STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 109

applied to predict binding of some D-seco analogs. Unfortunately, two D-seco
analogs with a saturated C ring, which is predicted to be similar to paclitaxel
in the free energy of drug binding, were inactive in bioassay. 142 This result
prompted the authors to improve their model. They changed the amino acid
H-bonding to the oxetane ring from Arg to Thr, and they incoprated more amino
acid residues close to the oxetane ring so that the inactivity of those D-seco analogs
can be explained. 142
The ''polar'' conformation, also called the ''hydrophobic collapse'' conforma-
tion since it was named in 1993, was proposed on the basis of NMR data of taxoids
in polar solvent and the x-ray structure of paclitaxel. Recently, Ojima et al. pro-
posed a common pharmcophore for paclitaxel and several other antimotic natural
products on the basis of NMR data recorded in DMSO-d 6 /D 2 O of a macrocyclic
pacliaxel analog, nonataxel, and molecular modeling results. 144 Later on, suppor-
tive evidences were collected in photoaffinity labeling experiments, 161 and
fluorescence spectroscopy/REDOR NMR by using C3 0 -N-(p-aminobenzoyl)pacli-
taxel as a fluorescence probe and 13 C, 15 N-radiolabeled 2-debenzoyl-2-(m-F-ben-
zoyl)- paclitaxel. 174 In the latter report, 174 the distance between C-3 0 N carbonyl
carbon and fluorine at C-2 benzoate was determined to be 9.8 ˚ and that between
C-3 0 methane and C-2 fluorine to be 10.3 ˚ , in agreement with ''hydrophobic
collapse'' conformation. Ojima et al. have suggested that two major ''collapsed''
conformations of paclitaxel, one with a H2 0 -C2 0 -C3 0 -H3 0 dihedral angle of 180
(the characteristics for the ''polar'' conformation mentioned earlier) and another
with the angle of 124 (which is believed to be the third ''active'' conformation
of paclitaxel at that time), are in equilibrium in the aqueous environment using
''fluorine-probe approach.'' 175 They explained the bioactivity of a series of
A-seco analogs 55 and fluorine-substituted analogs 25 in compliance with the ''polar''
conformation hypothesis. However, ''hydrophobic collapse'' conformation was
questioned as to whether it was an ''active'' conformation because some macrocyc-
lic tethered paclitaxel analogs mimicking ''hydrophobic collapse'' were found
inactive. 146
Snyder et al. proposed that the NMR reflect probably the dynamic averages of
large sets of conformers rather than one or two major conformers. Ojima et al. have
recognized the dynamic equlibrium behavior of paclitaxel conformers, but they
have not found the ''T-shaped'' conformer subsets. After reanalyzing paclitaxel
ROESY data published earlier with NMR analysis of molecular flexibility in solu-
tion (NAMFIS) techniques, Snyder et al. identified eight energy optimized confor-
mers, among which four represented 33% of the whole conformer mixture
belonging to neither ''nonpolar'' nor ''polar'' conformations but what they called
the ''open'' conformer subfamily. 176 Other studies led to the discovery of the
unique ''T-shaped'' (''open'') conformation of paclitaxel, which does not resemble
either of the above-mentioned conformations. 174 In this model constructed on the
electronic crystallographic data of b-tubulin and subsequent molecular simulation,
C-2 benzoate and C-3 0 of paclitaxel cannot collapse because of the prevention of
His-229 of the receptor protein. NAMFIS revealed that all three major groups
of conformers (nonpolar, polar, and T-shaped) existed in the solution for a group