Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases

Eur J Med Chem. 2020 Aug 15:200:112439. doi: 10.1016/j.ejmech.2020.112439.

Perihan A Elzahhar ¹, Shrouk M Abd El Wahab ², Mohamed Elagawany ³, Hoda Daabees ², Ahmed S F Belal ⁴, Ahmed F El-Yazbi ⁵, Ali H Eid ⁶, Rana Alaaeddine ⁶, Rehab R Hegazy ⁷, Rasha M Allam ⁷, Maged W Helmy ⁸, Bahaa Elgendy ⁹, Andrea Angeli ¹⁰, Soad A El-Hawash ¹¹, Claudiu T Supuran ¹²

Affiliations

1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: perihan.elzahhar@alexu.edu.eg.
2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, 22516, Egypt.
3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, 22516, Egypt; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO, 63110, USA.
4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
5 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; Department of Pharmacology and Toxicology, Faculty of Medicine, The American University of Beirut, Beirut, Lebanon.
6 Department of Pharmacology and Toxicology, Faculty of Medicine, The American University of Beirut, Beirut, Lebanon.
7 Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt.
8 Department of Pharmacology & Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22516, Egypt.
9 Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO, 63110, USA.
10 Università, Degli Studi di Firenze, NEUROFARBA Dept, Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.
11 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: soad.elhawash@alexu.edu.eg.
12 Università, Degli Studi di Firenze, NEUROFARBA Dept, Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 32485532 DOI: 10.1016/j.ejmech.2020.112439

Abstract

Cancer is a multifactorial disorder involving multiplicity of interrelated signaling pathways and molecular targets. To that end, a multi-target design strategy was adopted to develop some 1,2,3-triazoles hybridized with some pharmacophoric Anticancer fragments, as first-in-class simultaneous inhibitors of COX-2, 15-LOX and tumor associated Carbonic Anhydrase enzymes. Results revealed that compounds 5a, 5d, 8b and 8c were potent inhibitors of COX-2 and 15-LOX Enzymes. COX-2 inhibitory activity was further demonstrated by the inhibition of the accumulation of 6-keto-PGF1α, a metabolite of COX-2 products in two Cancer cell lines. The sulfonamide bearing derivatives 5d and 8c were effective nanomolar and submicromolar inhibitors of tumor associated hCA XII isoform, respectively. Strong to moderate inhibitory activities were observed in the in vitro antiproliferative assay on lung (A549), liver (HepG2) and breast (MCF7) Cancer cell lines (IC₅₀ 2.37-28.5 μM) with high safety margins on WI-38 cells. A cytotoxic advantage of CA inhibition was observed as an increased activity against tumor cell lines expressing CA IX/XII. Further mechanistic clues for the Anticancer activities of compound 5a and its sulfonamide analog 5d were derived from induction of cell cycle arrest at G2/M phase. They also triggered Apoptosis via increasing expression levels of caspase-9 and Bax together with suppressing that of Bcl-2. The in vitro anti-tumor activity was reflected as reduced tumor size upon treatment with 8c in an in vivo Cancer xenograft model. Docking experiments on the target Enzymes supported their in vitro data and served as further molecular evidence. In silico calculations and ligand efficiency indices were promising. In light of these data, such series could offer new structural insights into the understanding and development of multi-target COX-2/15-LOX/hCA inhibitors for Anticancer outcomes.

Keywords

1,2,3-Triazoles; 15-Lipoxygenase; Apoptosis; Cancer; Carbonic anhydrase; Cyclooxygenase-2; MTDL.

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