Discovery of Small-Molecule Inhibitors of Receptor Activator of Nuclear Factor-κB Ligand with a Superior Therapeutic Index.

Receptor activator of nuclear factor-κB ligand (RANKL) constitutes the master mediator of osteoclastogenesis, while its pharmaceutical inhibition by a monoclonal antibody has been approved for the treatment of postmenopausal osteoporosis. To date, the pursuit of pharmacologically more favorable approaches using low-molecular-weight inhibitors has been hampered by low specificity and high toxicity issues. This study aimed to discover small-molecule inhibitors targeting RANKL trimer formation.

Rationally designed less toxic SPD-304 analogs and preliminary evaluation of their TNF inhibitory effects.

SPD-304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD-304 contains a potentially toxic 3-alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD-304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF.

Larvicidal activity of naturally occurring naphthoquinones and derivatives against the West Nile virus vector Culex pipiens.

Concentration-dependent mortality effects were observed for three pure synthetic natural products (alkannin, shikonin, and shikalkin) and three acetylated derivatives of shikonin against Culex pipiens (Culicidae: Diptera) for the first time. The larvicidal properties of all naphthoquinones were evaluated under laboratory conditions against the larvae of the mosquito species C. pipiens biotype molestus, the anthropophilic biotype of the C.

A new efficient route for multigram asymmetric synthesis of alkannin and shikonin.

A short and convergent approach for the synthesis of alkannin, shikonin and shikalkin is presented. A Hauser-type annulation of cyanophthalide 26 with enone 7 affords the complete aromatic system in just one step with concomitant attachment of the entire side chain. Subsequent Corey's oxazaborolidine mediated asymmetric reduction of the above advanced intermediate, leads to the required isomer in high enantiomeric excess.