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C. A. Sanhueza et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3676–3681
having a hydroxyl group in the aglycon, as do 27–29,
exhibited a moderate cytotoxicity, their activity decreas-
ing as the length of the chain increased. Thus, while the
hydroxymethyl group had a GI50 of 25.8 lM (com-
pound 27), the 2-hydroxyethyl showed a higher value
of 30.2 lM (28) and the 3-hydroxypropyl had no activity
(29). b-C-Glucosides with branched or cyclic aglycons,
like the iso-butyl 20, phenyl 33, or cyclopropyl com-
pounds 41–43, were inactive. However, those com-
pounds having a cyclohexylmethyl (31) or benzyl
group (34) as aglycon were cytotoxic (GI50 9.5 and
17.4 lM, respectively).
instance, the n-propyl b-C-glucoside 14 had a GI50 of
17.2 lM, while its a stereoisomer 15 was not active. Sim-
ilarly, the cyclohexylmethyl b-C-glucoside 31 showed
significant antiproliferative activity (GI50 4.4 lM), while
its a stereoisomer 32 was less active (GI50 20.7 lM).
In summary, a large series of C-glycosides were syn-
thesized and screened against cervical carcinoma
(HeLa) and osteosarcoma (HOS) cell lines. Several
C-glucosides had high antiproliferative activity against
these cell lines. Thus, compounds 15, 31, and 38
showed GI50 values below 10 lM against the HeLa
cell line, while compounds 4, 31, 38, 41, 45, and 51
against HOS. The easy synthetic access to these C-gly-
cosides, together with their high activities, makes them
promising substrates against these cancer cell lines.
Some significant structure–activity relationships were
established.
Analysis of the data also reveals that the antiproliferative
activity is strongly dependent on the configuration at C-
1, although sometimes favoring the b stereoisomer and
other times the a. Thus, while the b stereoisomers of
the ethyl and cyclohexylmethyl glucosides (compounds
5 and 31) were active, their a stereoisomers 6 and 32 were
not. However, both stereoisomers of the n-propyl gluco-
sides 8 and 9 showed similar antiproliferative activities.
On the other hand, the a stereoisomer of the n-propyl
tri-O-(4-fluoro-benzyl) glucoside 15 was more active
(GI50 5.6 lM) than the b 14 (GI50 12.3 lM). This a pref-
erence was also observed in the stereoisomers of n-propyl
tri-O-(n-pentadecyl) glucosides 12 and 13, and in those of
the iso-butyl tri-O-benzyl derivatives 20 and 21.
Acknowledgments
This work was financed by the Universidad de La Lagu-
na, the EU INTERREG IIIB-MAC initiative (05/MAC/
2.5/C14 BIOPOLIS), the MEC, co-financed by the
European FEDER (CTQ2005-09074-C02-01/BQU)
and the Gobierno de Canarias. C.A.S. and C.M. thank
´
the Universidad de La Laguna and the Consejerıa de
Educacion y Deportes del Gobierno de Canarias for a
fellowship. J.M.P. thanks the Spanish MEC-FSE for a
´
Ramon y Cajal contract.
Osteosarcoma (HOS). Structural analysis of the C-gly-
cosides (Scheme 5) and of their corresponding data (Ta-
´
bles
1
and 2) reveals some structure–activity
relationships for this cell line. Besides the already-men-
tioned preference for the benzyl groups as substituents
for the hydroxyl groups at C-3, C-4, and C-6, other fea-
tures can be established. In contrast to that observed
with HeLa and HL60 cell lines, some C-glycosides with
an acetyl or carbonyl group at position 2 were more
cytotoxic than those with an underivatized hydroxyl
group. Thus, while the methyl glucoside 3 was inactive,
its acetyl derivative 4 had a GI50 of 8.8 lM. Moreover,
acetylation of the hydroxyl group at C-2 in the allyl glu-
coside 24 (GI50 44.1 lM), giving the allyl derivative 25,
led to higher antiproliferative activity (GI50 11.0 lM).
The 2-keto C-glycosides 45 and 51 (Table 2) also showed
higher cytotoxicity (GI50 4.3 and 7.6 lM,) than their
respective reduced compounds 5 and 24 (GI50 34.2 and
44.1 lM, respectively). Note that none of these 2-keto
C-glycosides had antiproliferative activity against HeLa.
References and notes
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7. For easier discussion, C-glycosides are numbered here
according to semisystematic names generally accepted for
this class of compounds.
Concerning the aglycon, C-glycosides having a cyclic
aglycon, such as the cyclohexylmethyl b-glucoside 31
(GI50 4.4 lM), or the benzyl derivatives 34 and 38
(29.2 and 6.1 lM, respectively), were more cytotoxic
than compounds with linear aglycons (GI50 > 35 lM)
(Table 1). However, 2-keto C-glycosides (Table 2) do
not seem to follow this relationship, since the ethyl
(45) and the allyl (51) were cytotoxic but not the benzyl
(50).
´
´
8. Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89,
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Regarding the configuration at C-1, all C-glucosides
with high antiproliferative activity against the HOS cell
line (Scheme 5) possessed a b configuration, with the
sole exception of the dichlorocyclopropyl 42. For
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10. Registry numbers for known compounds: 1, 91780-41-5; 2,
152840-34-1; 3, 105938-03-2; 4, 105938-04-3; 5, 909533-21-
Sanhueza, Carlos A.
