Počet záznamů: 1
Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX
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SYSNO ASEP 0524603 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX Tvůrce(i) Dvořanová, J. (CZ)
Kugler, Michael (UOCHB-X) RID, ORCID
Holub, Josef (UACH-T) SAI, RID, ORCID
Šícha, Václav (UACH-T) RID, ORCID, SAI
Das, V. (CZ)
Nekvinda, Jan (UACH-T) RID, SAI, ORCID
El Anwar, Suzan (UACH-T) SAI, ORCID, RID
Havránek, M. (CZ)
Pospíšilová, Klára (UOCHB-X)
Fábry, M. (CZ)
Král, V. (CZ)
Medvedíková, M. (CZ)
Matějková, Stanislava (UOCHB-X) RID, ORCID
Lišková, B. (CZ)
Gurská, S. (CZ)
Džubák, P. (CZ)
Brynda, J. (CZ)
Hajdúch, M. (CZ)
Grüner, Bohumír (UACH-T) RID, SAI, ORCID
Řezáčová, Pavlína (UOCHB-X) RID, ORCIDČíslo článku 112460 Zdroj.dok. European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 200, Aug 15 (2020)Poč.str. 13 s. Jazyk dok. eng - angličtina Země vyd. FR - Francie Klíč. slova anti-tumor agents ; carbonic anhydrase IX ; carboranes ; dicarbollide ; enzyme inhibitors ; drug penetration ; multicellular spheroids Vědní obor RIV CE - Biochemie Obor OECD Biochemistry and molecular biology Vědní obor RIV – spolupráce Ústav anorganické chemie - Anorganická chemie CEP GA18-27648S GA ČR - Grantová agentura ČR GA15-05677S GA ČR - Grantová agentura ČR TE01020028 GA TA ČR - Technologická agentura ČR LM2015064 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Způsob publikování Omezený přístup Institucionální podpora UOCHB-X - RVO:61388963 ; UACH-T - RVO:61388980 UT WOS 000546723400039 EID SCOPUS 85085747340 DOI 10.1016/j.ejmech.2020.112460 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2021 Elektronická adresa https://www.sciencedirect.com/science/article/pii/S0223523420304311?via%3Dihub
Počet záznamů: 1