PROGETTAZIONE E SINTESI DI POTENZIALI AGENTI ANTITUMORALI INIBITORI DEL CHAPERONE MITOCONDRIALE "TUMOR NECROSIS FACTOR-RECEPTOR ASSOCIATED PROTEIN 1" (TRAP1)

It is well known that Hsp90 chaperone protein contributes in stabilizing oncoproteins over-expressed in malignant cell lines, playing a key role in survival, proliferation, invasion, metastasis and angiogenesis, which represent the hallmark traits of the cancer.1 In the last decade Hsp90 has emerged as a possible therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. TRAP 1 (Tumor Necrosis Factor-Associated Protein ), the mitochondrial isoform of Hsp90, is a component of a mitochondrial pathway selectively up-regulated in tumor cells which antagonizes the proapoptotic activity of cyclophilin D, a mitochondrial permeability transition pore regulator, and is responsible together with Hsp90, for the maintenance of mitochondrial integrity, thus favoring cell survival. Interestingly, novel TRAP1 antagonists cause sudden collapse of mitochondrial function and selective tumor cell death, suggesting that this pathway may represent a novel molecular target to improve anticancer therapy. A number of derivatives from structures of known HSP90 inhibitors, previously synthesized by our research group, has been modified to direct them into mitochondria. The idea for a mitochondrial targeting of TRAP1 inhibitors is based on the assumption of the negative potential on the matrix face of the inner mitochondrial membrane. Thus, for a first synthetic approach we have decided to linking lipophilic cations to the Hsp90 molecule inhibitors, in order to give access to cationic drugs to internalize into the negative organelles: on the basis of literature data we selected different groups as the polyamines, which protonated at physiological pH, have the optimal characteristic to pass through the mitochondria membrane and internalize into the organelle. Alternatively a group of triphenylphosphonium salts derivatives as well as of pyridinium and guanidinium ones were also considered as cationic heads for targeting TRAP1 inhibitors into mitochondria. The preliminary biological results show that some Hsp90 inhibitors proved also of interest as TRAP1 ATPase inhibitors (IC50 0.4micromolar) and that some of these have the capacity to accumulate into mitochondrial compartment. A second synthetic approach, however, has been realized by acting directly on the pharmacophore, i.e. on the structure of resorcinol, making changes on some sites essential for the binding of Hsp90, in order to act, and then selectively inhibit TRAP1. In this case, starting from some biological activity of molecule inhibitors of cytosolic Hsp90, we have made changes to see if the interaction between them and the receptor site of TRAP1 can be improved. Biological assays of this second class of compounds are still in progress.