Epothilones as Lead Structures for the Synthesis-Based Discovery of New Chemotypes for Microtubule Stabilization

Abstract

Epothilones are macrocyclic bacterial natural products with potent microtubule-stabilizing and antiproliferative activity. They have served as successful lead structures for the development of several clinical candidates for anticancer therapy. However, the structural diversity of this group of clinical compounds is rather limited, as their structures show little divergence from the original natural product leads. Our own research has explored the question of whether epothilones can serve as a basis for the development of new structural scaffolds, or chemotypes, for microtubule stabilization that might serve as a basis for the discovery of new generations of anticancer drugs. We have elaborated a series of epothilone-derived macrolactones whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of a conformationally constrained side chain, the removal of the C3-hydroxyl group, and the replacement of C12 with nitrogen. So far, this approach has yielded analogs 30 and 40 that are the most advanced, the most rigorously modified, structures, both of which are potent antiproliferative agents with low nanomolar activity against several human cancer cell lines in vitro. The synthesis was achieved through a macrolactone-based strategy or a high-yielding RCM reaction. The 12-aza-epothilone ("azathilone" 40) may be considered a "non-natural" natural product that still retains most of the overall structural characteristics of a true natural product but is structurally unique, because it lies outside of the general scope of Nature's biosynthetic machinery for polyketide synthesis. Like natural epothilones, both 30 and 40 promote tubulin polymerization in vitro and at the cellular level induce cell cycle arrest in mitosis. These facts indicate that cancer cell growth inhibition by these compounds is based on the same mechanistic underpinnings as those for natural epothilones. Interestingly, the 9,10-dehydro analog of 40 is significantly less active than the saturated parent compound, which is contrary to observations for natural epothilones B or D. This may point to differences in the bioactive conformations of N-acyl-12-aza-epothilones like 40 and natural epothilones. In light of their distinct structural features, combined with an epothilone-like (and taxol-like) in vitro biological profile, 30 and 40 can be considered as representative examples of new chemotypes for microtubule stabilization. As such, they may offer the same potential for pharmacological differentiation from the original epothilone leads as various newly discovered microtubule-stabilizing natural products with macrolactone structures, such as laulimalide, peloruside, or dictyostatin.

The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR

“…Many of these compounds are potent antitumor drugs and several have found wide use in the clinic, like the MT-destabilizing Vinca alkaloids or the MT-stabilizing taxanes ( Fig. 1 ) Paclitaxel (PTX) and Docetaxel (DTX), while others, like the epothilones, are in the advanced stages of clinical trials [1][2][3] .…”

“…Known MT-destabilizing agents bind either to the colchicine or to the vinblastine binding sites. There are drugs representative of the three groups undergoing clinical trials, alone or in combination with others, for a number of therapeutic uses [1][2][3] . In addition, other binding sites have been proposed for novel classes of compounds, like those for the MT-stabilizers laulimalide and peloruside A [14][15][16][17] , tryprostatin A [18] or estramustine [19,20] .…”

Novel microtubule-targeting agents – the epothilones

“…The ability to modify the chemical structure also allows the solubility and stability of the agent to be adjusted for human use. In addition, the structure allows modifi cations that signifi cantly differ from the parent compound and yet allow the resulting compounds to remain tubulin binders (Feyen et al 2008). At present, epothilone D is not being actively clinically investigated.…”

A Systematic Review on Antitumor Agents with 1, 3, 5-triazines

“…It is utmost important to development of novel anticancer drugs and more effective treatment strategies for cancer as traditionally prescribed chemotherapeutic agents have problems with toxicity and drug resistance [149]. Despite the fact that, many kinase inhibitors have been discovered recently and some of them have been successfully developed for cancer therapy still there is urgent demand for discovery of improved cytotoxic agents.…”