Hypoxia-activated prodrug derivatives of anti-cancer drugs: a patent review 2006 - 2021.

INTRODUCTION: The hypoxic tumor microenvironment represents a persistent obstacle in the treatment of most solid tumors. In the past years, significant efforts have been made to improve the efficacy of anti-cancer drugs. Therefore, hypoxia-activated prodrugs (HAPs) of chemotherapeutic compounds have attracted widespread interest as a therapeutic means to treat hypoxic tumors. AREAS COVERED: This updated review paper covers key patents published between 2006 and 2021 on the developments of HAP derivatives of anti-cancer compounds. EXPERT OPINION: Despite significant achievements in the development of HAP derivatives of anti-cancer compounds and although many clinical trials have been performed or are ongoing both as monotherapies and as part of combination therapies, there has currently no HAP anti-cancer agent been commercialized into the market. Unsuccessful clinical translation is partly due to the lack of patient stratification based on reliable biomarkers that are predictive of a positive response to hypoxia-targeted therapy.

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

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.

Design, synthesis, in vitro inhibition and toxicological evaluation of human carbonic anhydrases I, II and IX inhibitors in 5-nitroimidazole series.

With the aim to obtain novel compounds possessing both strong affinity against human carbonic anhydrases and low toxicity, we synthesised novel thiourea and sulphonamide derivatives 3, 4 and 10, and studied their in vitro inhibitory properties against human CA I, CA II and CA IX. We also evaluated the toxicity of these compounds using zebrafish larvae. Among the three compounds, derivative 4 showed efficient inhibition against hCA II (KI = 58.6 nM). Compound 10 showed moderate inhibition against hCA II (KI = 199.2 nM) and hCA IX (KI = 147.3 nM), whereas it inhibited hCA I less weakly at micromolar concentrations (KI = 6428.4 nM). All other inhibition constants for these compounds were in the submicromolar range. The toxicity evaluation studies showed no adverse effects on the zebrafish larvae. Our study suggests that these compounds are suitable for further preclinical characterisation as potential inhibitors of hCA I, II and IX.