Conjugates of biologically relevant compounds
In this field, we have been focused on development of synthetic tools to enable simple preparation of different conjugates for chemical biology. The general strategy consisted in the preparation of preloaded resin which enables the preparation of desired conjugates using the rapid procedure „shake-wash-cleave“. Our first reported preloaded resin enabled the preparation of conjugates of semisynthetic triterpenes with the cytotoxic activity but unknown mode of action. Their conjugation with biotin yielded compounds applicable to affinity chromatography (Bioconjug. Chem. 2015, 26(12), 2563-2570).
In the following study, we focused on the visualization of small molecules in cells which becomes an essential tool in drug discovery. The most commonly used method is fluorescent microscopy in which the studied molecule is equipped with a fluorescent label and the method allows for direct visualization of cellular uptake and distribution of the drug within the cell. A number of various conjugates of small molecules with fluorescent tags were reported to date with the application as probes, photosensitizers or luminescence switches and sensors. We focused on development and study of conjugates of cytotoxic triterpenes with BODIPY (Chem. Eur. J. 2018, 24 (19), 4957-4966).
The approach of preloaded resins was also used in the field of proteolysis targeting chimeras (PROTACs). PROTAC concept is based on the preparation of conjugates consisting of two main parts connected through a suitable linker, which is typically an ethylene-oxy-based aliphatic chain. One part of the conjugate interacts with the protein of interest, whereas the other binds to a component of E3 ubiquitin ligase. The phthalimide family is often employed as a part of PROTACs to hijack CRBN to target proteins. Pharmacological targeting of protein kinases has been validated as an effective therapeutic strategy, and over 37 kinase inhibitor drugs have received approval for clinical use in certain cancers. However, specific resistance often reduces the sensitivity of targeted kinases to drugs during therapy, and therefore novel molecules or approaches are intensively sought. Kinase degradation induced by PROTACs thus provides an interesting alternative not only for mechanistic studies or therapy but also for kinases with kinase-independent functions. In our contribution, we introduced the high-throughput synthesis of PROTACs for the degradation of different protein kinases (Chem. Commun. 2019, 55, 7, 929-932).
The solid-phase synthesis was also used in the preparation of conjugates of protein kinases with folic acid, although in this case without using the concept of preloaded resin (J. Org. Chem. 2017, 82 (24), 13530-13541). Little or no specificity to cancer cells is one of the most serious problems of traditional chemotherapy of cancer as it leads to systemic toxicity. The systemic toxicity of conventional chemotherapy causes serious side effects and is also one of the limiting factors of treatment efficiency. The use of small molecule delivery systems is a promising approach which can decrease the systemic toxicity of cytotoxic drugs to rapidly dividing normal cells. Tumor targeting delivery systems have been intensively studied in the last three decades and represent one of the promising approaches for increasing of chemotherapy selectivity together with decreasing of systemic toxicity. Selective drug delivery is based on frequent overexpression of many receptors in tumor cells, which can serve as targets to deliver cytotoxic agent selectively into tumor. The relatively selective transport into tumor cells can be realized with the use of conjugates of cytotoxic agent and tumor recognition moiety.