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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 is a common feature of solid tumours and is characterised by a very low oxygen content, typically less than 1%. This poor oxygen level contributes to a harsher tumour environment and is associated with poor patient prognosis. Additionally, hypoxia is also known to induce tumour progression and resistance to conventional therapies. Therefore, hypoxia represents an extremely valuable target to be exploited for certain anti-cancer therapy strategies. One way of exploiting tumour hypoxia in anti-cancer treatments is to target the hypoxia responsive pathway (HIF-1α) which plays a key role in the hypoxic tumour microenvironment. Another way of exploiting tumour hypoxia is by using hypoxia-activated prodrugs (HAPs). The HAP purpose is to deliver an active drug selectively in the hypoxic environment. In this thesis we describe the design, synthesis and biological evaluation of different novel HAPs. We propose the development of carbonic anhydrase IX inhibitor HAPs, immunotherapeutic HAPs and of a new immunotherapeutic HAP for antibody-HAP conjugation in order to improve tumour targeting.

Hypoxia, a common feature of solid tumours&rsquo, 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 &micro, M) and shows interesting results on viability assays.