Reversibility of protein synthesis inhibition by quassinoid antineoplastic agents in a rabbit reticulocyte system

Antineoplastic Agents and Their Analogues from Chinese Traditional Medicine

“…Protein biosynthesis of P-388 cells was blocked by these compounds at the elongation step by interfering with peptide bond formation (77). The same mechanism was also observed with 46 in a rabbit reticulocyte system (78,79). The 46-related quassinoids deserve further study as useful anticancer agents.…”

“…Naphthoquinone derivatives (77)(78)(79)(80) were prepared and exhibited superior cytotoxic activity to that of 76 (99).…”

Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity—implications for therapeutic targeting of Nrf2

“…An understanding of the mechanism(s) by which brusatol inhibits Nrf2 is critical to evaluating the benefit:risk ratio of the compound, and other Nrf2 inhibitors, in therapeutic contexts. We noted that brusatol and structurally related compounds have been shown previously to inhibit general protein synthesis at micromolar concentrations [17,18] . We also noted that, among the panel of proteins measured by Ren et al [12] in their recent report, only c-Myc, which has a relatively short half-life of 20–30 min, was depleted in response to brusatol, albeit to a lesser degree than Nrf2.…”

“…Although brusatol and structurally related compounds can serve as general protein synthesis inhibitors at micromolar concentrations [17,18] , the lack of effect of brusatol on the levels of other proteins [12] , including those with short (cyclin A, HIF-1α, p53, and survivin) and long (Keap1, p62, and actin) half-lives studied here, indicates that the depletion of Nrf2 provoked by nanomolar concentrations of brusatol is specific and not a consequence of a broader effect on protein synthesis. Previous work has demonstrated that brusatol is able to deplete Nrf2 in cancer cell lines harboring wild-type or mutated Keap1 [12] .…”

Antimalarial quassinoids: past, present and future

“…Bruceantin binds to the peptidyl transferase center on ribosomes, whereas the affinity for the compound on polysomes is much weaker (K d = 0.34 µM vs. 557 µM) [43] . Therefore, quassinoids are inhibitors of polypeptide chain elongation that prevent only the first round of peptide bond formation prior to polysome formation and the inhibition is reversible [42][43][44][45] . The environment of several nucleotides in the peptidyl transferase site is altered on bruceantin binding with ribosomes [46] , suggesting that the peptidyl transferase site is the binding site of quassinoids.…”