Krystina Kuna

Histone deacetylase (HDAC) inhibitors with a novel connecting unit linker region reveal a selectivity profile for HDAC4 and HDAC5 with improved activity against chemoresistant cancer cells.

The synthesis and biological evaluation of new potent hydroxamate-based HDAC inhibitors with a novel alkoxyamide connecting unit linker region are described. Biological evaluation includes MTT and cellular HDAC assays on sensitive and chemoresistant cancer cell lines as well as HDAC profiling of selected compounds. Compound 19i (LMK235) (N-((6-(hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide) showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. Subsequent HDAC profiling yielded a novel HDAC isoform selectivity profile of 19i in comparison to vorinostat or trichostatin A (TSA). 19i shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range.

Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages

In this work we investigated the antiplasmodial activity of a series of HDAC inhibitors containing an alkoxyamide connecting-unit linker region. HDAC inhibitor 1a (LMK235), previously shown to be a novel and specific inhibitor of human HDAC4 and 5, was used as a starting point to rapidly construct a mini-library of HDAC inhibitors using a straightforward solid-phase supported synthesis. Several of these novel HDAC inhibitors were found to have potent in vitro activity against asexual stage Plasmodium falciparum malaria parasites. Representative compounds were shown to hyperacetylate P. falciparum histones and to inhibit deacetylase activity of recombinant PfHDAC1 and P. falciparum nuclear extracts. All compounds were also screened in vitro for activity against Plasmodium berghei exo-erythrocytic stages and selected compounds were further tested against late stage (IV and V) P. falciparum gametocytes. Of note, some compounds showed nanomolar activity against all three life cycle stages tested (asexual, exo-erythrocytic and gametocyte stages) and several compounds displayed significantly increased parasite selectivity compared to the reference HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). These data suggest that it may be possible to develop HDAC inhibitors that target multiple malaria parasite life cycle stages.

Synthesis, Antimalarial Properties, and SAR Studies of Alkoxyurea-Based HDAC Inhibitors

Histone deacetylase (HDAC) inhibitors are an emerging class of potential antimalarial drugs. We investigated the antiplasmodial properties of 16 alkoxyurea‐based HDAC inhibitors containing various cap and zinc binding groups (ZBGs). Ten compounds displayed sub‐micromolar activity against the 3D7 line of Plasmodium falciparum. Structure–activity relationship studies revealed that a hydroxamic acid ZBG is crucial for antiplasmodial activity, and that the introduction of bulky alkyl substituents to cap groups increases potency against asexual blood‐stage parasites. We also demonstrate that selected compounds cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs. To assess the selectivity of alkoxyurea‐based HDAC inhibitors for parasite over normal mammalian cells, the cytotoxicity of representative compounds was evaluated against neonatal foreskin fibroblast (NFF) cells. The most active compound, 6‐((3‐(4‐(tert‐butyl)phenyl)ureido)oxy)‐N‐hydroxyhexanamide (1 e, Pf3D7 IC50: 0.16 μM) was 31‐fold more toxic against the asexual blood stages than towards normal mammalian cells. Moreover, a subset of four structurally diverse HDAC inhibitors revealed moderate activity against late‐stage (IV–V) gametocytes.

Design, Synthesis, and Conformational Analysis of Trispyrimidonamides as α-Helix Mimetics

The straightforward synthesis of trispyrimidonamides as a new class of α-helix mimetics is reported. Because of the versatility of our synthetic protocol, a variety of side chains including aliphatic, basic, aromatic, and heteroaromatic residues were included. A comprehensive conformational analysis revealed that in polar solvents a trimeric compound adopts conformations that can lead to i, i + 4, i + 8, or i, i + 8 patterns of side chain orientation. This suggests that trispyrimidonamides could be promising α-helix mimetics to target hot spots that are distributed over a wider angular range of an α-helix interface than in the classical i, i + 4, i + 7 case.

Untersuchung zur 6-Hydroxyindol-Bildung bei der Nenitzescu-Reaktion, IV [1]. Cyclisierung von N-(Chinonylalkyl)enaminon-Derivaten, II [2] / Investigation on the Formation of 6-Hydroxyindole in the Nenitzescu Reaction, IV [1]. Cyclization of N-(Quinonylalkyl)enaminone Derivatives, II [2]

Quinonylmethylenaminones 5 and 6 are synthesized and cyclized to spiro compounds 7 and 8. Quinonylpropylenaminone 15 is made in the same way. Cyclization in acetic acid yields quinolines 11 and 12, in trifluoroacetic acid/trifluoroacetic anhydrid diacylenamine 16 is obtained. The product of 15 in perchloric acid is benzazocine 20. The structure of 20 is proven by X-ray analysis. The course of the reaction is discussed.