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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
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- experimentální nádory farmakoterapie metabolismus MeSH
- inhibitory karboanhydras chemická syntéza chemie farmakologie MeSH
- karboanhydrasa IX antagonisté a inhibitory metabolismus MeSH
- kultivované buňky MeSH
- léky antitumorózní - screeningové testy 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
- psi MeSH
- rekombinantní proteiny metabolismus 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
Icosahedral heteroboranes and especially metallacarboranes, which have recently been shown to act as potent HIV-1 protease inhibitors, are a unique class of chemical compounds with unusual properties, one of which is the formation of dihydrogen bonds with biomolecules. In this study, we investigate the effect of various metal vertices and exo-substitutions on several series of heteroboranes, including 11-vertex carborane cages [nido-7,8-C2B9Hn]n-13(n= 11,12,13), closo-1-SB11H11, closo-1-NB11H12, metal bis(dicarbollides)[3,3'-M (1,2-C2B9H11)2]n(M/n=Fe/2-, Co/1-, Ni/0) and fluoro (F), amino (NH2) and hydroxo (OH) derivatives of the metal bis(dicarbollides). Besides the properties of isolated systems (geometries, electronic properties and hydration), we study their interactions with a tetrapeptide, which models their biomolecular partner. Calculations have confirmed that the extra hydrogen in [nido-7,8-C2B9H12]- forms a bridge, which fluctuates between two stationary states. Using RESP-derived charges, it was ascertained that the negative charge of heteroboranes is located mainly on boron-bound hydrogens. An increase of the negative total charge (from 0 to -1 or -2) of heteroboranes yields an increase in the stabilisation energies of heteroborane[dot dot dot]peptide complexes and also a substantial increase in the hydration free energies of heteroboranes. Compared to the substitutions of metal vertices, the exo-substitutions of metallacarboranes cause a larger increase in stabilisation energies and a smaller increase in desolvation penalties. These two terms, stabilisation energies and desolvation penalties, contribute in opposite directions to the total heteroborane-biomolecule binding energy and must both be taken into account when designing new HIV-1 protease inhibitors.
Platinum compounds remain the first-line drugs for the treatment of most lethal gynecological malignancies and ovarian cancers. Acquired platinum resistance remains a major challenge in gynecological oncology. Considering the unique physicochemical properties of the metallacarboranes modifier and the significant role of nucleoside derivatives as anticancer antimetabolites, we designed and synthesized a set of adenosine conjugates with metallacarboranes containing iron, cobalt, or chromium as semi-abiotic compounds that influence the cisplatin sensitivity of ovarian cancer cells. Adherent cultures of ovarian carcinoma cell lines and multicellular spheroids, ranging from sensitive to highly resistant including experimental cell lines "not responding" to platinum drugs were used. Iron-containing metallacarborane conjugates showed the best anticancer activity, especially against resistant cells. Compound modified at the C2' nucleoside position showed the best activity in resistant cancer cells and highly resistant cancer spheroids exposed to cisplatin, increasing cell cycle arrest, apoptosis or necrosis, and reactive oxygen species production. Moreover, it showed high cellular accumulation and did not induce cross-resistance to cisplatin, carboplatin, doxorubicin, paclitaxel, or gemcitabine in long-term cultures. The reference nido-carborane derivative (no metal ions) and unmodified nucleosides were not as effective. These findings indicate that metallacarborane modification of adenosine may sensitize ovarian cancer cells to cisplatin in combination treatment.
- Publikační typ
- časopisecké články MeSH
