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Tesi etd-10262015-130009

Thesis type
Tesi di laurea magistrale LM5
Design and Synthesis of New ADAMTS5 Inhibitors
Corso di studi
relatore Dott.ssa Nuti, Elisa
Parole chiave
  • aggrecanase inhibitors
  • ADAMTS-5
  • aggrecan
  • Osteoarthritis
  • dimers
  • hydroxamic derivatives
Data inizio appello
Data di rilascio
Riassunto analitico
ADAMTS family is made by 19 secreted zinc metalloproteinases which have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration.1 Among these, ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2) have been identified as the major enzymes responsible for the cleavage of the aggrecan which endows articular cartilage with its unique compressive resistance. The physiological regulation of aggrecanase activity in necessary to maintain a fine balance between aggrecan anabolism and catabolism. In pathologies as Osteoarthritis the balance is disturbed in favor of catabolism and we assist to a progressive destruction of articular cartilage. At the moment the OA treatment is limited to steroidal and non-steroidal anti-inflammatory drugs to obtain a relief for pain and inflammation but they do not arrest or slow down the progression of the disease. For this reason it is crucial to design some specific aggrecanase inhibitors which can be eventually used as potential therapeutic agents for OA.
The catalytic site of ADAMTS 5 is characterized by a deep solvent-exposed cleft between the two pockets S1’ and S2’ which present at the center a catalytic zinc ion.2 The majority of the disclosed aggrecanase inhibitors is characterized by the presence of a zinc binding group (ZBG) and of lipophilic components which can interact with the S1’ and S2’ pockets of the enzyme.3 The design of selective inhibitors of ADAMTS5 is essential to avoid the undesired inhibition of other ADAMTS or other metalloproteases. Comparing different inhibitors structures, it has been shown that the specificity of inhibition is driven by different factors such as water binding, zinc rigidity, pocket size, shape and conformation flexibility.4
The project of my thesis was focused on the optimization of some derivatives which have been previously described with good results by Prof Rossello’s group.5 To improve potency and selectivity the arylsulfonamidic structure was modified to obtain dimeric derivatives and monomeric derivatives with different Zinc binding groups. The newly synthesized compounds will be tested by in vitro fluorimetric assay for their inhibitory activity against ADAMTS5.

1Suneel S. Apte, A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motifs: the ADAMTS family, Int. J. Biochem. Cell Biol., (2004), 36: 981-985 2Maingot, L., Elbakali, J., Dumont, J., Bosc, D., Cousaert, N., Urban, A., Deglane, G., Villoutreix, B., Nagase, H., Sperandio, O., Leroux, F., Deprez, B., Deprez-Poulain, R., Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group, Eur. J. Med. Chem., (2013), 69: 244-261 3Gilbert, A., Bikker, J., O’Neil, S., Advances in the development of novel aggrecanase inhibitors, ExpertOpin.Ther. Patents, (2011), 21(1): 1-12 4Tortorella, M., Tomaselli, A., Mathis, K., Schnute, M., Woodard, S., Munie, G., Williams, J., Caspers, N., Wittwer, A., Malfait, A., Shieh, H., Structural and inhibition analysis reveals the mechanism of selectivity of a series of aggrecanase inhibitors, J. Biol. Chem., (2009), 284(36): 24185-24191
5Nuti, E., Santamaria, S., Casalini, F., Yamamoto, K., Marinelli, L., La Pietra, V., Novellino, E., Orlandini, E., Nencetti, S., Marini, A. M., Salerno, S., Taliani, S., Da Settimo, F., Nagase, H., Rossello, A., Arylsulfonamide inhibitors of aggrecanses as potential therapeutic agents for osteoarthritis: Synthesis and biologicalevaluation, Eur. J. Med. Chem., (2013), 62, 379-394