A common pharmacophore for cytotoxic natural products that stabilize microtubules

Abstract

Taxol (paclitaxel), a complex diterpene obtained from the Pacific yew, Taxus brevifolia, is arguably the most important new drug in cancer chemotherapy. The mechanism of cytotoxic action for paclitaxel-i.e., the stabilization of microtubules leading to mitotic arrest-is now shared by four recently identified natural products, eleutherobin, epothilones A and B, and discodermolide. Their ability to competitively inhibit [ 3 H]paclitaxel binding to microtubules strongly suggests the existence of a common binding site. Recently, we have developed nonaromatic analogues of paclitaxel that maintain high cytotoxicity and tubulin binding (e.g., nonataxel). We now propose a common pharmacophore that unites paclitaxel, nonataxel, the epothilones, eleutherobin, and discodermolide, and rationalizes the extensive structure-activity relationship data pertinent to these compounds. Insights from the common pharmacophore have enabled the development of a hybrid construct with demonstrated cytotoxic and tubulin-binding activity.

The bioactive Taxol conformation on β-tubulin: Experimental evidence from highly active constrained analogs

“…The second point follows, which is that the present results contrast sharply with those derived by bridging from either the C-3Ј phenyl (25,28,29) or the benzamido (26,30,31) side chain directions to the C-2 position of the baccatin core; cases in which the activity is either nonexistent or at best one-tenth that of Taxol. The fundamental reason for activity in the present series and its absence in other bridging schemes is related to the location of ␤-tubulin's His-227 in the taxoid binding pocket.…”

“…Examination of the computationally refined tubulin binding site illustrates that His-227 resides between these two rings. This accounts for the fact that previous attempts to bridge the C-2 and C-3Ј positions have delivered either inactive Taxol analogs (28) or compounds that are one or two orders of magnitude less active than Taxol itself (25,26,29,30,31). By contrast, inspection of T-Taxol reveals that the C-4 acetate methyl hydrogens are just 2.5-2.9 Å and 4.3-4.9 Å distant from the o-and m-hydrogens of the C-3Ј phenyl, respectively (Fig.…”

“…On the other hand, it can provide a conceptual model for the synthesis of simplified analogs that may well retain the full activity of the parent compound. Several experimental attempts to identify this conformation have been made by NMR measurement of internuclear distances within Taxol bound to microtubules (23,24), and by the synthesis of various conformationally restricted Taxol analogs (25)(26)(27)(28)(29)(30). In addition, studies have compared the conformations of Taxol and epothilone B by molecular modeling and other methods (29,(31)(32)(33).…”

“…Several experimental attempts to identify this conformation have been made by NMR measurement of internuclear distances within Taxol bound to microtubules (23,24), and by the synthesis of various conformationally restricted Taxol analogs (25)(26)(27)(28)(29)(30). In addition, studies have compared the conformations of Taxol and epothilone B by molecular modeling and other methods (29,(31)(32)(33). Separate investigations have proposed distinguishable conformations of the Taxol side chain, with a T-shaped conformation being favored on the basis of its fit with the election-density map of zinc-induced tubulin sheets (34,35).…”

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

“…2b) (27). More recently, during the processing of this manuscript, a pharmacophore model (28) and two studies using This paper was submitted directly (Track II) to the PNAS office.…”