![]() ![]() In this context, different classes of tricyclic systems containing the oxale ring were synthetized and evaluated for their antitumor activity. In particular, 4,5-diarylisoxazoles demonstrated potent antiproliferative activity, ability in the induction of G2/M phase cell cycle arrest and potent antitubulin activity. Cis-restricted CA-4 analogues were synthetized to stabilize the cis configuration of the olefinic double bond, which is crucial for their activity. CA-4 can also disrupt tumor vasculature, resulting in necrosis of tumor cells. Combretastatin A-4 (CA-4) represents a promising lead compound since it has demonstrated potent activity against different cancer cell lines through the inhibition of tubulin polymerization binding at the colchicine site. In the drug discovery process, molecules binding at the colchicine site attract great attention, as there is no approved candidate so far. ![]() This evidence rekindled the interest of medical research toward the design of novel MTAs with lower toxicity and increased selectivity to reduce the off-target effects that constitute the major limit for clinical practice. Among these mechanisms are the decrease of angiogenesis and cell migration, as well as the stimulation of the immune response. However, the classical view of MTAs was overcome over time thanks to the additional molecular mechanisms that emerged as being responsible for their therapeutic effect. The MT-stabilizing agents (MSAs) are able to bind taxane or laulimalide/peloruside sites, while the MT-destabilizing agents (MDAs) are able to bind vinca or maytansine domain, colchicine, pironectin or gatorbulin sites. MTAs are conventionally divided into two groups depending on their ability to stabilize or destabilize MT polymers through the binding of one of the seven sites of tubulin. These agents interfere with the microtubule (MT) dynamics killing proliferating cells via mitotic arrest and apoptosis. Microtubule targeting agents (MTAs) are commonly used for the treatment of cancer patients within conventional regimens, especially for tumors that lack actionable mutations and/or are resistant to personalized treatments. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2α protein level. We found that the treatment with SIX2G inhibited cell viability by inducing G2/M phase cell cycle arrest and apoptosis. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1/GADD34 complex. On these bases, a new class of tricyclic compounds, containing the oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. A novel diaryl oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment.
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