Sergio De Munari

Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer

The ubiquitin-proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2 S,3 R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.

Synthesis of 6′- and 7′-(3-furylmethyl) derivatives of endo-1′,2′,3′,4′-tetrahydro-1′,4′-ethano-2′-naphthylethanol with potential activity on Na+, K+-ATPase

The 6′- and 7′-(3-furylmethyl) derivatives of endo-1′,2′,3′,4′-tetrahydro-1′,4′-ethano-2′-naphthylethanol 1 have been synthesized as simplified analogues of digitoxigenin. The skeleton was built starting from 3,4-dihydro-1,4-ethanonaphthalen-2(1H)-one 2; the substituents were introduced by a Wittig–Horner reaction followed by a highly stereoselective hydrogenation to form the endo derivative 4 and successive acylation with 3-furoyl chloride to give the intermediates 8a and 8b. Tested compounds showed only moderate activity on the Na+, K+-ATPase, with IC50 values in the 10–4 mol dm–3 range.