Histone deacetylase and microtubules as targets for the synthesis of releasable conjugate compounds

Abstract

Design and synthesis of an HDAC inhibitor and its merger with three tubulin binders to create releasable conjugate compounds is described. The biological evaluation includes: (a) in vitro reactivity with glutathione, (b) antiproliferative activity, (c) cell cycle analysis and (d) quantification of protein acetylation. The cellular pharmacology study indicated that the HDAC-inhibitor-drug conjugates retained antimitotic and proapoptotic activity with a reduced potency.

Synthesis of Thicolchicine‐Based Conjugates: Investigation towards Bivalent Tubulin/Microtubules Binders

“…Bifunctional drugs, bearing chemical entities that are able to bind to separate sites of the protein, recently attracted the attention of the scientific community, thanks to their possible great pharmacological potential. The idea of conjugating different MTs binders into bivalent entities led to the obtainment of novel antimitotic agents, including taxoid‐colchicine, vinca alkaloid‐taxoid hybrids, colchicine−tubulizine, colchicine‐pironetin, podophyllotoxin‐thiocolchicine and hybrids merging histone deacetylase inhibitors with different tubulin binders ,. On one hand the use of too short or rigid linkers prevents the interaction with the desired binding site and leads to steric clashes.…”

“…The idea of conjugating different MTs binders into bivalent entities led to the obtainment of novel antimitotic agents, including taxoid-colchicine, [5] vinca alkaloid-taxoid hybrids, [6] colchicineÀ tubulizine, [7] colchicine-pironetin, [8] podophyllotoxin-thiocolchicine and hybrids merging histone deacetylase inhibitors with different tubulin binders. [9,10] On one hand the use of too short or rigid linkers prevents the interaction with the desired binding site and leads to steric clashes. On the other hand, the use of a too long and flexible linker may lead to solubility and cell internalization problems.…”

Stereochemistry and complete 1H and 13C NMR signal assignment of C‐20‐oxime derivatives of posterone 2,3‐acetonide in solution state

“…In our previous work, we applied two different types of linkers: one only with CH 2 units and another with S―S disulfide bridge in the middle of this unit. This last one was found rather advantageous to release the drug molecules from a prodrug form mainly in the inner environment of cancer cells . As part of a research program aiming to prepare and study such compounds from certain ecdysteroids, we turned our attention towards the 20‐oxime of poststerone 2,3‐acetonide, a potentially strong antitumor ecdysteroid derivative, and its conjugates with long lipophilic side‐chains.…”

Perspectives in the development of hybrid bifunctional antitumour agents

“…However, the mechanism of interaction appears to be complex and likely involves modulation of protective factors [46]. Based on the evidence of synergistic interaction, antimicrotubule agents have been conjugated with a HDAC inhibitor through a disulfide linker to allow thiol-mediated release of the two moieties inside the cell [47]. In spite of the rational design, these compounds were characterized by a reduction of the cytotoxic potency.…”