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.
Highlights
Intratumoral heterogeneity, a main feature of solid tumours, is one of the causes of the intractability of cancers [1]
Because of the low reactivity observed, the introduction of the carbamate linker proved to be challenging for some derivatives and two approaches were used to achieve the synthesis of these inhibitors starting from the nitroaromatic alcohols: (i) a reaction with carbonyldiimidazole to access to the carbamoyl imidazole derivatives that reacted, in a one-pot reaction, with aminomethyl- or aminoethyl- benzenesulfonamide, or (ii) a reaction with phosgene to yield to the chloroformates which were reacted with aminomethyl- or aminoethyl- benzenesulfonamide in the presence of triethylamine (Scheme 1) [31]
Literature studies have shown that the electron-withdrawing nitro group conjugated with the carbamate linker resulted in a remarkable electron-withdrawing nitro group conjugated with the carbamate linker resulted in a remarkable decrease in stability, which may explain the apparent low inhibitory potency of these compounds decrease in stability, which may explain the apparent low inhibitory potency of these compounds toward fatty acid amide hydrolase (FAAH), due to decomposition under the assay conditions [33]
Summary
Intratumoral heterogeneity, a main feature of solid tumours, is one of the causes of the intractability of cancers [1]. Several key proteins and buffer systems [6], including monocarboxylate transporters (MCTs), isoforms of anion exchanger, Na+ /HCO3 – co-transporters, Na+ /H+ exchangers, and carbonic anhydrases (CAs) isoforms IX and XII are involved in this pH regulatory process to maintain a physiological intracellular pH accompanied with extracellular acidification [7]. This acidosis strongly contributes to the malignant progression, aggressive phenotype, and resistance to therapy (chemotherapy and radiation) of the cancer cells, leading to a poor prognosis regardless of treatment [8]. As part of an effort to discover novel small-molecule inhibitors of hCA to enhance cancer therapy, we report a new class of 2- and 5-nitroimidazole, nitrofuran, nitrothiophene and nitrogen mustards- (alkylating agents) based bio-reducible drugs harboring a benzenesulfonamide to target hCA IX
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