F10 melanoma cell lines. Journal of Agricultural and Food Chemistry, 63, 10856–10861.
5.
YuanY., Win AungK.K., RanX.K., WangX.T., DouD.Q., DongF. (2017) A new sesquiterpene lactone from yacon leaves. Natural Product Communications, 31, 43–49.
6.
HongS.S., LeeS.A., HanZ.H., LeeM.H., HwangJ.S., ParkJ.S., OhK-W, HanK., LeeM.K., LeeH., KimW., LeeD., HwangB.Y. (2008) Melampolides from the leaves of Smallanthus sonchifolius and their inhibitory activity of LPS-induced nitric oxide production. Chemical & Pharmaceutical Bulletin, 56, 199–202.
7.
MercadoM., Coll AráozM.V., ManriqueI., GrauA., CatalánC.A.N. (2014) Variability in sesquiterpene lactones from the leaves of yacon (Smallanthus sonchifolius) accessions of different geographic origin. Genetic Resources and Crop Evolution, 61, 1209–1217.
8.
PlögerM., SendkerJ., LangerK., SchmidtT. (2015) Covalent modification of human serum albumin by the natural sesquiterpene lactone parthenolide. Molecules, 20, 6211–6223.
9.
BeekmanA.C., WoerdenbagH.J., UdenW., PrasN., KoningsA.W.T., WikströmH.V., SchmidtT.J. (1997) Structure-cytotoxicity relationships of some helenanolide-type sesquiterpene lactones. Journal of Natural Products, 60, 252–257.
10.
GhantousA., Gali-MuhtasibH., VuorelaH., SalibaN.A., DarwicheN. (2010) What made sesquiterpene lactones reach cancer clinical trials?. Drug Discovery Today, 15, 668–678.
11.
JaneckiT., BłaszczyK.E., StudzianK., RóżalskiM., KrajewskaU., JaneckaA. (2002) New stereocontrolled synthesis and biological evaluation of 5-(1'-Hydroxyalkyl)-3-methylidenetetrahydro-2-furanones as potential cytotoxic agents. Journal of Medicinal Chemistry, 45, 1142–1145.
12.
RiveroA., QuintanaJ., EiroaJ.L., LópezM., TrianaJ., BermejoJ., EstévezF. (2003) Potent induction of apoptosis by germacranolide sesquiterpene lactones on human myeloid leukemia cells. European Journal of Pharmacology, 482, 77–84.
13.
SiriwanD., NaruseT., TamuraH. (2011) Effect of epoxides and α-methylene-γ-lactone skeleton of sesquiterpenes from yacon (Smallanthus sonchifolius) leaves on caspase-dependent apoptosis and NF-κB inhibition in human cervical cancer cells. Fitoterapia, 82, 1093–1101.
14.
KitaiY., ZhangX., HayashidaY., KakehiY., TamuraH. (2017) Induction of G2/M arrest and apoptosis through mitochondria pathway by a dimer sesquiterpene lactone from Smallanthus sonchifolius in HeLa cells. Journal of Food and Drug Analysis, 25, 619–627.
