2. Academic Validation
  3. Natural inspired ligustrazine-based SLC-0111 analogues as novel carbonic anhydrase inhibitors

Natural inspired ligustrazine-based SLC-0111 analogues as novel carbonic anhydrase inhibitors

  • Eur J Med Chem. 2022 Jan 15;228:114008. doi: 10.1016/j.ejmech.2021.114008.
Diaaeldin M Elimam 1,  Wagdy M Eldehna 2,  Rofaida Salem 3,  Alessandro Bonardi 4,  Alessio Nocentini 5,  Sara T Al-Rashood 6,  Mahmoud M Elaasser 7,  Paola Gratteri 8,  Claudiu T Supuran 9,  Heba Abdelrasheed Allam 10
Affiliations

Affiliations

  • 1 Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt. Electronic address: [email protected].
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt.
  • 4 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy; Department of NEUROFARBA - Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 5 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 6 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
  • 7 The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt.
  • 8 Department of NEUROFARBA - Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 9 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: [email protected].
  • 10 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
PMID: 34871842 DOI: 10.1016/j.ejmech.2021.114008
Abstract

Ligustrazine is the principle bioactive alkaloid in the widely-used Chinese herb Chuan Xiong rhizome. Herein, a series of novel derivatives has been designed as human carbonic anhydrases inhibitors (hCAIs) starting from the natural product Ligustrazine inserted as a tail instead of the 4-fluorophenyl tail of SLC-0111, a front-runner selective hCA IX inhibitor currently in clinical trials as antitumor/antimetastatic agent. Other derivatives were designed via incorporation of different linkers, of amide and ester type, or incorporation of different zinc anchoring groups such as secondary sulfamoyl and carboxylic acid functionalities. The newly designed molecules were prepared following different synthetic pathways, and were assessed for their inhibitory actions against four isoforms: the widespread cytosolic (hCA I and II), and the transmembrane tumor-related (hCA IX and XII). The primary sulfonamides efficiently inhibited the target hCA IX and hCA XII in the nanomolar range (KIs: 6.2-951.5 nM and 3.3-869.3 nM, respectively). The most selective hCA IX inhibitors 6c and 18 were assessed for their potential Anticancer effects, and displayed anti-proliferative activity against MCF-7 Cancer cell line with IC50s of 11.9 and 36.7 μM, respectively. Molecular modelling studies unveiled the relationship between structural features and inhibitory profiles against the off-target hCA II and the target, tumor-related isoforms hCA IX and XII.

Keywords

Anticancer agents; Carbonic anhydrase inhibitors; Ligustrazine; SLC-0111 analogues; Tail approach; Ureido benzenesulfonamides.

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