Adam Anthony Needle
PC25 – Adam Anthony Needle
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic
ORCID
needlea@faf.cuni.cz
| Thymosin β4 as a Metal‑Responsive Regulator of Ferroptosis and Cellular Stress: Implications for Medicinal Chemistry |
| Needle Adam A.1, Doležal Martin1, and Kučerová-Chlupáčová Marta1 1 Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03 Hradec Králové, Czech Republic |
| Abstract Castration resistant prostate cancer, which does not respond to second generation nonsteroidal anti-androgen treatment, is putting pressure on the development of new agents that will antagonise mutant androgen receptor variants and inhibit the binding of male sex hormones [1]. A recent publication by our team has revealed that it is possible to replace the nitro group in the structure of flutamide with a boronic acid functional group [2]. In the structures of second-generation nonsteroidal anti-androgens, the nitrile functional group replaces the original nitro group. We have replaced the nitrile group in enzalutamide analogues with a boronic acid residue that contains two oxygen atoms, which could mimic the nitro group in the flutamide molecule. The initial idea was that boron can form a dative bond with biological nucleophiles in amino acid residues [3]. Preliminary in silico studies have shown a hydrogen bond between Met745 and the boronic acid moiety instead of the proposed Arg752. Therefore, non-covalent binding modes may also provide promising molecules. This could lead to the discovery of an agent effective for the treatment of castration-resistant prostate cancer. The effect of structural modifications on antiandrogenic activity is being studied by introducing various hydrophilic, lipophilic, electron-withdrawing, and electron-donating groups into the structure. Variation of the halogen adjacent to the boronic acid moiety is also examined. Our five-step synthesis process has been successfully optimised and can be utilised in the synthesis of further series. The first series is being evaluated in the LAPC-4 androgen dependent human prostate cancer cell line and in the PC-3 androgen independent human prostate adenocarcinoma cell line. The selectivity of the compounds will be assessed in HepG2 and HK-2 cell lines. To confirm the interaction of the prepared ligands with the androgen receptor, a fluorescence polarisation-based competition binding assay is planned. |
| References [1] Schmidt, K.; Huitema, A.; et al. Resistance to second-generation androgen receptor antagonists in prostate cancer. Nat. Rev. Urol. 2021, 18, 209–226. DOI: https://doi.org/10.1038/s41585-021-00438-4 [2] Šlechta, P.; Viták, R.; et al. Replacement of nitro function by free boronic acid in non-steroidal anti-androgens. RSC Med. Chem. 2024, 15(12), 4018–4038. DOI: DOI: https://doi.org/10.1039/d4md00343h [3] Grams, R.; Santos, W.; et al. The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology. Chem. Rev. 2024, 124 (5), 2441-2511. DOI: https://doi.org/10.1021/acs.chemrev.3c00663 |