Comprehensive analysis of resorcinyl-imidazole Hsp90 inhibitor design.

Human Hsp90 chaperones are implicated in various aspects of cancer. Due to this, Hsp90 has been explored as potential target in cancer treatment. Initial attempts to use Hsp90 inhibitors in drug trials failed due to toxicity and inefficacy. The next generation of drugs were less toxic but still insufficiently effective in a clinical setting. Recently, a lot of effort is being put into understanding the consequences of Hsp90 isoform selective inhibition, expecting that this might hold the key in targeting Hsp90 for disease treatment. Here we investigate a series of compounds containing the aryl-resorcinol scaffold with a 5-membered ring as a promising class of new human Hsp90 inhibitors, reaching nanomolar affinity. We compare how the replacement of 5-membered ring, from thiadiazole to imidazole, as well as a variety of their substituents, influences the potency of these inhibitors for Hsp90 alpha and beta isoforms. To further elucidate the dissimilarity in ligand selectivity between the isoforms, a mutant protein was constructed and tested against the ligand library. In addition, we performed a series of molecular dynamics (MD) and docking simulations to further explain our experimental findings as well as evaluated key compounds in cell assays. Our results deepen the understanding of Hsp90 isoform ligand selectivity and serve as an informative base for further Hsp90 inhibitor optimization.

Improving the Hsp90 Inhibitors Containing 4-(2,4-Dihydroxyphenyl)-1,2,3-thiadiazole Scaffold: Synthesis, Affinity and Effect on Cancer Cells.

BACKGROUND: Human Hsp90 chaperone inhibitors are known to be potential anticancer drugs. Previously we have shown a couple of 5-aryl-4-(2,4-dihydroxyphenyl)-1,2,3-thiadiazoles to be promising anticancer agents. OBJECTIVE: To improve the compounds containing 4-(2,4-dihydroxyphenyl)-1,2,3-thiadiazole scaffold as human Hsp90 inhibitors. METHOD: We employed chemical synthesis to obtain new compounds and assayed their binding to Hsp90 using the fluorescence thermal shift assay and used MTT assays to determine their effect on cancer cells. RESULTS: A series of compounds containing the 4-(2,4-dihydroxyphenyl)-1,2,3-thiadiazole scaffold were synthesized as Hsp90 inhibitors. Analysis of their binding to the recombinant N-terminal domain of Hsp90 revealed that four of these compounds bound to Hsp90 with Kd of 0.6 to 0.8 nM. The compounds fully inhibited the growth of all tested cancer cell lines: A549 (lung adenocarcinoma), IGR39 (melanoma), and U87 (glioblastoma), with the effective antiproliferative concentration (EC50) of the compounds reaching 0.35 µM. CONCLUSION: This series of 14 novel and efficient Hsp90 inhibitors provided additional information on the structure-activity relationship of Hsp90 inhibitors and may be further developed into drugs targeting Hsp90.

Synthesis and antiproliferative activity of α-branched α,ß-unsaturated ketones in human hematological and solid cancer cell lines.

A series of α-branched α,ß-unsaturated ketones were prepared via boron trifluoride etherate mediated reaction between arylalkynes and carboxaldehydes. The evaluation of the antiproliferative activity over hematological (NB4) and solid cancer (A549, MCF-7) cell lines provided a structure-activity relationship. 5-Parameter QSAR equations were built which were able to explain 80%-92% of the variance in activity. The resulting selective lead compound showed IC50 value 0.6 µM against the hematological cell line and did not cause apoptosis, but blocked cell cycle in G0/G1. Moreover, it was demonstrated that this compound enhances and accelerates retinoic acid induced granulocytic differentiation.

Effect of 1-acyl-5,6-dialkoxy-2-alkylthiobenzo[d] imidazoles on the action potential duration and isometric contraction in guinea pig atrium activated by carbachol and in guinea pig heart papillary muscles.

BACKGROUND: Studies have shown that some benzo[d]imidazole derivatives (1-(5,6-dimethoxy-2-methylthio-1H-benzo[d]imidazol-1-yl)-1-ethanone (1), 1-(6-ethylthio-5H[1,31dioxolo[4',5':4,5] benzo[d]imidazol-5-yl)-1-propanone (2), 1-(2-ethylthio-6,7-dihydro-1H[1,4]dioxino [2:3':4,5]benzo[d]imidazol-1-yl)-1-pro-panone (3) and 2,3,9,10-tetrahydro-8H [1,4]dioxino[2' 3":4',5']benzo[4,5]imid-azo[2,1-b][1,3]thiazin-10-one (4)) possess strong cardiotonic activity. The goal of this study was to investigate the effect of compounds 1-4 on the action potential (AP) duration and contractile force in guinea pig atrium activated by carbachol and in guinea pig heart papillary muscles. METHODS: The experiments were carried out on the guinea pig papillary muscles and atrium. Isometric contraction and transmembrane potential were recorded using a force transducer and standard microelectrode technique. RESULTS: Compounds 1-4 exerted a positive inotropic effect in a dose-dependent manner on the electrically driven left atrium and papillary muscles, more pronounced in atrium. In response to 1 micromol/L carbachol the AP duration at a 90 % repolarization in atrium shortened more than 70 %, the isometric contraction decreased to the similar level as well. Compounds 1 and 4 significantly antagonized the shortening of the AP duration induced by carbachol and increased it. Compound 1 abolished the reduction of isometric contraction as well. Derivative 3 significantly lengthened (31 ms) the AP duration at a 90 % repolarization in papillary muscles, while 1 and 4 failed to affect this index. The selective blockade of the rapid component of the delayed rectifier potassium current (Ikr) by dl-sotalol (1 micromol/L) did not show the substantial influence on benzimidazole effects. CONCLUSION: These findings support the hypothesis that the tested benzo[d] imidazole derivatives abolish the influence of carbachol on AP and the isometric contraction by inhibition of acetylcholine-activated potassium current (KACh) in guinea pig atrial myocytes and therefore may be beneficial for the prognosis of patients with advanced heart failure and atrial fibrillation.