Synthesis of a HDAC inhibitor–nanogold probe for cryo-EM visualization in class I HDAC co-repressor complexes

• Wiktoria A. Pytel,
• John W. R. Schwabe and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2026, 22, 480–485, doi:10.3762/bjoc.22.35

• LE1 7RH, UK 10.3762/bjoc.22.35 Abstract Class I histone deacetylases (HDACs 1–3) serve as catalytic subunits within seven multiprotein co-repressor complexes, each of which has distinct functions in the cell. We report the synthesis of a HDAC inhibitor–nanogold probe, derived from the class I HDAC

• synthesize a nanogold-conjugated HDAC inhibitor and evaluate its applicability in single-particle cryo-EM to unambiguously determine the positioning and orientation of the HDAC active site within the CoREST complex. Results and Discussion Design and synthesis of a HDAC inhibitor–nanogold probe For the basis

• of the HDAC inhibitor–nanogold probe we utilized the class I HDAC inhibitor CI-994 (Figure 1). CI-994 is an inhibitor of HDAC1–3 and it inhibits HDAC1-CoREST-LSD1, HDAC2-CoREST-LSD1, and HDAC3-SMRT complex with IC50 values of 0.53 µM, 0.62 µM, and 0.14 µM, respectively [14][15]. Additionally, CI-994

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

• Virginija Jakubkiene,
• Gabrielius Ernis Valiulis,
• Markus Schweipert,
• Asta Zubriene,
• Daumantas Matulis,
• Franz-Josef Meyer-Almes and
• Sigitas Tumkevicius

Beilstein J. Org. Chem. 2022, 18, 837–844, doi:10.3762/bjoc.18.84

• HDAC proteins, gives them good biological activity in inhibiting these proteins. To date, three HDAC inhibitor drugs containing this functional group in their structure have been approved [6][7] (Figure 1). However, the main disadvantage of many HDAC inhibitors is their low selectivity: most of them

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• , such as histone deacetylases. Keywords: chelated enolate; Claisen rearrangement; HDAC inhibitor; peptide; late stage modification; Introduction Among natural products, peptidic structures have entered the limelight due to their extraordinary biological activities [1]. Often found as secondary

• reactions. The chain length in 14 should generally be suitable for effective HDAC inhibition and the thioester moiety might act as a prodrug as described for the natural HDAC inhibitor largazole. Further investigations are currently in progress. Naturally occurring HDAC inhibitors. Naturally occurring HDAC

α,ß-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA

• Shital K. Chattopadhyay,
• Subhankar Ghosh,
• Sarita Sarkar and
• Kakali Bhadra

Beilstein J. Org. Chem. 2019, 15, 2524–2533, doi:10.3762/bjoc.15.245

• hydroxamic acid derivative belinostat (2) is also approved for the treatment of peripheral T-cell lymphoma (PTCL) [9]. On the other hand, trichostatin A (3), containing an α,ß-unsaturated hydroxamic acid unit is the best known HDAC inhibitor which shows antifungal activities [10][11]. Because of the

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• extended lifespan as compared to untreated animals [71]. Furthermore, astrogliosis and neuron loss in the lumbar spinal cord were attenuated with drug treatment [71], indicating that inhibition of HDACs was neuroprotective in ALS models. Yoo et al. [72] obtained similar results using the HDAC inhibitor

Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors

• Matthias G. J. Baud,
• Thomas Leiser,
• Vanessa Petrucci,
• Mekala Gunaratnam,
• Stephen Neidle,
• Franz-Josef Meyer-Almes and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2013, 9, 81–88, doi:10.3762/bjoc.9.11

• potent and isoform selective HDAC inhibitor. Here we report our preliminary studies on thioester HDAC inhibitors derived from the active monomeric (thiol) form of psammaplin A, as a means to improve compound delivery into cells. We have discovered that such compounds exhibit both potent cytotoxicity and

• represents the first example of a disulfide and oxime containing metabolite isolated from a marine sponge. Since its initial report by Crews and co-workers as a potent HDAC inhibitor [16], psammaplin A has provided inspiration for the development of new HDAC inhibitors with novel structures [19]. Recently

• standard incubation time of thioesters in our HDAC inhibitor assay is 20–30 minutes; however, no evidence of thiol formation was observed after up to 100 minutes of incubation in the assay buffer. This data therefore does not support the hydrolysis of our thioester inhibitors in the assay buffer. Two