Inclusion of a 5-fluorouracil moiety in nitrogenous bases derivatives as human carbonic anhydrase IX and XII inhibitors produced a targeted action against MDA-MB-231 and T47D breast cancer cells.

Clicks: 361
ID: 95231
2020
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal
Emerging

Ranked #50 of 406 articles by views in European journal of medicinal chemistry

Most read Least read

Bar heights use a square-root scale. Only the 120 most-read articles are drawn; the journal has 406 in total.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
A new series of pyrimidine derivatives as human carbonic anhydrases (CA, EC 4.2.1.1) inhibitors is here designed by including a 5-fluorouracil (5-FU) moiety, broadly used anticancer medication, in nitrogenous base modulators of the tumor-associated CAs. Most sulfonamide derivatives efficiently inhibit the target CA IX (Ks in the range 0.47-44.7 nM) and CA XII (Ks in the range 2.9-83.1 nM), while the 5-FU coumarin derivatives showed a potent and totally selective inhibitory action against the target CA IX/XII over off-target CA I/II. The X-ray solved crystal structure of CA II in adduct with a representative uracil derivative provided insights on the binding mode to the target of such pyrimidine derivatives. On the basis of potency and selectivity inhibition profiles, coumarin 12a, the sulfonamide CAIs showing the greatest II/IX specificity (4e, 6b and 6d) and the unique subnanomolar CA IX inhibitor 10a were tested in vitro for their antiproliferative action against a panel of eight cancer cell lines. The breast cancer cell lines MDA-MB-231 and T47D were the most susceptible with IC values in low to medium micromolar ranges (2.45 ± 0.07-18.86 ± 0.72 μM and 6.86 ± 0.31-40.92 ± 1.59 μM, respectively). A cell cycle analysis showed that 4e and 6d arrest T-47D cells mainly in the G2/M phase. Using an annexin V-FITC apoptosis assay, 4e and 6d were shown to induce an approximately 23.6-fold and 34.8-fold total increase in apoptosis compared to the control, corroborating the concrete potential of 5-FU CAIs for the design of new effective anticancer strategies.
Reference Key
petreni2020inclusioneuropean Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Petreni, Andrea;Bonardi, Alessandro;Lomelino, Carrie;Osman, Sameh M;ALOthman, Zeid A;Eldehna, Wagdy M;El-Haggar, Radwan;McKenna, Robert;Nocentini, Alessio;Supuran, Claudiu T;
Journal European journal of medicinal chemistry
Year 2020
DOI
S0223-5234(20)30079-9
URL
Keywords
Breast cancer anticancer selectivity 5-fluorouracil carbonic anhydrase annexin

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.