Protein homeostasis or proteostasis is achieved through a dynamic balance between protein synthesis and degradation. The ubiquitin proteasome pathway is responsible for the breakdown of approximately 80% of intracellular proteins. The protein is firstly tagged by ubiquitin molecules, and then targeted for degradation by the proteasome. Abnormalities in protein synthesis, folding, transportation, degradation, chromosomal imbalance, oncogenic activation, and translation errors can lead to an imbalance in the protein homeostasis and result in a wide range of human illnesses and diseases, such as cancer, autoimmune diseases, and neurodegenerative disorders.
Proteasome inhibition has emerged as a powerful strategy for anti-cancer therapy. The constitutive proteasome, commonly referred to as the 26S proteasome, is a large, multicatalytic enzyme complex of approximately 2.5 MDa, consisting of a 20S catalytic core particle made up of seven α subunits (α 1-7) and seven β subunits (β 1-7), with catalytic protease activity residing in the β1, β2, and β5 subunits. The 20S core is associated with one or two regulatory particles, which could be 19S (PA700), which is ATP-dependent, as well as 11S (PA28, PA26, REG) or PA200 which are ATP-independent.
Proteasome inhibitors mediate their apoptotic effect in tumor cells via the inhibition of NFκB activity, inhibition of angiogenesis and DNA repair, altered degradation of cell-cycle-related proteins, altered pro-apoptotic and anti-apoptotic protein balance, and endoplasmic reticulum stress.
Ridaifen (RID) compounds are tamoxifen (TAM) analogues, with RID-F featuring two homopiperidine moieties on rings B and C. RID-F was the most effective in inhibiting all three proteasome functions, which are chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-peptidyl glutamyl peptide hydrolase (PGPH).
Besides the established role of proteasome inhibitor (PI) drugs in the treatment of hematological malignancies such as multiple myeloma and mantle cell lymphoma, PIs have emerged as promising drug candidates for other conditions, including neurodegenerative disorders, inflammation, immune diseases, ischemic stroke, and tuberculosis.
In light of this, we report the design and synthesis of novel ridaifen analogues that target the proteasome enzyme. The synthesized analogues maintained the triphenylethylene scaffold of ridaifen, while varying the substituents on rings A, B and C.
