Bulkier Compounds Research Articles

Styryl dyes with N-Methylpiperazine and N-Phenylpiperazine Functionality: AT-DNA and G-quadruplex binding ligands and theranostic agents

New monomethine, unsymmetrical styryl dyes consisting of benzothiazole and N-methylpiperazine or N-phenylpiperazine scaffolds were synthesized, and their binding affinities for different ds-polynucleotides and G-quadruplex were studied. Substitution of piperazine unit with methyl or phenyl group strongly influenced their binding modes, binding affinities, spectroscopic responses and antiproliferative activities. Compounds with N-methylpiperazine substituents showed a significant preference for AT-DNA polynucleotides and demonstrated AT-minor groove binding, which manifested in strong fluorescence increase, significant double helix stabilization, and positive induced circular dichroism spectra. These compounds formed complexes with G-quadruplex by π-π stacking interactions of dye with the top or bottom G-tetrad. Bulkier compounds with N-phenylpiperazine function are probably bound to ds-polynucleotide by partial intercalation between base pairs. On the other hand, they showed stronger stabilization of G-quadruplex compared to methyl-substituted compounds. Fluorimetric titrations pointed to possible mixed stoichiometry’s: 1:1 complex with π-π stacking interactions of dye on the top or bottom G-tetrad and 1:2 complex with dye positioned between two G-quadruplex molecules. Bulkier dyes with N-phenylpiperazine fragments demonstrated micromolar and submicromolar antiproliferative activity that was especially pronounced for leukaemia and lymphoma. Flow cytometric assay shows dose- and time-dependent increase in SubG0/G1 phase. Furthermore, the compounds enter the cells readily and accumulate in the mitochondrial space, co-localize with the standard mitochondrial markers.

Iridium Pincer Catalysts for Silane Dehydrocoupling: Ligand Effects on Selectivity and Activity

Catalytic reactions of bisphosphinite pincer-ligated iridium compounds p-XR(POCOP)IrHCl (POCOP) [2,6-(R2PO)2C6H3, R = iPr, X = H (1); R = tBu, X = COOMe (2); = H (3); = NMe2 (4)] with primary and secondary silanes have been performed. Complex 1 is primarily a silane redistribution precatalyst, but dehydrocoupling catalysis is observed for sterically demanding silane substrates or with aggressive removal of H2. The bulkier compounds (2–4) are silane dehydrocoupling precatalysts that also undergo competitive redistribution with less hindered substrates. Products generated from reactions utilizing 2–4 include low molecular weight oligosilanes with varying degrees of redistribution present or disilanes when employing more sterically demanding silane substrates. Selectivity for redistribution versus dehydrocoupling depends on the steric and electronic environment of the metal but can also be affected by reaction conditions.

Carbonic anhydrase inhibitors. Inhibition and homology modeling studies of the fungal β-carbonic anhydrase from Candida albicans with sulfonamides

The β-carbonic anhydrase (CA, EC 4.2.1.1) from the fungal pathogen Candida albicans (Nce103) is involved in a CO 2 sensing pathway critical for the pathogen life cycle and amenable to drug design studies. Herein we report an inhibition study of Nce103 with a library of sulfonamides and one sulfamate, showing that Nce103, similarly to the related enzyme from Cryptococcus neoformans Can2, is inhibited by these compounds with K Is in the range of 132 nM–7.6 μM. The best Nce103 inhibitors were acetazolamide, methazolamide, bromosulfanilamide, and 4-hydroxymethylbenzenesulfonamide ( K Is < 500 nM). A homology model was generated for Nce103 based on the crystal structure of Can2. The model shows that compounds with zinc-binding groups incorporating less polar moieties and compact scaffolds generate stronger Nce103 inhibitors, whereas highly polar zinc-binding groups and bulkier compounds appear more promising for the specific inhibition of Can2. Such compounds may be useful for the design of antifungal agents possessing a new mechanism of action.

Carbonic anhydrase inhibitors that directly inhibit anion transport by the human Cl−/HCO3−exchanger, AE1

Carbonic anhydrases (CA, EC 4.2.1.1.) catalyze reversible hydration of CO2 to HCO3- + H+. Bicarbonate transport proteins, which catalyze the transmembrane movement of membrane-impermeant bicarbonate, function in cooperation with CA. Since CA and bicarbonate transporters share the substrate, bicarbonate, we examined whether novel competitive inhibitors of CA also have direct inhibitory effects on bicarbonate transporters. We expressed the human erythrocyte membrane Cl-/HCO3- exchanger, AE1, in transfected HEK293 cells as a model bicarbonate transporter. AE1 activity was assessed in both Cl-/NO3- exchange assays, which were independent of CA activity, and in Cl-/HCO3- exchange assays. Transport was measured by following changes of intracellular [Cl-] and pH, using the intracellular fluorescent reporter dyes 6-methoxy-N-(3-sulfopropyl)quinolinium and 2',7'-bis-(2-carboxyethyl)-5-(and-6)carboxyfluorescein, respectively. We examined the effect of 16 different carbonic anhydrase inhibitors on AE1 transport activity. Among these 12 were newly-reported compounds; two were clinically used non-steroidal anti-inflammatory drugs (celecoxib and valdecoxib) and two were anti-convulsant drugs (topiramate and zonisamide). Celecoxib and four of the novel compounds significantly inhibited AE1 Cl-/NO3- exchange activity with EC50 values in the range 0.22-2.8 microM. It was evident that bulkier compounds had greater AE1 inhibitory potency. Maximum inhibition using 40 microM of each compound was only 22-53% of AE1 transport activity, possibly because assays were performed in the presence of competing substrate. In Cl-/HCO3- exchange assays, which depend on functional CA to produce transport substrate, 40 microM celecoxib inhibited AE1 by 62+/-4%. We conclude that some carbonic anhydrase inhibitors, including clinically-used celecoxib, will inhibit bicarbonate transport at clinically-significant concentrations.

Cavities, Layers, and Channels in the Hosting Framework of Molecular Complexes Derived From Cephradine

The cephalosporin-type antibiotics Cephradine, Cephalexin, and Cefaclor form clathrate-type complexes with a variety of naphthalene derivatives. The crystal structures of these complexes are isomorphous. Interestingly, the hosting framework formed by these cephalosporins can adapt to the guest molecule. This phenomenon of induced-fit appears to have a much larger potential, with the consequence that a series of smaller compounds (such as benzene derivatives) as well as bulkier compounds can also be hosted by Cephradine. When benzene derivatives were used as guests, pronounced deviations in the antibiotic framework were observed, and it is possible to induce deviations strikingly different from those found for the complexes with the naphthalene derivatives. Evidently, the hosting structure formed by Cephradine is highly flexible. Hosting frameworks containing layers, channels, and various other types of cavities can be obtained by selection of an appropriate guest molecule. Remarkably, a number of structural features and interactions remain unaffected in all these antibiotic frameworks. These persistent features seem to delineate the boundaries of framework formation for these antibiotics, thus defining the scope of complex formation.