Epothilone derivatives natural products

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

The epothilones 6 (and Fig. la), which are produced by So-rangium cellulosum, are mixed NRPS-polyketide derived natural products that possess potent antitumor activity. Interestingly,... 

The extraordinary biological activity of epothilones has spurred interest of scientists around the world. Indeed, several epothilones and many derivatives are currently in different phases of clinical trials for the treatment of various forms of cancer. Also the synthetic community has given a great deal of attention to these remarkable compounds, probably more than to any other compound in the last ten years. This is not very surprising, because in comparison to paclitaxel (which until recently was one of the main success stories of natural products research), the epothilones have a relatively simple structure, which allows easier modification, and they display higher in vitro activity as well as better pharmacokinetic properties. 

The first total syntheses of epothilones A and B were published by the groups of Danishefsky [49] and Nicolaou [83] only shortly after publication of the absolute stereochemistry of the natural products. Various other (formal) total syntheses followed, in which many different approaches and reaction types were used. Also, a variety of analogues was synthesized and even libraries were created [9, 84]. Several reviews on the properties and synthesis of epothilones and derivatives have been published [9-13]. 

The next task was to form the C2-C3 aldol bond stereoselectively. However, asymmetric coupling of acetate derivatives to aldehydes is often accompanied by poor / -induction [89]. Moreover, the C3-C4 bond is particularly sensitive to retro-aldol reaction, especially under basic conditions. In the natural products, this was observed to be the main decomposition reaction. The first total syntheses of epothilones circumvented this problem by constructing this part of the molecule in an indirect manner, e.g., by using reduced forms at Cl or C5. We decided to employ our chromium-Reformatsky methodology, which avoids these problems and allows the direct use of reagents in the correct oxidation state. The non-basic reaction conditions, the intermediacy of a chromium(III) aldolate that is resistant to retro-aldol reaction, and the potential of a direct asymmetric carboxymethyl ( acetate ) transfer favor the use of this method [90]. 

Natural products have been identified as the active principle of herbs and extracts used in folk medicine [1], The importance of natural products in the pharmaceutical industry has continued to the present day and is reflected by the fact that close to half of the best selling pharmaceuticals are either natural products (e.g. cyclosporine, Taxol, FK 506) or derivatives thereof [3]. In high throughput screening processes performed by the pharmaceutical industry natural product extracts exhibit a hit rate which is estimated to be substantially higher than the hit rate of random libraries from combinatorial chemistry. Natural products such as epothilones, discodermolide or ecteinascidin are promising clinical candidates for future cancer treatment. 

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of Epothilones and Polyether Natural Products. 1 73-104 Normant JF (2003) Enantioselective Carbolithiations. 5 287-310 Norton JR see Cummings SA (2005) 10 1-39... 

This type of tubulin activity has so far been exclusively found in the four above-mentioned natural products and some derivatives, although far more then 140000 synthetic compounds and extracts have been tested. Of these four compounds, epothilones appear to be the best candidates. They are equally or even more active, e.g. up to 35 000 times better then Taxol in resistant cell lines [2]. They also have better cytotoxic potential connected to the tubulin activity, as not all microtubule stabilizers lead to sufficient cell death, and they allow extensive derivatization much faster then Taxol or discodermolide [3, 4]. Also, improvements in the applicability to patients compared to the sparingly soluble Taxol arc expected, eliminating some of the severe side effects connected to the latter drug. Since the binding sites of Taxol and epothilones overlap, epitope comparisons and models of binding... 

While there are many natural products that are either NRPS or PKS derived, there are multidomain megasynthases that contain both NRPS and PKS biosynthetic features. Examples of such biosynthetic motifs are epothilone, jamaicamide, and the endiyne C-1027.33-35 At NRPS-PKS interfaces in these systems, the condensation of malonyl takes place with an amino acid that was activated by an A domain. Alternatively, an amino acid loaded on a T domain condenses with an elongating polyketide. Since the substrates and intermediates in NRPS, PKS, or hybrid NRPS/PKS biosynthesis introduce mass changes on T domains, they are ideal candidates for investigation by MS. 

The use of natural products from microbes in cancer is extremely well described in a series of chapters in a recent book so we will not be describing any of the classes covered in that compendium except for an update on the epothilones and the halichondrin B-derived E7389. Instead, we will show how over the past few years, the actual source(s) of many agents in clinical use, in clinical trials, or in preclinical investigations directed toward clinical trials, are now thought to involve microbes of one type or another, rather than to be solely the product of the organism(s) from which they were first isolated and identified. We will describe selected compounds demonstrating some directly from microbes, some now known to be from microbes, and some where microbes could well be involved. 

Thiazine containing alkaloids are relatively rare in Nature, but they range in structural complexity from simple monocyclic derivatives such as chondrine and benzothiazines such as the aplidinones, to more complex tri- and polycyclic compounds exemplified by ansafhiazin and the shermilamines. On the other hand, the simplest N,S-heterocycle - the 5-membered thiazole - is relatively common in Nature, and, for example, plays a vital role in the function of thiamine (vitamin Bi). Thiazole rings also occur in important biologically active natural products such as the epothilones (Figure 1). 

Aza-epothilone 1 (( )-(25,95,7 0f ,77f ,745)-10,14-dihydroxy-9,l 1,13,13-tetramethyl-2-[2-(l,2-dimethyl-benzimidazol-5-yl]-12,16-dioxo-l-oxa-5-aza-cyclo-hexadecane-5-carboxylic acid tert-butylester) and its 7,8-dehydro analogue 2 are potent inhibitors of human cancer cell growth, and represent a structurally new class of natural product-derived microtubule-stabilizing agents. 

On the basis of these data, epothilones A, B and some congeners have been widely pursued as lead structures for the development of a new generation of non-taxane-derived microtubule stabilizers for cancer treatment [5]. Five representatives of this class are currently undergoing clinical evaluation in humans. This outcome confirms the view that natural products provide a vast pool of potential lead structures for drug discovery. In a very general sense, the strategy that resulted in 12-aza-epothilones could be viewed as the synthesis-based equivalent to the discovery of a new natural product with a specific biological activity. 

The clinical success of Paclitaxel has stimulated research into compounds with similar modes of action with antineoplastic efficacy while minimizing its less desirable properties, such as water insolubility, difficult synthesis, and emerging resistance. The epothilones are a novel class of natural product cytotoxic compounds derived from the fermentation of the Sorangium cellulosum, which are non-taxane microtubule-stabilizing compounds that trigger apoptosis [182-189]. The natural product epothilone B 144 (Figure 4.39) has demonstrated broad-spectrum antitumor activity... 

The third chapter of the volume describes the in vitro and in vivo activity of the natural occurring microtubule stabilizer epothilone B and its analogs. This macrocyclic natural product has been the subject of extensive medicinal chemistry research and numerous derivatives have been studied pre-clinically and clinically for oncology indications. One such compound, ixabepilone (BMS-247550 Ixempra ) was approved by the FDA in 2007 for the treatment of breast cancer. 

Attempts have been made to assess the validity of the various models by designing bridged epothilone analogs (Figure 3.13), which on the basis of the EC-derived model were anticipated to retain good activity (or even to show enhanced activity over the natural products). However, such compounds proved to be only poorly active. ... 

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