Human carbonic anhydrase IX (CA IX), a protein specifically expressed on the surface of solid tumour cells, represents a validated target both for anticancer therapy and diagnostics. We recently identified sulfonamide dicarbaboranes as promising inhibitors of CA IX with favourable activities both in vitro and in vivo. To explain their selectivity and potency, we performed detailed X-ray structural analysis of their interactions within the active sites of CA IX and CA II. Series of compounds bearing various aliphatic linkers between the dicarbaborane cluster and sulfonamide group were examined. Preferential binding towards the hydrophobic part of the active site cavity was observed. Selectivity towards CA IX lies in the shape complementarity of the dicarbaborane cluster with a specific CA IX hydrophobic patch containing V131 residue. The bulky side chain of F131 residue in CA II alters the shape of the catalytic cavity, disrupting favourable interactions of the spherical dicarbaborane cluster.
- MeSH
- antigeny nádorové genetika MeSH
- HEK293 buňky MeSH
- hydrofobní a hydrofilní interakce MeSH
- inhibitory karboanhydras chemie farmakologie MeSH
- karboanhydrasa IX antagonisté a inhibitory genetika MeSH
- katalytická doména MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- protinádorové látky chemie farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- sekvence aminokyselin MeSH
- sloučeniny boru chemie MeSH
- sulfonamidy chemie farmakologie MeSH
- vazba proteinů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Carbonic anhydrase IX (CA IX) is a transmembrane enzyme overexpressed in hypoxic tumors, where it plays an important role in tumor progression. Specific CA IX inhibitors potentially could serve as anti-cancer drugs. We designed a series of sulfonamide inhibitors containing carborane clusters based on prior structural knowledge of carborane binding into the enzyme active site. Two types of carborane clusters, 12-vertex dicarba-closo-dodecaborane and 11-vertex 7,8-dicarba-nido-undecaborate (dicarbollide), were connected to a sulfonamide moiety via aliphatic linkers of varying lengths (1-4 carbon atoms; n = 1-4). In vitro testing of CA inhibitory potencies revealed that the optimal linker length for selective inhibition of CA IX was n = 3. A 1-sulfamidopropyl-1,2-dicarba-closo-dodecaborane (3) emerged as the strongest CA IX inhibitor from this series, with a Ki value of 0.5 nM and roughly 1230-fold selectivity towards CA IX over CA II. X-ray studies of 3 yielded structural insights into their binding modes within the CA IX active site. Compound 3 exhibited moderate cytotoxicity against cancer cell lines and primary cell lines in 2D cultures. Cytotoxicity towards multicellular spheroids was also observed. Moreover, 3 significantly lowered the amount of CA IX on the cell surface both in 2D cultures and spheroids and facilitated penetration of doxorubicin. Although 3 had only a moderate effect on tumor size in mice, we observed favorable ADME properties and pharmacokinetics in mice, and preferential presence in brain over serum.
- MeSH
- antigeny nádorové metabolismus MeSH
- experimentální nádory farmakoterapie metabolismus MeSH
- inhibitory karboanhydras chemická syntéza chemie farmakologie MeSH
- karboanhydrasa IX antagonisté a inhibitory metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- myši inbrední BALB C MeSH
- myši SCID MeSH
- myši MeSH
- nádory prsu farmakoterapie metabolismus MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- psi MeSH
- rekombinantní proteiny metabolismus MeSH
- screeningové testy protinádorových léčiv MeSH
- sulfonamidy chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Although 1-Ph-2-X-closo-1,2-C2B10H10 (X = F, Cl, Br, I) derivatives had been computed to have positive values of the heat of formation, it was possible to prepare them. The corresponding solid-state structures were computationally analyzed. Electrostatic potential computations indicated the presence of highly positive σ-holes in the case of heavy halogens. Surprisingly, the halogen•••π interaction formed by the Br atom was found to be more favorable than that of I.
The world's population is now over 50% urban, and cities make an important contribution to national greenhouse gas (GHG) emissions. Many cities are developing strategies to reduce their emissions. Here we ask how and why emissions differ between cities. Our study often global cities shows how a balance of geophysical factors (climate, access to resources, and gateway status) and technical factors (power generation, urban design, and waste processing) determine the GHGs attributable to cities. Within the overall trends, however, there are differences between cities with more or less public transit while personal income also impacts heating and industrial fuel use. By including upstream emissions from fuels, GHG emissions attributable to cities exceed those from direct end use by upto 25%. Our findings should help foster intercity learning on reducing GHG emissions.
- MeSH
- atmosféra MeSH
- látky znečišťující vzduch chemie MeSH
- skleníkový efekt * MeSH
- velkoměsta * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Geografické názvy
- Česká republika MeSH
- Jihoafrická republika MeSH
- Kanada MeSH
- Londýn MeSH
- Španělsko MeSH
- Spojené státy americké MeSH
- Švýcarsko MeSH
- Thajsko MeSH
- velkoměsta * MeSH
Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARdelta activators. The alkynylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 were obtained by stepwise changing the structure of the known PPARpan agonist 5 into Y-shaped compounds. The most active and selective compound, 6f, had a PPARdelta potency of 0.13 microM, which is 50-fold more potent than compound 5.
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il. ; 32 cm
Neinvazivní monitorování novorozeneckých ikterů a měření intenzity ozáření při fototerapii. XXX XXX XXX
- MeSH
- fototerapie metody MeSH
- hyperinzulinismus MeSH
- jednotky intenzivní péče o novorozence MeSH
- monitorování radiace MeSH
- novorozenecká žloutenka terapie MeSH
- Konspekt
- Pediatrie
- NLK Obory
- perinatologie a neonatologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Nestr. : il. ; 32 cm
- MeSH
- bilirubin přístrojové vybavení krev MeSH
- hyperbilirubinemie diagnóza MeSH
- nemoci novorozenců diagnóza MeSH
- Konspekt
- Lékařské vědy. Lékařství
- NLK Obory
- pediatrie
- radiologie, nukleární medicína a zobrazovací metody
- chemie, klinická chemie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
