Engaging Libraries of Promising Oxindoles as Tyrosine-Kinase InhibitorS in Cancer Target Therapy

Health is crucial to keep the world wheels spinning. It is outlined by the United Nations 2030 Agenda for sustainable development and validated by the current global disturbing and disrupting pandemic crisis. Cancer is one of the leading causes of death worldwide and still a major problem for society and a major challenge for scientific community. 20 years ago, with the discovery of imatinib (Gleevec®), targeted therapy come up to change the state of the art of cancer therapeutics, and the beginning of a new era in drug discovery. A new generation of small molecule inhibitors were synthesized targeting specific proteins involved in tumorigenesis, triggering an increase quality in the therapy of several cancer types, like lung, colorectal and breast cancers, lymphoma, and leukemia. Drugs for some specific targets are hard to develop due to therapeutic target’s structure and physiological role. Considering the properties exhibited by imatinib and sunitinib, with this multi-disciplinary proposal, we conceive a new strategy to design and synthesized new libraries of oxindole-type small molecules with tyrosine kinase (TK) inhibitor activity, focusing on BCR-ABL and VEGFR TK proteins.Despite the development of therapeutics, TK inhibitors (TKIs) represents a therapeutical breakthrough and a hot topic in drug discovery, but several difficulties remain in their discovery, like the financial burden. The challenges in modern medicinal/synthetic chemistry go beyond the creation of new molecules. Nowadays, the environmental concerns displayed by society and regulatory authorities automatically promote the creation of sustainable and eco-friendly methods in lab and industry scales. Therefore, the central synthetic strategy of this application will be the use of new (and not so new) multicomponent reactions (MCRs), in one-pot or sequential tactic, and procedures with high economic and low environmental footprints, focused on the use of greener methodologies to access the desired oxindole-type derivatives. The aim is to take benefit of the massive advantages of MCRs on developing elegant and sustainable atom economical synthetic routes, decreasing the production of by-products and the use of other expensive consumables, like solvents. The overall strategy of this proposal is to extend the chemical space around the oxindole core, introducing previously selected key units to obtain libraries of new hybrid molecules that will be evaluated in in vitro assays regarding cancer cell lines. Assessment of appropriate physicochemical and pharmacokinetic properties and in silico studies regarding small-molecule TK target will be conducted. Since this is an exploratory application (individual submission) all the tasks involved in the preparation of the TK inhibitors will be performed by the PI (Carolina Marques, University of Évora), who has great know-how in the field, supported by the Co-PI (António Teixeira, University of Évora) with noteworthy knowledge in heterocyclic chemistry and medicinal chemistry. A master student will be involved in the team, having a 6-month scholarship to develop the work concerning the synthesis of these interesting scaffolds within the scope of his/her master’s thesis. External collaborators will provide, in a regularly basis, crucial information regarding in silico and in vitro studies. The overall data from all the tasks involved will assess the potential of the devised strategy regarding the activity on BCR- ABL and VEGFR TK proteins, leading to good tumor cell anti-proliferation inhibitors, encouraging a future hit to lead development. Other TK targeted proteins involved in cancer therapy could be evaluated. Oxindole-type scaffolds are well known for its extensive biological profile, and other properties like cholinesterase inhibition (in which the PI have know-how), antibacterial or antiviral activities should be considered in the future as part of a back-up plan concerning the faith of these new scaffolds. It is expected that the results of these investigations could be an important step in drug discovery of TKIs and, in a prosperous future, patients who might benefit from protein TK-antagonist drug development process.