Andrea Chiminazzo

Low toxicity and unprecedented anti-osteoclast activity of a simple sulfur-containing gem-bisphosphonate: A comparative study

Bisphosphonates (BPs) are key drugs for the treatment of bone resorption diseases like osteoporosis, Pagets disease and some forms of tumors. Recent findings underlined the importance of lipophilic N-containing BPs to ensure high biological activity. Herein we present some unprecedented results concerning the low toxicity and good anti-osteoclast activity of low molecular weight hydrophilic S-containing BPs. A series of S and N-containing BPs bearing aromatic and aliphatic substitution were prepared through Michael addition reaction between vinylidenebisphosphonate tetraethyl ester and the proper nucleophile under basic catalysis. S-containing BPs showed a generally low toxicity, determined with the neutral-red assay using the L929 cell line, and, in particular for an aliphatic one, a good biological activity assessed on primary cultures of human osteoclasts.

Copper‐mediated 1,4‐Conjugate Addition of Boronic Acids and Indoles to Vinylidenebisphosphonate leading to gem‐Bisphosphonates as Potential Antiresorption Bone Drugs

A wide range of gem‐bisphosphonate tetraethyl esters as precursors for bisphosphonic acids, which are potent inhibitors of bone resorption, bearing alkyl, aryl, and indole substituents in the β position were prepared through the CuII‐catalyzed 1,4‐conjugate addition of boronic acids and indoles to vinylidenebisphosphonate tetraethyl ester.

Water enhanced synthesis of gem-bisphosphonates via Rh(I) mediated 1,4-conjugate addition of aryl boronic acids to vinylidenebisphosphonate esters

A new synthetic method characterized by low environmental impact for the synthesis of a wide range of gem-bisphosphonates bearing aryl substituents in β position as potential anti-resorption species to contrast osteoporosis is reported. The pivotal role played by water ensures higher yields compared to the organic medium in the rhodium-catalyzed 1,4-conjugate addition of arylboronic acids to vinylidenebisphosphonate tetraethylester, as well as easy product isolation.

Pyrrolidine Containing Bisphosphonates as Potential Anti-Resorption Bone Drugs

Bisphosphonates, particularly those with N-substituted groups, are currently the most popular drugs for the treatment of osteoporosis. However, their chemical structures are still rather simple and new synthetic methods are needed to expand their molecular complexity and also improve their specificity of action towards other targets as anticancer, antibacterial, and antimalarial drugs. Herein, we report a new class of potential antiresorption bisphosphonate drugs that have a pyrrolidine unit with different substituents, obtained through a simple dipolar cycloaddition reaction between azomethine ylides and vinylidenebisphosphonate derivatives as precursors. The methodology led to the efficient preparation of a wide range of (1-methylpyrrolidine-3,3-diyl)bis(phosphonic esters) derivatives with different substituents in position 4.