Design, synthesis and biological activity of protaxols

Abstract

Taxol is a product isolated from the Pacific yew tree (Taxus brevifolia) and is a potent microtubule-stabilizing agent which has recently been approved for treatment of otherwise intractable ovarian cancer. Despite taxol's therapeutic promise, its aqueous insolubility (< 0.004 mg ml-1) hampers its clinical application. Here we report the design, synthesis and biological activity of a series of taxol-releasing compounds (protaxols) with improved pharmacological properties. These prodrugs were designed to increase their aqueous solubility and allow for taxol release under basic or physiological conditions. We demonstrate the stability of these prodrugs at pH < or = 7 and their ability to release taxol in a basic medium. Taxol-like microtubule-stabilizing activity appears after the release of taxol. In vitro these prodrugs have cytotoxic properties against tumour cell lines comparable to those of taxol; moreover, human plasma catalyses the release of active taxol. These protaxols have greater potential as anticancer agents than the parent compounds taxol and taxotere (Fig. 1a).

The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Hyaluronic Acid as Drug Delivery System: Synthesis, Self-Assembled Property, Drug Release, and In Vitro Efficiency

“…Nicolaou (44) and co-workers synthesized a series of paclitaxel prodrugs and demonstrated that strong electron withdrawing substituent in the α-position of the paclitaxel ester may accelerate the hydrolytic cleavage of paclitaxel. Our previous work showed that direct ester bond between carrier and drug was difficult to hydrolyze.…”

A new diaryl urea compound, D181, induces cell cycle arrest in the G1 and M phases by targeting receptor tyrosine kinases and the microtubule skeleton

“…Because drugs that arrest the cell cycle in the M phase are mostly tubulin-targeting agents [22][23][24][25][26][27][28][29][30][31], we hypothesized that D181 might also target tubulin. Indeed, we found that D181 triggered rapid morphological changes in HepG2 cells (Fig.…”

“…The polymerizing or depolymerizing dynamics of microtubules play crucial roles in chromosomal division during mitosis and other normal cellular functions, such as cytokinesis and vesicular transport [19]. Disruption and interference of microtubule polymerization dynamics would induce mitotic catastrophe and would ultimately lead to cell death [20][21][22]. Therefore, microtubules have become wellcharacterized targets for many clinical anticancer drugs, including some natural cytotoxic products.…”

“…Natural products, such as the vinca alkaloids [23,24], cryptophycins [25] and colchicines [26], function as microtubule polymerization inhibitors by binding to the vinca site or the colchicine site on the tubulin heterodimer. Conversely, taxol, taxotere [22], epothilones [27] and discodermolide [28] are able to stimulate the polymerization and stabilization of microtubules. Recently, studies also reported that tubulin-binding agents significantly disrupted small blood vessel formation during tumorigenesis [29][30][31].…”

Chemistry, biology and medicine of selected tubulin polymerizing agents

“…Perhaps the most notable of the analogs we prepared was the pyridinium derivative 19 [22]. This molecule, a prodrug of taxol [23], exhibits far greater water solubility than the natural product which should allow for easier formulation, whilst retaining high activity.…”