Epothilones modifications

Formally, the N-atom of azithromycin is inserted into the macrolide ring of erythromycin, and the carbonyl group is reduced to methylene. In contrast, in 12-aza-epothilones, the C12 atom in natural epothilones is replaced by an N-atom, and epoxide oxygen is reduced. While the first substantial alteration of the macrolactone ring was achieved in a few steps firom erythromycin, the second epothilone modification cannot be made with compoxmds from the natural pool, and required total synthesis of the target stmctures. 

First we consider the acyl sector of the epothilones, which proved to be intolerant of modification. For example, inversion of stereochemistry at C3 (S toR), or reduction at C5 results in serious arrest of activity. Analogs with functionality at C3, C5, C6, C7 and C8 removed demonstrate both diminished tubulin-binding activity and cytotoxidty (structures not shown). Ddetion of the single methyl group at C8 has a highly pronounced deleterious effect on activity. Removal of the C9 methylene group resulting in a 15-membered macrolide, 87, results in a major loss of activity in tubulin polymerization/depolymerization assays. 

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. 

Fig. 7 Scheme of the structures of epothilone analogues studied in [36], the chemical differences between them, and the effect of these modifications in the free energy of binding to their site in microtubules at 35°C. Taken from [36]... 

Fig. 15 Favorable modifications of Quadrant II atoms, a trans cyclopropyl analog (7) is shown with mesh Connally surface over the 8-11 section. The Cl2 methyl directed toward solvent explains why such substitutions have little effect on this framework s binding, b The rigidified 10-11 of (8) is associated with good potency, c Compound (9), Fludelone, is one of the most active epothilones tested. The trifloromethane at C12 has excellent complementarity shown as a translucent surface. The trans double bond at 9-10 rigidities the contact relationships with the protein at C12-C13 and C8...

As for other modifications in the Northern part of the epothilone macrocycle, the replacement of CIO by oxygen has recently been shown to be detrimental for biological activity, " whereas the incorporation of a furan moiety incorporating C8, C9, and CIO seems to be better tolerated. ... 

A large part of the early SAR work on epothilones has focused on modifications of the epoxide moiety at positions 12/13 of the macrolactone ring. These studies have demonstrateded that the presence of the epoxide ring is not an indispensible prerequisite for efficient microtubule stabilization and potent antiproliferative activity. Thus, Epo C (10) and D (11) (Figure 1-1) are virtually equipotent inducers of tubulin polymerization as Epo A and B, respectively. They are also potent inhibitors... 

A convergent strategy was chosen, which allows the introduction of modifications at nearly every position of the macrolactone. During the research more than 350 active epothilone analogues were synthesized and it was found that the side chains at C-15 and C-6 are responsible for the tolerability and efficacy. ... 

End, N., Bold, G., Caravatti, G., Wartmann, M., Altmann, K.-H., Synthetic epothilone analogs with modifications in the northern hemisphere and the heterocyclic side-chain-synthesis and biological evaluation. Proceedings of ECSOC-4, Sept. 1-30, 2000, http //www.mdpi.org/ecsoc-4.htm. 

From a totally synthetic aspect, another group has introduced a very interesting molecule that is now in Phase II clinical trials with Schering AG. This is the molecule known as ZK-EPO (Figure 8.11), which for a number of years did not have a published structure. In 2006, the full rationale for and synthetic methods employed were pubhshed for this molecule, which is a modification of epothilone B with a benzothiazole in place of the thiazole on the Western side (effectively a ring-closure of the pendant thiazole in epothilone B), and the substitution of an allyl group for the methyl on the Eastern side of epothilone B. Although these... 

With the identification of the myxobacterial products epothilones A and B (64, 65 Figure 12) as tubulin stabilizers (a similar mechanism to that of paclitaxel) by Bollag et in 1995 came a veritable avalanche of modifications of the base structure by chemical, biochemical, and even genomic means in order to further explore the utility of the base skeleton. This culminated in the approval in October 2007 by the FDA of the semisynthetic epothilone, 16-aza-epothilone B, known genetically as ixabepilone (66, Figure 12 Ixempra) for treatment of breast cancer. 

Owing to the clinical importance of several epothilones, and considering the tolerance shown by several modules of the epothilone PKS to substrate modification, several reports appeared on the manipulation of the epothilone PKS to produce potentially superior epothilone analogs. Thus, a system was developed that comprised of modules 6-9 of the epothilone synthetase for the precursor-directed biosynthesis of epothilones in E. coli, and the ability of the crucial first module in this engineered pathway, EpoDM6, to accept, elongate, and process unnatural substrates was... 

In a novel strategy for the construction of natural product-based libraries by combinatorial chemical synthesis of hybrid structures, chiral building blocks obtained by selective chemical fragmentation and further modification of epothilone A and other myxobacterial natural products (soraphen A, sorangicin A, myxothiazol A and Z, apicularen A), were recombined on solid-phase support via a... 

Synthetic highlights Natural macrocycUc compounds have been subjected to both extensive and peripheral structural modifications in the search for new lead compounds. An example of the former is the antibiotic azithromycin, whereas 12-aza-epothilones must be approached by total synthesis. This total synthesis of epothilones involves ring closure metathesis using heteroleptic complexes as catalysts and has proved to be an efficient approach to non-natural, macrocyclic natural products . In one of the critical steps of this pathway to azathilones, creative site-selective diimide reduction of an allylic C=C bond was applied. 

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