Hypoxia-Activated Prodrug Derivatives of Carbonic Anhydrase Inhibitors in Benzenesulfonamide Series: Synthesis and Biological Evaluation

Abstract

Hypoxia, a common feature of solid tumours’ microenvironment, is associated with an aggressive phenotype and is known to cause resistance to anticancer chemo- and radiotherapies. Tumour-associated carbonic anhydrases isoform IX (hCA IX), which is upregulated under hypoxia in many malignancies participating to the microenvironment acidosis, represents a valuable target for drug strategy against advanced solid tumours. To overcome cancer cell resistance and improve the efficacy of therapeutics, the use of bio-reducible prodrugs also known as Hypoxia-activated prodrugs (HAPs), represents an interesting strategy to be applied to target hCA IX isozyme through the design of selective carbonic anhydrase IX inhibitors (CAIs). Here, we report the design, synthesis and biological evaluations including CA inhibition assays, toxicity assays on zebrafish and viability assays on human cell lines (HT29 and HCT116) of new HAP-CAIs, harboring different bio-reducible moieties in nitroaromatic series and a benzenesulfonamide warhead to target hCA IX. The CA inhibition assays of this compound series showed a slight selectivity against hCA IX versus the cytosolic off-target hCA II and hCA I isozymes. Toxicity and viability assays have highlighted that the compound bearing the 2-nitroimidazole moiety possesses the lowest toxicity (LC50 of 1400 µM) and shows interesting results on viability assays.

Anticancer active trifluoromethylated fused triazinones are safe for early-life stages of zebrafish (Danio rerio) and reveal a proapoptotic action

“…This modern vertebrate model is popular in testing the safety of new drug-like compounds. The early-life stages of zebrafish, mainly embryos and non-feeding larvae, are considered more sensitive to chemical compounds than adult individuals and can therefore serve as an ideal screening tool in the preclinical phase of drug development or repositioning 11,14,16,23,25 . Zebrafish embryogenesis is completed within 72 h after fertilisation, while the major organs and tissues are developed within 120 h after fertilisation, making it easy to track druginduced effects during different developmental stages 15,26 .…”

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

“…The hypoxia-inducible carbonic anhydrase CAXII contributes to supporting the acidic extracellular microenvironment found in hypoxic cancers. Anduran et al [60] prepared a number of prodrugs of the CAXII inhibitor benzenesulfonamide. The best of these prodrugs (59) showed modest (2.5-fold) selectivity towards hypoxic over oxic HCT29 and HCT116 colorectal cancer cell lines in culture.…”

<p>Experimental Carbonic Anhydrase Inhibitors for the Treatment of Hypoxic Tumors</p>

“…Significant contributions to the discovery of interesting CA IX/XII inhibitors were made by Winum's group in Montpellier, in collaboration with Lambin's group in Maastricht, Parkkila's group in Tampere and our group in Florence. [74][75][76][77][78][79] Only the most relevant papers for the present review will be considered here. In fact many other contributions were achieved by these researchers in other fields connected to CAIs, which have been reviewed elsewhere.…”

“…The Figure 3 Nitroazole-containing CAIs of types 8-11. [74][75][76][77][78][79] Journal of Experimental Pharmacology 2020:12 submit your manuscript | www.dovepress.com…”

“… 74 , 75 Furthermore, these compounds were shown to be non-toxic in vivo in several animal models 77 , 78 whereas some newer congeners were also reported recently. 79 …”