Current Pharmaceutical Design - Volume 11, Issue 13, 2005

Epothilones A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at nM or even sub-nM concentrations. In contrast to paclitaxel (Taxol®) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo (epothilone B). Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and epothilone B is currently undergoing phase II clinical trials. Numerous synthetic and semi-synthetic analogs have been prepared since the absolute stereochemistry of epothilone B was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least four compounds (in addition to epothilone B), which are currently at various stages of clinical evaluation in humans. This review is first intended to provide a summary of the basic features of the in vitro biological profile of epothilone B, with particular emphasis on recent developments in this area. A second part will outline the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. This will include a brief discussion of research directed at the determination of the bioactive conformation of epothilones. In a final section, the preclinical profile of those epothilone analogs currently in clinical development will be discussed in greater detail.

The macrocylic polyketide class of compounds known as the epothilones has generated substantial interest over the last few years in the areas of chemistry, biology, and medicine due to their interesting structure and, more importantly, their activity against numerous cancer cell lines, including drug-resistant, especially Taxol®-resistant, cancer cell lines. To date, numerous total syntheses have been published, hundreds of epothilone analogues have been synthesized, and detailed structure activity relationship studies have been conducted. The purpose of this review is to give a brief summary of the latest advances made concerning the epothilones. Recent total or partial syntheses will be presented along with the syntheses of new epothilone analogues and their corresponding biological data. In addition, we will look at the current state of research into an economically viable method for the biosynthesis of the epothilones and related analogues.

The design of novel anticancer agents based on the combretastatins, a group of antimitotic agents isolated from the bark of the South African willow tree Combretum caffrum Kuntz, is of considerable contemporary interest. Combretastatin A-4, the most active compound in the group, due to its unique dual features of antitubulin and antivascular properties, has drawn significant attention of medicinal chemists for the design of analogues as novel antitumor agents. To date, 252 references have been published since 1982 and 187 references have been published since 1998 related to combretastatins research. The 102 references related to chemistry efforts can be classified into three different categories including one-atom, two-atom, and three-atom bridgeheads as linker between two aryl rings of combretastatins. This review will particularly elucidate the rationale and strategic tactics towards the development of novel classes of antimitotic agents, based upon combretastatin A-4 as a promising lead.

The development of combretastatin as an antimitotic agent has led to an enormous effort to design other tubulin-targeting agents. The intriguing discovery that combretastatin A-4 phosphate causes selective damage to tumor vasculature has stimulated even more activity in this field. This attention to tubulin binding agents and their antivasculature activity is highly likely to lead to significant clinical advances for the treatment of cancer. This review focuses on the development of ketones as tubulin-binding agents such as chalcones and related enones as surrogates of combretastatin and colchicine.

Podophyllotoxin is an antimitotic natural product. Its inhibitory activity on cell growth led to the development of the clinically valuable anticancer agents, etoposide, teniposide and the water-soluble prodrug, etoposide phosphate. The cytotoxic mechanism of these drugs is the inhibition of topoisomerase II, unlike the lead compound which inhibits mitosis. Through extensive structure-activity relationship studies, several potential drug candidates were synthesized such as GL-331, TOP 53, NK611, and azatoxin. Recently, more complex and diverse analogues have been synthesized either to get more potent compounds or to overcome drug resistance. At the same time, a number of prodrug approaches have been tried to enhance the tumor selectivity or to increase the aqueous solubility. The prodrugs can release cytotoxic etoposide through the actions of hydrolysis, enzymes or catalytic antibodies. More sophisticated prodrug strategies have been applied in etoposide and these produced some interesting results. In this review, the current research trends in the design of new derivatives will be covered with a brief introduction of podophyllotoxin and related analogues.

Natural product drugs that target the tubulin/microtubule system remain an important component in the therapeutic arsenal to treat many types of malignancies. Agents such as the taxanes and vinca alkaloids bind to β-tubulin and disrupt microtubule dynamics by inducing a potent mitotic block and subsequent cell death. Understanding why certain cancers do not respond to treatment or develop resistance has been the subject of numerous studies in recent years. An increasing body of evidence suggests that alterations in the drug target, such as tubulin mutations, altered microtubule dynamics, altered tubulin isotype expression, and modifications in microtubule regulatory proteins, are key mechanisms of antimicrotubule drug resistance. In addition, recent work indicates that other cytoskeletal proteins that can regulate microtubule dynamics through signaling or structural interactions may be important determinants of antimicrotubule resistance. As our understanding of drug action and resistance mechanisms has increased, we can now begin to exploit these to design strategies that overcome, or counteract resistance, hence improving the efficacy of antimicrotubule agents for the treatment of cancer. This review highlights the major areas of investigation as they relate to the tubulin/microtubule system and discusses opportunities that potentially exist for improved therapeutic benefit in the treatment of drug resistant disease.