Modified Cap Group Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitor Derivatives Reveal Improved Selective Antileukemic Activity

Abstract

A series of SAHA cap derivatives was designed and prepared in good-to-excellent yields that varied from 49% to 95%. These derivatives were evaluated for their antiproliferative activity in several human cancer cell lines. Antiproliferative activity was observed for concentrations varying from 0.12 to >100 μM, and a molecular modeling approach of selected SAHA derivatives, based on available structural information of human HDAC8 in complex with SAHA, was performed. Strikingly, two compounds displayed up to 10-fold improved antileukemic activity with respect to SAHA; however, these compounds displayed antiproliferative activity similar to SAHA when assayed against solid tumorderived cell lines. A 10-fold improvement in the leukemic vs peripheral blood mononuclear cell therapeutic ratio, with no evident in vivo toxicity toward blood cells, was also observed. The hereindescribed compounds and method of synthesis will provide invaluable tools to investigate the molecular mechanism responsible for the reported selectively improved antileukemic activity.

The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer

“…This value is similar to those experimentally obtained for [ 18 F]-FAHA (1.39) and SAHA (1.04) and those simulated for other SAHA analogs bearing aniline ring substitutions (generally 1.0–2.0). [33, 43, 52]…”

“…While FESAHA’s fluoroethyl appendage may appear structurally trivial at first glance, it is important to note that other seemingly innocuous modifications made to the SAHA core structure have rendered the resultant inhibitors orders of magnitude less active in both HDAC inhibition and anti-proliferation assays. [33, 36, 46, 52] Thus, the in vitro success of FESAHA serves as an important reminder of two critical principles in the design of radiotracers that are based on known drugs: (1) be mindful when designing the attachment of the radionuclide to the parent molecule and (2) even if the modification seems harmless, perform assays comparing the biochemical behavior of the unlabeled daughter molecule to that of the parent. In this case, by studying published structure-activity relationships and performing some rudimentary molecular modeling, a modification strategy was chosen that interfered only minimally, if at all, with the HDAC inhibition and anti-proliferative activity of the parent molecule.…”

“…Overall, the crystal structure suggests that aniline ring of the inhibitor, while undoubtedly involved in interactions with the hydrophobic shell of the protein, seems to play a less significant role in the molecular recognition of SAHA than the other two structural moieties, an assertion supported by structure-activity relationships delineated by other researchers. [33–36]…”

An Environmentally Sustainable Mechanochemical Route to Hydroxamic Acid Derivatives

“…N 1 , N 8 ‐Dihydroxyoctanediamide (29) : White solid; yield: 144 mg (71%); mp 163–164 °C (Lit . 164 °C).…”

Novel 64Cu-Labeled CUDC-101 for in Vivo PET Imaging of Histone Deacetylases

“…22,23 As a member of hydroxamates HDACi, CUDC-101 has the distinguishing characteristics including a hydroxamic acid group interacting with zinc at the active site of HDACs to interfere with enzyme activity, carbon linker, and capping group. 24 The capping group is solvent-exposed and interacts with amino acids near the entrance of the active site. 25,26 In this study, chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA, Macrocyclics, TX) was conjugated to CUDC-101 with a hydrophobic carbon chain linker by click reaction.…”