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possess cytotoxic activities comparable to cisplatin in
the same assay.
The fact that the hydrogenated congeners 2(H) and 3(H)
are much less active or do not show appreciable cyto-
toxicity may suggest that a certain rigidity of the scaffold
is crucial for the biological activities. On the other hand,
the result that the open-chain ‘taxoid-mimic’ 3 is a little
more potent than the macrocyclic ‘taxoid-mimic’ 2 may
imply an advantage of rather flexible side chains to
accommodate favorable conformation(s) for bioactivity.
It was found, however, that none of the ‘taxoid-mimics’
showed appreciable activity in promoting the formation
of microtubules in the standard in vitro tubulin poly-
merization assay.
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Biological Questions Through Organic Synthesis. In
Organic Synthesis, From Gnosis to Prognosis (NATO
Advanced Study Institute); Chatgilialoglu, C., Snieckus,
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Accordingly, it is very likely that these two compounds,
albeit bearing taxoid side chains (macrocyclic or open-
chained), derive cytotoxic activities through a different
mechanism of action from that of paclitaxel and taxoids.
More specifically, these results suggest that (i) the iso-
serine moiety at the C13 position and the benzoate
moiety at the C2 position of taxoids, although crucial
for achieving extremely strong cytotoxicity, have to be
combined with a close mimic of the baccatin scaffold,
and (ii) oversimplified baccatin core mimics might miss
some of the key baccatin–tubulin interactions crucial for
potent tubulin binding activity (C9 carbonyl orientation,
C and D rings).
ꢁ
ꢁ
8. Gueritte-Voegelein, F.; Mangatal, L.; Guenard, D.;
Potier, P.; Guilhem, J.; Cesario, M.; Pascard, C. Acta
Crystallogr. 1990, C46, 781.
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Bioorg. Med. Chem. Lett. 2002, 12, 349.
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Soc., Perkin Trans. 1 1991, 1511.
20
D
15. Macrocycle 2: A white solid, mp 148–150 °C; ½aꢂ þ34.0 (c
Nevertheless, compounds 2 and 3, possessing micro-
molar level cytotoxicity, could certainly serve as leads
for the development of de novo anticancer agents,
considering the numerous functionalization possibilities
in their simple structure. Further studies on the molec-
ular target of compounds 2 and 3, SAR, and optimiza-
tion of these compounds as well as exploration of new
baccatin surrogate scaffolds are actively underway in
these laboratories.
0.05, CHCl3); 1H NMR (300 MHz, CDCl3) d 1.74 (s, 3H),
1.82 (s, 3H), 2.02–2.12 (m, 1H), 2.41–2.42 (m, 1H), 3.20 (br
s, 1H), 3.76–3.82 (m, 1H), 3.95–4.32 (m, 4H), 4.22 (m, 1H),
4.76 (m, 1H), 5.06 (d, J ¼ 9:4 Hz, 1H), 5.28 (d,
J ¼ 10:3 Hz, 1H), 5.34 (d, J ¼ 12:0 Hz, 1H), 5.58 (br s,
1H), 6.02 (d, J ¼ 8:0 Hz, 1H), 6.63 (d, J ¼ 16:0 Hz, 1H),
6.59–6.70 (m, 1H), 7.39 (m, 2H), 7.87 (d, J ¼ 6:7 Hz, 1H),
8.18 (br s, 1H); 13C NMR (62.9 MHz, CDCl3) d 18.4, 18.8,
25.6, 25.8, 29.7, 38.3, 39.2, 50.3, 51.2, 51.5, 57.4, 57.9, 65.1,
73.0, 73.1, 73.3, 73.7, 77.2, 122.1, 126.1, 127.9, 128.1,
128.4, 129.1, 131.3, 132.5, 136.4, 137.5, 139.6, 155.9, 162.3,
164.9, 172.8. HRMS (FAB) m=e calcd for C26H29N2O8Hþ:
Acknowledgements
497.1924, found: 497.1926 (D ¼ ꢀ0:4 ppm).
20
16. Compound 3: A white solid, mp 78–80 °C; ½aꢂ ꢀ10.9 (c
This work has been supported by a grant from the
National Institutes of Health (NIGMS/NCI). The au-
thors are grateful to Dr. Lifeng He and Prof. Susan B.
Horwitz, Department of Molecular Pharmacology, Al-
bert Einstein College of Medicine, for in vitro tubulin
polymerization assay.
D
1
1.8, CHCl3); H NMR (300 MHz, CDCl3) d 1.23 (s, 9H),
1.71 (br s, 6H), 2.04–2.17 (m, 1H), 2.59–2.63 (m, 1H), 3.21
(d, J ¼ 5:7 Hz, 1H), 3.80 (m, 2H), 3.85 (s, 3H), 4.10 (br s,
1H), 4.21 (m, 1H), 4.69–4.78 (m, 2H), 5.22 (d, J ¼ 7:2 Hz,
1H), 5.48 (br s, 1H), 5.78 (d, J ¼ 11:4 Hz, 1H), 6.03 (d,
J ¼ 9:9 Hz, 1H), 6.53 (d, J ¼ 9:9 Hz, 1H), 7.13 (d,
J ¼ 6:0 Hz, 1H), 7.36 (t, J ¼ 7:8 Hz, 1H), 7.57 (s, 1H),
7.66 (d, J ¼ 7:5 Hz, 1H); 13C NMR (62.9 MHz, CDCl3) d
18.6, 25.6, 28.1, 37.8, 51.1, 51.2, 55.5, 58.2, 58.5, 73.0, 73.6,
76.5, 79.4, 114.5, 117.6, 120.1, 121.3, 122.4, 125.9, 129.5,
130.3, 132.0, 137.1, 140.5, 155.1, 159.6, 162.3, 165.6, 172.3,
172.4. HRMS calcd for C28H36N2O9Naþ 567.2319, found
567.2320 (D ¼ ꢀ0:3 ppm).
References and notes
1. Thayer, A. M. Chem. Eng. News 2000, 78, 20.
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665.