Comparative Molecular Field Analysis of A Series of Paclitaxel Analogues

Abstract

A series of 94 paclitaxel analogues exhibiting antitumor activity by promoting the assembly of microtubules and inhibiting the disassembly process of microtubules to tubulin were investigated using the comparative molecular field analysis (CoMFA) method. These compounds belonging to 10 structural classes were randomly divided into a training set of 80 compounds and a test set of 14 compounds. Since the three-dimension structure of ligand--receptor complex is unknown, from X-ray and NMR data we rationally selected the three-dimension structure of paclitaxel in a polar solution as the active conformation and starting structure for molecule modeling, the other molecules were aligned using this molecule model as the template. The most optimal CoMFA yielded a two-components model, with significant cross-validation r2cv of 0.640 and conventional r2 of 0.868. The predictive ability of training set model was tested on the test set of 14 compounds. The tests not only revealed the robustness of the CoMFA model but demonstrated that for our model r2pred based on the mean activity of test set compounds can accurately estimate external predictivity but r2pred based on the mean activity of training set compounds overestimated the model. The CoMFA model explained why the activity of taxoid is sensitive to the stereochemistry of the atoms at C-2' and C-3' positions and the presence of hydroxyl group at C-2' position. The other factors affecting activity were also elucidated according to standard coefficient contour maps of steric and electrostatic fields derived from the CoMFA model.

A critical review of lipid-based nanoparticles for taxane delivery

“…[166] In contrast, 7-OH is not as essential for the cytotoxicity of taxanes as 2′-OH but derivatives at 7-OH position are very stable under physiological conditions. [167, 168] As a result, derivatives of taxanes are almost always carried out at 2′-OH generating less toxic taxane prodrugs. Besides the improvement of drug encapsulation in lipid nano-carriers, taxane prodrugs have other advantages such as reduced systemic toxicity and potential of site-specific release of active drugs depending on the conjugation chemistry.…”

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

“…However, almost immediately it was realized that not all positions could be modified without reducing paclitaxel antitumor potency. In general, not only the taxane ring is necessary for activity, but also the N-acylated a-hydroxy-b-amino acid moiety [251,252]. Based on their SAR study, Ojima et al indicated that the C-3 0 phenyl group and 3 0 -N group can be replaced with other similar groups, the C-10 position can be modified with some acyl groups, and the C-2 position can be substituted [241].…”

“…Paclitaxel prodrugs are usually designed by introducing a masking moiety to the C-2 0 position as this hydroxyl group seems to be required for cytotoxic effects [251,252]. Esters at this position can be synthesized selectively without protecting of the less reactive C-7 hydroxyl group.…”

Application of the O-N Intramolecular Acyl Migration Reaction in Medicinal Chemistry

“…Additionally, according to the previous SAR studies on paclitaxel derivatives [75,76] as it is known that both N-acyl and free 2'-OH groups are required for taxoid activity [76], these prodrugs are not expected to be active themselves. This prodrug strategy was also applied for the design of a docetaxel (21) prodrug.…”