Synthesis and bioactivity of a side chain bridged paclitaxel: A test of the T-Taxol conformation

Abstract

A knowledge of the bioactive tubulin-binding conformation of paclitaxel (Taxol™) is crucial to a full understanding of the bioactivity of this important anticancer drug, and potentially also to the design of simplified analogs. The bioactive conformation has been shown to be best approximated by the T-Taxol conformation. As a further test of this conclusion, the paclitaxel analog 4 was designed as a compound which has all the chemical functionality necessary for activity, but which cannot adopt the T-Taxol conformation. The synthesis and bioassay of 4 confirmed its lack of activity, and thus provided further support for the T-Taxol conformation as the bioactive tubulin-binding conformation.The anticancer drug paclitaxel (1, Taxol™, PTX) is one of the most important anticancer natural products ever discovered, and has contributed significantly to human health. First reported from the Western yew, Taxus brevifolia, in1971, 1 it went through a long period of development, and was finally approved by the FDA for clinical use in 1992.A turning point in its development came with the discovery of its then unique mechanism of action as a promoter of the assembly of tubulin into microtubules. 2 The microtubule has been Correspondence to: David G. I. Kingston. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The normal functioning of tubulin assembly and disassembly is crucial to cell division, and any interference with this process disrupts cell division and leads to cell death by apoptosis. PTX owes its activity to its ability to bind to tubulin and suppress microtubule assembly dynamics. 3 Thus the nature of the binding of paclitaxel to tubulin, and in particular the tubulinbinding conformation of PTX, is an important question with potential applications in the design of improved taxoid drugs. NIH Public AccessSince PTX has a large flexible side chain at C13 and smaller flexible side chains at C2, C4, and C10, many different conformations are possible. Various proposals for the binding conformation have been made based on studies of the solution NMR spectra of PTX. NMR studies in nonpolar solvents suggested a "nonpolar" conformation, 6-8 while a "polar" conformation featuring hydrophobic interactions between the C2 benzoate, the C3′ phenyl group and the C4 acetate was proposed on the basis of NMR studies in polar solvents. 9-12 A third approach involved NMR studies using the NAMFIS deconvolution method, and this showed that PTX adopts 9-10 conformations in CDCl 3 . 13 An analysis of the electron crystallographic data in combination with the NAMFIS results suggested that t...

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

“…Apart from their pharmacological use, β -lactams have been used as synthons in the preparation of various heterocyclic compounds of biological significance 17 . For example, suitably substituted hydroxyl β -lactam has been used in the semisynthesis of a side chain bridged paclitaxel 18 . Importantly, some β -lactam analogues were shown to cause apoptosis in cancer cells through induction of microtubule disorganization and mitotic catastrophe 19 , 20 .…”

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

“…24 In previous studies on bioactive small molecules binding to proteins, the bioactive, protein-bound conformation for flexible molecules has been located by NAMFIS as a minor constituent in solution. 19,23 In at least two cases, 37,38 synthetic manipulations to these minor conformations have led to an increase in potency, validating these conformations as possible bioactive entities. Similar synthetic modifications to the currently derived stevastelins structures may help shed light on their bioactive conformations and aid in the design of more active analogs.…”

β‐Lactam Preparation via Staudinger Reaction with Activated Dimethylsulfoxide

“…Other biological activity of 2‐azetidinones is also well documented, and they have been found to be useful in a variety of biological applications . Furthermore, the considerable variety of transformations related to the selective bond cleavage of the 2‐azetidinone core has suggested an interesting use of the β‐lactam skeleton as a synthon in organic synthesis and in the semisynthesis of taxol derivatives .…”