Histone Deacetylase And Microtubules As Targets For The Synthesis Of Releasable Conjugate Compounds
The rationale for the synthesis of the novel prodrugs described in the present study stems from the combination of two moieties, antimicrotubule agent and HDAC inhibitor, each affecting different cellular targets and able to act synergistically when released simultaneously inside the tumor cells. All the tested conjugates, prepared using various antimicrotubule agents, exhibited an appreciable reduction of the cytotoxic potency. The cellular/molecular basis of the disappointing result is unclear, because in vitro glutathione was able to promote the release of the drug moieties. A plausible explanation of this behaviour could be a inefficient release of the HDAC inhibitor as suggested by a delayed increase of the tubulin acetylation in cells treated with 24 (Fig. 3). In addition, since the acetylation of protein substrates by the HDAC inhibitory moiety is dose-dependent and an effective inhibition could be achieved at higher concentration ( 1 µM) than that released by the conjugate at the tested concentration ( 0.3 µM), it is likely that the intracellular level of the HDAC inhibitor is inadequate to produce the expected synergistic interaction. Alternatively, and perhaps concomitantly, a reduced tubulin interaction of the conjugate itself or of the released mercapto-acylated thiocolchicine could account for the lower potency as compared with free drug. This interpretation is consistent with the marked reduction ( 10 fold) of the potency of the paclitaxel conjugate 28. Indeed, substituents at the 2’-position are expected to impair drug-microtubule interactions. Finally, it should be noted that the large molecular size of the conjugates may impair their ability to penetrate cell membrane. Thus a low membrane permeability could contribute to the observed reduction of potency. If this is the case, antimicrotubule agents with lower molecular weight may be more appropriate in this approach. In spite of the reduction of the cytotoxic potency, we retain that the dynamics of the release of the conjugate compounds described in the present study have to be investigated in order to take out any possible suggestion that could be useful in the design of new anticancer compounds. At the same time, the therapeutic advantages of these conjugates should be documented by in vivo models.
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