STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 108

the microtubule, and C-7 is close to a positively charged peptide segment of M-loop
in the b-unit of the microtubule.
In 2001, several articles revealed a microtubule structure with improved resolu-
tion. 170,171 In the refined tubulin structure, the binding pocket of paclitaxel was
modified slightly. 170 These structures will provide a good starting point in the
construction of the pharmacophores of paclitaxel and other antitubulin drugs.
Although many studies concentrated on b-tubulin, the role of a-tubulin in the
binding process was still scarcely known. In a recent report, the authors found
that the assembly of different a-tubulin isoforms differs greatly in the presence
of paclitaxel, and thus they proposed at least partial involvement of a-tubulin in
the binding process. 172
3.3.2 Identification of Bioactive Conformations and Quest
for a Pharmacophore for Paclitaxel
What conformation paclitaxel adopts when it binds to its receptor tubulin is an
important question to be answered. There are many efforts on the construction of
common pharmacophore for several other antitubulin natural products sharing the
same binding site with paclitaxel.
In a hypothetical common pharmacophore for a nonaromatic analog of paclitaxel
and other antimicrotubule agents, it was proposed that the baccatin core structure is
not essential to activity but it acts as a scaffold for the substituents. 173 A more
recent report noted the importance of the baccatin structure and the usefulness of
C-13 and C-2 side chains in enhancing the binding of taxoid to its receptor. 163
Because of the rigid structure of the tetracyclic core of taxane with less change
during binding, people focused on the side chain of paclitaxel, especially C-13 iso-
serine and substitutions at other sites. In 1993, the first hypothesis on ''active'' con-
formation, ''hydrophobic collapse,'' was established on the basis of NOESY data of
paclitaxel in DMSO-d 6 /D 2 O solution. It was proposed that 3 0 -Ph, phenyl rings of
3 0 -NH and 2-benzoate as well as 4-OAc were close to each other in the hydrophilic
environment. Major differences in paclitaxel conformations in nonpolar and polar
solvents were found, and those conformations were assigned as ''nonpolar'' and
''polar'' as two representative groups, respectively. Despite the difference, both
''nonpolar'' and ''polar'' conformations showed to some extent the ''hydrophobic
collapse'' property. In 2001, a noncollapsed ''T-shaped'' conformation on the basis
of molecular simulation was proposed as the binding conformation of paclitaxel to
tubulin. 174
The ''nonpolar'' conformation, also termed the ''extended'' conformation, was
established on the basis of NMR data of paclitaxel and docetaxel in nonpolar sol-
vent such as chloroform, as well as crystallographic data of docetaxel. Its presence
was experimentally confirmed by fluorescence and solid-state NMR spectroscopies
(REDOR). 163 Wang et al. selected 20 amino acid residues and paclitaxel conforma-
tion in CDCl 3 as a starting point to construct a ''mini-receptor'' model 57 for both
paclitaxel and epothilone, a family of macrocyclic antimitotic agents that was
assumed to bind to the same site on tubulin as paclitaxel. This model has been