Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of new anticancer agents

Analysis of the literature data reveals that while inhibition of cancer-related carbonic anhydrase IX and XII isoforms continues to be an important enrichment factor for designing anticancer agent development libraries, exclusive reliance on the in vitro inhibition of these two recombinant isozymes in nominating candidate compounds for evaluation of their effects on cancer cells may lead not only to identifying numerous compounds devoid of the desired cellular efficacy but also to overlooking many promising candidates which may not display the best potency in biochemical inhibition assay. However, SLC-0111, now in phase Ib/II clinical trials, was developed based on the excellent agreement between the in vitro, in vivo and more recently, in-patient data

Low-temperature thermal conductivity in polycrystalline graphene

The low-temperature thermal conductivity in polycrystalline graphene is theoretically studied. The contributions from three branches of acoustic phonons are calculated by taking into account scattering on sample borders, point defects and grain boundaries. Phonon scattering due to sample borders and grain boundaries is shown to result in a $T^{\alpha}$-behaviour in the thermal conductivity where $\alpha$ varies between 1 and 2. This behaviour is found to be more pronounced for nanosized grain boundaries. PACS: 65.80.Ck, 81.05.ue, 73.43.C

7-Acylamino-3H-1,2-benzoxathiepine 2,2-dioxides as new isoform-selective carbonic anhydrase IX and XII inhibitors

A series of 3H-1,2-benzoxathiepine 2,2-dioxides incorporating 7-acylamino moieties were obtained by an original procedure starting from 5-nitrosalicylaldehyde, which was treated with propenylsulfonyl chloride followed by Wittig reaction of the bis-olefin intermediate. The new derivatives, belonging to the homosulfocoumarin chemotype, were assayed as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Four pharmacologically relevant human (h) isoforms were investigated, the cytosolic hCA I and II and the transmembrane, tumour-associated hCA IX and XII. No relevant inhibition of hCA I and II was observed, whereas some of the new derivatives were effective, low nanomolar hCA IX/XII inhibitors, making them of interest for investigations in situations in which the activity of these isoforms is overexpressed, such as hypoxic tumours, arthritis or cerebral ischaemia

Aryl derivatives of 3H-1,2-benzoxathiepine 2,2-dioxide as carbonic anhydrase inhibitors

A new series of homosulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) possessing various substitution patterns and moieties in the 7, 8 or 9 position of the heterocylic ring were prepared by original procedures and investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII. The 8-substituted homosulfocoumarins were the most effective hCA IX/XII inhibitors followed by the 7-substituted derivatives, whereas the substitution pattern in position 9 led to less effective binders for the transmembrane, tumour-associated isoforms IX/XII. The cytosolic isoforms hCA I and II were not inhibited by these compounds, similar to the sulfocoumarins/coumarins investigated earlier. As hCA IX and XII are validated anti-tumour targets, with one sulphonamide (SLC-0111) in Phase Ib/II clinical trials, finding derivatives with better selectivity for inhibiting the tumour-associated isoforms over the cytosolic ones, as the homosulfocoumarins reported here, is of crucial importance

Discovery and SAR exploration of N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines as potential therapeutic agents for prostate cancer

A new chemical series of antiproliferative compounds was identified via high-throughput screening on DU-145 human prostate carcinoma cell line (hit compound potency - 5.7 μM). Exploration of the two peripheral diversity vectors of the hit molecule in a hit-targeted library and testing of the resulting compounds led to SAR generalizations and identification of the 'best' pharmacophoric moieties. The latter were merged in a single compound that exhibited a 200-fold better potency than the original hit compound. Specific cancer cell cytotoxicity was confirmed for the most potent compounds

Purcell effect in Hyperbolic Metamaterial Resonators

The radiation dynamics of optical emitters can be manipulated by properly designed material structures providing high local density of photonic states, a phenomenon often referred to as the Purcell effect. Plasmonic nanorod metamaterials with hyperbolic dispersion of electromagnetic modes are believed to deliver a significant Purcell enhancement with both broadband and non-resonant nature. Here, we have investigated finite-size cavities formed by nanorod metamaterials and shown that the main mechanism of the Purcell effect in these hyperbolic resonators originates from the cavity hyperbolic modes, which in a microscopic description stem from the interacting cylindrical surface plasmon modes of the finite number of nanorods forming the cavity. It is found that emitters polarized perpendicular to the nanorods exhibit strong decay rate enhancement, which is predominantly influenced by the rod length. We demonstrate that this enhancement originates from Fabry-Perot modes of the metamaterial cavity. The Purcell factors, delivered by those cavity modes, reach several hundred, which is 4-5 times larger than those emerging at the epsilon near zero transition frequencies. The effect of enhancement is less pronounced for dipoles, polarized along the rods. Furthermore, it was shown that the Purcell factor delivered by Fabry-Perot modes follows the dimension parameters of the array, while the decay rate in the epsilon near-zero regime is almost insensitive to geometry. The presented analysis shows a possibility to engineer emitter properties in the structured metamaterials, addressing their microscopic structure

Combining carbonic anhydrase and thioredoxin reductase inhibitory motifs within a single molecule dramatically increases its cytotoxicity

A hypothesis that simultaneous targeting cancer-related carbonic anhydrase hCA IX and hCA XII isoforms (whose overexpression is a cancer cell’s defence mechanism against hypoxia) along with thioredoxin reductase (overexpressed in cancers as a defence against oxidative stress) may lead to synergistic antiproliferative effects was confirmed by testing combinations of the two inhibitor classes against pancreatic cancer cells (PANC-1). Combining both pharmacophoric motifs within one molecule led to a sharp increase of cytotoxicity. This preliminary observation sets the ground for a fundamentally new approach to anticancer agent design

Localization of charge carriers in materials with high polaron concentration

Abstract The influence of polaron concentration on the type of transition from band to activate conductivity has been investigated. For a single polaron in the crystal lattice or for material with polaron concentration higher than the percolation threshold, such a transition is continuous, in accordance with theory. However, for intermediate cases this process becomes step-like, because the rapid increase of density of states at Fermi level leads to a change of polaron characteristics. These suppositions are illustrated by experimental results (XPS-spectra, crystal structure analysis, DC conductivity) for intercalation compounds based on titanium dichalcogenides.