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</i>, <i>i</i> + 4, <i>i</i> + 8, or <i>i</i>, <i>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</i>, <i>i</i> + 4, <i>i</i> + 7 case

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 <b>19i</b> (LMK235) (<i>N</i>-((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 <b>19i</b> in comparison to vorinostat or trichostatin A (TSA). <b>19i</b> shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range

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</i>, <i>i</i> + 4, <i>i</i> + 8, or <i>i</i>, <i>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</i>, <i>i</i> + 4, <i>i</i> + 7 case

α-Substituted β-Oxa Isosteres of Fosmidomycin: Synthesis and Biological Evaluation

Specific inhibition of enzymes of the non-mevalonate pathway is a promising strategy for the development of novel antiplasmodial drugs. α-Aryl-substituted β-oxa isosteres of fosmidomycin with a reverse orientation of the hydroxamic acid group were synthesized and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of Plasmodium falciparum and for their <i>in vitro</i> antiplasmodial activity against chloroquine-sensitive and resistant strains of P. falciparum. The most active derivative inhibits IspC protein of P. falciparum (<i>Pf</i>IspC) with an IC₅₀ value of 12 nM and shows potent <i>in vitro</i> antiplasmodial activity. In addition, lipophilic ester prodrugs demonstrated improved P. falciparum growth inhibition <i>in vitro</i>

Additional file 10: of Effects of novel HDAC inhibitors on urothelial carcinoma cells

Figure S7. Effects of treatment with 19i on primary normal urothelial cells using High Content Analysis-based fluorescent live/dead assay. Percentage of control cell counts of primary urothelial cells (culture # UP281) after 72 h treatment with TMP269 using High Content Analysis-based fluorescent live/dead assay. Data shown are mean from n = 3. (JPG 1137 kb

Binding Modes of Reverse Fosmidomycin Analogs toward the Antimalarial Target IspC

1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodium falciparum (<i>Pf</i>IspC, <i>Pf</i>Dxr), believed to be the rate-limiting enzyme of the nonmevalonate pathway of isoprenoid biosynthesis (MEP pathway), is a clinically validated antimalarial target. The enzyme is efficiently inhibited by the natural product fosmidomycin. To gain new insights into the structure activity relationships of reverse fosmidomycin analogs, several reverse analogs of fosmidomycin were synthesized and biologically evaluated. The 4-methoxyphenyl substituted derivative <b>2c</b> showed potent inhibition of <i>Pf</i>IspC as well as of P. falciparum growth and was more than one order of magnitude more active than fosmidomycin. The binding modes of three new derivatives in complex with <i>Pf</i>IspC, reduced nicotinamide adenine dinucleotide phosphate, and Mg²⁺ were determined by X-ray structure analysis. Notably, <i>Pf</i>IspC selectively binds the <i>S</i>-enantiomers of the study compounds

Additional file 1: of Effects of novel HDAC inhibitors on urothelial carcinoma cells

Figure S1. Lentiviral vector used for HDAC4 overexpression. (JPG 2487 kb

Additional file 3 of Effects of novel HDAC inhibitors on urothelial carcinoma cells

Table S2. Antibodies and conditions used for Western blotting. (DOCX 15 kb

Additional file 2: of Effects of novel HDAC inhibitors on urothelial carcinoma cells

Table S1. Primers used for PCR. (DOCX 21 kb

Additional file 7: of Effects of novel HDAC inhibitors on urothelial carcinoma cells

Figure S5. Expression of HDAC1, HDAC2 and HDAC6 mRNA following treatment of UCCs with 19i or SAHA. Effects of 24 and 48 h treatment with 19i (2 μM), SAHA (2.5 μM) or DMSO as solvent control on mRNA expression of HDAC1, HDAC2 and HDAC6 in VM-CUB1, UM-UC-3 and 639-V cells. All values indicate relative expression compared to a standard for each gene, adjusted to TBP as a reference gene and set as 1 for the solvent control. Significance levels likewise refer to the solvent control (* = p < 0.05). Data shown are mean from n = 3. (PDF 105 kb