T. Motoyama et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2089–2092
2091
the present study. Under the same experimental condi-
tions, IC50 of 1 was 3.1 nM, and complete inhibition was
attained at about 10 nM. Thus, irrespective of drastic
shorting of the tail length, compound 1 retained suffi-
ciently potent inhibitory activity, indicating that large
hydrophobicity of the tail is not essentially important
for the activity. This result is consistent with the obser-
vations that the presence of polar hydroxy group(s) in
the tail of some natural acetogenins is not unfavorable
for the activity.2a,5a
not support the model proposed by Shimada et al. The
active conformation of acetogenins in complex I
remains to be elucidated. However, we cannot necessa-
rily exclude the validity of their model for partitioning of
acetogenins into the liposomal membrane. In the lipo-
somal membrane, the average location of THF and g-
lactone ring moieties could be primarily determined by
their hydrophobicity.16
Acknowledgements
We thank Dr. Kazuhiro Irie for his help in measure-
ment of HRMS spectra.
Discussion
In general, the activities of potent biologically active
compounds are markedly diminished (by several orders
of magnitude) by structural modification of essential
structural unit(s). In this sense, essential structural fac-
tors of the THF and the g-lactone ring moieties of
acetogenins are not necessarily obvious, except for the
important role of the alkyl spacer connecting both ring
moieties, as described in the introductory section. In
addition to the THF ring with flanking hydroxy groups
and the g-lactone ring, the presence of a long alkyl tail is
also a common structural feature of a large number of
natural acetogenins.1a Our results indicated that the
hydrophobic tail is preferable for the activity, but is not
an essential structural factor. Thus, regardless of the
very potent activity, crucial structural features of acet-
ogenins are quite ambiguous. This unusual character-
istic may be related to the high degree of flexibility of
the alkyl spacer that links the functionally important
THF and g-lactone ring moieties. The present study
provided useful insight into design strategies of novel
acetogenin mimics for further wide structural modifi-
cations, which would enable development of novel
agents for pharmaceutical and agrochemical use.
References and Notes
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1
Based on the results of H NMR and differential scan-
ning calorimetry studies of acetogenins in liposomal
membrane, Shimada et al. proposed a model of active
conformation of these inhibitors, wherein the alkyl tail
and THF ring with flanking hydroxy groups work as
hydrophobic and hydrophilic anchors, respectively, in
the mitochondrial membrane, and only the g-lactone
interacts directly with the target site of complex I by
lateral diffusion in the membrane.6 As a prerequisite for
the conformational model of Shimada et al., they noted
a significant contribution of the intermolecular hydro-
gen bonds between the hydroxy groups in the adjacent
THF rings and the oxygen atoms in the glycerol back-
bone of the phospholipid when the THF rings moiety
acts as hydrophilic anchor at the liposomal membrane
surface. If the hydrogen bond-donating ability of the
hydroxy groups is important for complex I inhibition,
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7.23 (d, J=8.2 Hz, 2H), 4.65 (ddd, J=4.6, 4.6 and 4.6 Hz, 1H),
4.28 (m, 1H), 3.92–3.80 (m, 3H), 3.69 (dd, J=12.2 and 4.5 Hz,
1H), 3.59 (m, 1H), 2.94 (ddd, J=4.2, 4.2 and 2.3 Hz, 1H), 2.72
(dd, J=6.2 and 3.1 Hz, 1H), 2.64 (m, 1H), 2.39 (s, 3H), 2.12–
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1
Compound 10: H NMR (300 MHz, CDCl3) d 3.97–3.89 (m,
4H), 2.96(ddd, J=4.2, 4.2 and 2.3 Hz, 2H), 2.76–2.70 (m, 4H),
2.18–2.05 (m, 2H), 2.03–1.92 (m, 2H), 1.88–1.75 (m, 4H). 13C
NMR (75 MHz, CDCl3) d 82.1, 78.8, 54.2, 44.1, 28.8, 27.9. MS
23
(ESI) m/z 249 [M+Na]+. ½aꢂD =ꢀ15.9 (c 3.34, ethyl acetate).
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