STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 110

O

O

HO

O

H O

O

O

O

HO

O

O

O

O

O

O

O

O

O O

O O

O

O O

O O

O O

O H

N

O

O

O

HO

HO
N

O

HO

N
H

O

O

T-conformation “polar” conformation “nonpolar” conformation

Figure 3-1. Active conformations proposed for paclitaxel.

of C2 0 -C3 0 -Ph tethered analogs of paclitaxel (Figure 3-1). 45 In fact, extended
conformations predominate in the mixture of conformers, and three T-shaped
conformers constitute 59% of the extended conformers. In another picosecond
fluorescence spectroscopy experiment, the data supported the binding of paclitaxel
in ''T-shaped'' conformation to tubulin. 169 In a conformation study conducted in
2003 149 for C3 0 -N-C2 linked macrocyclic analogs, a conformer situated between
''nonpolar'' and ''T-shaped'' forms was identified as the bioactive conformation.
It should be noted that in 2004, Ganesh et al. 151 and in 2000, Snyder et al. 176
claimed in their articles that only the T-conformation was the conformation to be
adopted by paclitaxel when binding to tubulin, whereas collapsed ''polar'' and
''nonpolar'' conformations do not work. Their conclusion was supported by com-
puter simulation and NMR experiments of semisynthetic taxoids, in which the C-4
alkyl terminal and the C3 0 -Ph ortho-position were linked. 151
Some reports focused on conformation of the C-13 phenylisoserine side chain of
paclitaxel. 177 From the point of view of setting up an ''active'' conformation model
for paclitaxel, a drug-receptor complex rather than a part of the drug, for example,
the C-13 side chain, will be more informative and meaningful.
The oxetane D-ring in paclitaxel also attracts a lot of attention. Previous SAR
studies have suggested it plays a critical role in binding, either through taxane ske-
leton rigidification or a weak hydrogen bonding acceptor. But its essence in binding
is not acknowledged in some reports. 140,178 Wang et al. tried to reveal the role of
the D-ring in paclitaxel in 2000, showing that the binding energies of some D-seco
analogs of paclitaxel are comparable with that of paclitaxel. They predicted that
some analogs without an intact oxetane D ring can still bind to tubulin very
well. 178 Barboni et al. 142 and Boge et al. 179 found that conformational changes
are relayed from ring C to A in the D-seco analogs. Another consequence of the
SAR study of D-seco analogs 142 is that the second generation of the paclitaxel-

minireceptor 57,178

epothilone was revised because of its inconsistency with

experimental results.