| Title: |
Extending artificial metalloenzymes for the uncaging of drugs on cells |
| Authors: |
Boris, Lozhkin |
| Contributors: |
Ward, Thomas R. R.; Sparr, Christof; Unciti Broceta, Asier |
| Publication Year: |
2022 |
| Collection: |
University of Basel: edoc |
| Description: |
Bioorthogonal transformations are of particular interest in the context of cancer therapy. Acting like conventional batch catalysts, metal cofactors allow new-to-nature reactions inside living cells or in tumor tissue. In this work, we present a Ru-deallylation cofactor associated with a low-molecular, highly specific binder of hCAIX (a known marker of various cancer cell lines). The ability of HeLa cells to express hCAIX exclusively under hypoxic conditions made it possible to use this cell line as a single model for healthy and diseased cells. The specificity of binding of the anchor to the tumor marker was demonstrated by FACS and super-resolution microscopy. A library of new prodrugs capable of Ru-catalyzed uncaging was also synthesized. Due to the limited applicability of conventional alloc-protection for highly potent cytotoxins, a new protecting group that allows caging of two drug molecules has been developed. The obtained results open-up prospects for further study of this catalytic system for targeted delivery of the Ru-cofactor to the cell surface, discriminating diseased cells against healthy ones. In addition, as part of the work on designing the substrate for in vivo synthesis of bioactive molecules, we developed an approach to monosubstituted benzenes under RCM conditions. Unfortunately, this method was inapplicable for the synthesis of the tamoxifen precursor. However, this approach complements and completes the arsenal of methods for the synthesis of aromatic compounds under Ru-catalysis. A precursor of pacritinib has also been synthesized. It has been shown that this bioactive molecule can be obtained by RCM in various solvents, including water. Due to the controversial clinical status of the drug in 2019, it was not then tested on cancer cells. Even so, in early 2022 it was approved by the FDA, and therefore is a potential subject for further in vivo studies. New approaches to caging phenols and amines relying on a Ru-cleavable protecting group have also been developed. In particular, SN-38 ... |
| Document Type: |
thesis |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://edoc.unibas.ch/90879/1/PhD_Thesis_Boris_Lozhkin_to%20download_1.pdf; Boris, Lozhkin. Extending artificial metalloenzymes for the uncaging of drugs on cells. 2022, Doctoral Thesis, University of Basel, Faculty of Science.; urn:urn:nbn:ch:bel-bau-diss148943 |
| Availability: |
https://edoc.unibas.ch/90879/; https://edoc.unibas.ch/90879/1/PhD_Thesis_Boris_Lozhkin_to%20download_1.pdf |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.21CFE880 |
| Database: |
BASE |