Design, synthesis and biological evaluation of small molecule-based aldehyde dehydrogenase (ALDH) inhibitors

Aldehyde dehydrogenases (ALDHs) play a vital role in the body by detoxifying aldehydes. Some isoforms (i.e., ALDH1A1, 3A1), are recognised as multifunctional crystallins in the cornea and lens, and an imbalance in their activity might affect the progression/severity of some ocular diseases, leading to vision impairment through several mechanisms. The main aim of this project was to investigate compounds that could interfere with ALDH activity to study a potential ocular application. For that, potential ALDH inhibitors were synthesised and kinetically characterised. Results from the biochemical screen yielded promising compounds i.e., ALDH1A3-selective DEAB analogue compound 29 (IC50 = 0.63 µM) or the ALDH3A1-selective 33 (IC50 = 1.61 µM). Compounds resulting from other libraries i.e., 13 and 14, yielded ALDH3A1 selective inhibition with IC50 values of 4.28 and 6.12 µM; or compounds 94 and 95, both showing excellent ALDH1A3 inhibition with IC50 values of 0.22 and 1.28 µM, respectively. In addition, an optimal methodology to produce recombinant ALDH7A1 was successfully applied, and a small panel of ALDH-targeting compounds was kinetically characterised. Notably, results highlighted compound 121, able to inhibit ALDH7A1 (IC50 = 5.3 µM) while no effect on 1A1 and reduced activity on 1A1 and 3A1 was observed. Finally, novel liposomal formulations containing ALDH-targeting compounds DSF and 3b were developed and characterised in vitro using ocular-related hFB and IOBA-NHC cell lines. Results showed dose dependent cytotoxicity and suitable release of the compounds, promising for further development of the drug delivery system, including the optimisation of liposome-laden hydrogels to enhance ocular uptake.

URI

https://bradscholars.brad.ac.uk/handle/10454/20595

Type

Thesis

Qualification name

PhD