Abstract
12-Aza-epothilones (azathilones) incorporating quinoline side chains and bearing different N12-substituents have been synthesized via highly efficient RCM-based macrocyclizations. Quinoline-based azathilones with the side chain N-atom in the meta-position to the C15 atom in the macrocycle are highly potent inhibitors of cancer cell growth in vitro. In contrast, shifting the quinoline nitrogen to the position para to C15 leads to a ca. 1000-fold loss in potency. Likewise, the desaturation of the C9-C10 bond in the macrocycle to an E double bond produces a substantial reduction in antiproliferative activity. This is in stark contrast to the effect exerted by the same modification in the natural epothilone macrocycle. The conformation of a representative azathilone bound to α/β-tubulin heterodimers was determined based on TR-NOE measurements and a model for the posture of the compound in its binding site on β-tubulin was deduced through a combination of STD measurements and CORCEMA-ST calculations. The tubulin-bound, bioactive conformation of azathilones was found to be overall similar to that of epothilones A and B.
Highlights
Epothilones A and B (Figure 1) are the major representatives of a larger family of natural products that were first isolated from the myxobacterium Sorangium cellulosum by Reichenbach andHöfle in 1987 [1,2]
Analog 1, like urethane-based azathilones, appeared to be less susceptible to Pgp-mediated drug efflux than the other urethane-based azathilones, appeared to be less susceptible to Pgp-mediated drug efflux than corresponding amides. Building on these early findings we explored if the potency of 1 could the corresponding amides. Building on these early findings we explored if the potency of 1 could be improved by the replacement of the natural thiazolyl-vinyl side chain by a dimethylbenzimidazole be improved by the replacement of the natural thiazolyl-vinyl side chain by a dimethylbenzimidazole moiety (Figure 1, analog 2) [16], a modification which we had previously shown to lead to enhanced antiproliferative activity for polyketide-based epothilone analogs [23,24,25]
Intriguing is the fact that the in potency [16]; this is fundamentally different from the effect observed for the same modification in desaturation of the C9-C10 bond in 1 or 2 to a trans double bond is associated with a profound loss epothilone analogs that are based on a regular polyketide-derived macrolactone ring [14,26,27]
Summary
Epothilones A and B (Figure 1) are the major representatives of a larger family of natural products that were first isolated from the myxobacterium Sorangium cellulosum by Reichenbach and. In order to address this issue, we have candidates is rather limited, which could restrict the potential for pharmacological differentiation extensively investigated a number wethis have termed hypermodified analogs, i.e., between these compounds. In orderof towhat address issue, we have extensivelyepothilone investigated a number analogs are of termed only limited structural similarity with the original natural that products. Partpolyketide of these studies had throughout [12,13,14], more focused on structures where carbon 12 [12,13,14], has beenour replaced targeted analogs thatour were stillrecent basedwork on ahas regular polyketide backbone throughout more by an work acylated atom, leading to 12-aza-epothilones or azathilones [15,16,17].
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