br Introduction br Cancer caused more than
Cancer caused more than 9 million deaths worldwide in 2018 and the number of new cases is constantly increasing. Among different approaches, chemotherapy is largely used in medical oncology. Nonetheless, most of the currently employed chemotherapies against cancer are almost as toxic for the normal cells as for the tumor cells. Thus, there is an urgent need for the development of new and specific chemotherapies, capable of exploiting the differences between normal and tumor cells in order to increase the potency and therapeutic index by improving the balance between efficacy and toxicity. During the last decades, the prodrug strategy has emerged, involving the development of activity-masked molecules designed for being rapidly activated through enzymatic or chemical reactions inside the tumors or within the tumor microenvironment. This approach ideally ensures a high selectivity against targets and low toxicity, since drugs are liberated specifically at the tumor area, generally by targeting the overexpression of enzymes or reactive oxygen species (ROS) surrounding the tumor, or the hypoxic environment of the tumor. Furthermore, the prodrug strategy remains faster than the development of novel therapeutic agents with appropriate drug-like characteristics.
Among various metabolic pathways, the activation of antitumor prodrugs by ROS seems particularly promising. Biological study of tumors have revealed that cancer cells have a higher level of oxidative stress compared to healthy cells. This oxidative stress results in the
overproduction of ROS including hydrogen peroxide (H2O2), hydroxyl radical (HO●) and superoxide anion (O2●-). These ROS contribute significantly in different tumor progression processes such as cell proliferation and angiogenesis. Neovascularization is a critical element of tumor metastasis since it allows access of certain cancer cells to the bloodstream leading to colonization of new organs. In addition, H2O2 molecules produced in tumor cells will generate migration of these cells, which is also an important factor in the metastatic process.
Arylboronic acids and their corresponding esters have been widely used as temporary drug masking groups since activation is made possible by ROS (Scheme 1).[7,8] These temporary moieties are triggered by H2O2, the most abundant and stable ROS produced by cancer cells, to further afford non-toxic boric acid. Boronic Calcipotriol groups were either directly linked to the drug or branched through a quinone methide-based self-immolative spacer. Oxidation of the carbon-boron bond will allow the formation of a hydroxy group. In the case of the self-immolative spacer, the latter electron donor function will cause electronic delocalization within the aromatic nucleus leading to the release of the drug. Remarkably, arylboronic acid spacers are employed to link either alcohol or amine function-bearing drugs through ether, carbonate or carbamate bonds. The spacer is also commonly used to hinder the drug and allow a better masking of the biological activity.
Boronic acid/boronate prodrug
Arylboronic acid/boronate prodrug
RO B OR
Scheme 1. Conversion of boron-containing prodrug into active drug.
From this literature, we observed that the different arylboronic acid and ester precursors were evaluated on various cell lines with disparate cytotoxic results. The cancer cell line sensitivity to arylboronic prodrugs does not follow a clear trend from one study to another. In regards to a particular cell line, the structure of the arylboronic acid derivative has therefore a strong influence on the biological activity. The clear identification of the type of cancer sensitive to these
boron-based prodrugs is central since none of these molecules has entered clinical trial so far. In this work, we decided to develop potent arylboronate-drug conjugates and further select the most receptive target among several cancer cell lines in order to identify the type of cancer that responds well towards these precursors. First, we selected doxorubicin (DOX), a good candidate for the design of prodrug. Indeed, DOX is a very effective antitumor drug with limited therapeutic efficacy due to stochastic repartition in the patient organs resulting in important cardiotoxicity. Arylboronate-based self-immolative spacers were then used in order to branch the free amine function of DOX (Figure 1). Several arylboronate moieties were used in order to study their influence on the kinetic of DOX release in presence of H2O2. Three different scaffolds were envisioned: (i) the unsubstituted benzeneboronate; (ii) a fluorinated benzene homolog since electron withdrawing atom were shown to increase the kinetic of oxidation; (iii) a furan ring, described as effective self-immolative spacer, to add a strong structural modification in comparison with the two aforementioned benzene moieties.