Tubulin and microtubules as drug targets for potential cancer chemotherapy and CNS-directed therapies

Microtubules (MTs) are key components of the cytoskeleton in most eukaryotic cells. One of the distinctive characteristics of MTs is the “dynamic instability” as their assembly is a dynamic process characterized by the continuous transitions between polymerization and depolymerization. Because of their dynamicity, MTs play a significant role in a number of essential cellular functions, such as maintenance of cell shape, cell motility, intracellular transport and cell division. Interfering with the dynamic MT equilibrium prevents proper cellular functions and ultimately leads to cell death. This strategy resulted in a productive approach that has been widely used in different therapeutic areas for the development of efficient drug treatments. Chapters 2−4 of this thesis describe the three main projects that underpin my research activity in the PhD program: (a) Drug design and synthesis of 2-phenylindole derivatives as new tubulin polymerization inhibitors and selective colchicine-binding site competitors that showed potent antimitotic activity against multi-drug resistant cell lines. These novel compounds exhibited potential to treat cancer via both MT-based and MT-independent pathways. Moreover, selected examples strongly inhibited the Hedgehog signaling pathway. (b) Structure-activity relationship (SAR) studies of multitargeted imidazoles as drug candidates for a potential therapeutic approach for Alzheimer’s disease and related neurodegenerative diseases. This study led to the identification of several compounds that exhibit balanced in vitro multitargeted activity as MT-stabilizing agents and/or cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors in the low micromolar range. In addition, several of these multitargeted agents were found to be brain-penetrant. (c) Evaluation of central nervous system (CNS)-active, tubulin polymerization promoters as potential candidate therapeutics for the human African trypanosomiasis and possible other neuroparasitic infections. These studies led to the identification of a promising drug candidate, which combines both in vitro anti-trypanosomal activity and favorable drug-like properties, including brain penetration, metabolic stability and oral bioavailability. Furthermore, SAR studies conducted on a series of MT-stabilizing triazolopyrimidine and phenylpyrimidine analogues led to the identification of several examples that kill Trypanosoma brucei in vitro with IC50 values in the single-digit nanomolar range. Finally, preliminary screening against another CNS-invasive parasite, Naegleria fowleri, revealed that this type of compounds may be of potential use in the context of different parasitic infections. Chapters 5–7 briefly present other research collaborations, in which I have been involved: (d) Discovery of 1,1′-biphenyl-4-sulfonamides as potent inhibitors of the human carbonic anhydrase ezymes. (e) SAR studies of arylboronic acids as dual ligands of fatty acid amide hydrolase (FAAH) enzyme and transient receptor potential vanilloid 1 (TRPV1) channel. (f) Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives thereof as bioisosteres of the carboxylic acid functional group and dual COX/5-LOX inhibitors.