"Oxindolic antiangiogenic molecules and cytotoxicity of the sunitinib prodrug SAP-S-S-Py"

Abstract

Cancer is one of the biggest health problems in the modern world. The appearance of cancer is caused by the uncontrolled and continuous proliferation of cancer cells, as they do not respond effectively to the signals that control the behavior of normal cells. This is why cancer cells eventually spread throughout the body, infecting normal tissues and organs. One of the cancer treatment strategies aims to stop the blood supply to the cancer cells, thus stopping their growth. One such drug is Sunitinib. However, due to increased toxicity and various side effects, its use is limited. Targeted delivery of the drug to cancer cells is required to reduce the toxicity of Sunitinib and increase its use.

For this reason various approaches have been reported for targeted drug delivery to cancer cells via target conjugates. Because Sunitinib does not provide direct access to target conjugates of this type due to a lack of functional groups in the part of the molecule exposed to the solvent front, a new Sunitinib analogue called SAP was designed and synthesized.

This molecule was designed to maintain the potency of Sunitinib but with several advantages over the original molecule, as after evaluation and comparison it was found to show improved pharmacokinetic parameters, as well as a larger polar surface, lower hematotoxicity, inhibit more receptors with action tyrosine kinase, inhibits the RET proto-oncogene, shows reduced cancer markers Ki-67 and CD31, as well as better solubility but also has the important coupling position offered by the introduction of the piperazine ring, which makes the new analog more suitable for either with target peptides or with other chemical groups.

In the present dissertation we focused on the study of the cytotoxicity of the oxidol antiangiogenic molecules of the prodrug Sunitinib SAP-S-S-Py and SAP.HCL for a more effective and targeted action against cancer cells and tumors overexpressed by various receptors. The results we obtained were encouraging and it turned out that SAP.HCL was more effective in terms of toxicity than SAP-S-S-Py. Such target conjugates could therefore be a new therapeutic approach for future studies to better treat a variety of cancers.

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