Development of a Multigram Synthesis of URB937, a Peripherally Restricted FAAH Inhibitor

A new synthetic approach to URB937 was developed starting from the inexpensive and widely available 4-benzyloxyphenol. A reproducible four-step procedure, requiring no chromatographic purifications, was optimized that allowed the preparation of 100 g of URB937 in 45% overall yield. © 2013 American Chemical Society

Potent Vinblastine C20′ Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line

A series of disubstituted C20′-urea derivatives of vinblastine were prepared from 20′-aminovinblastine that was made accessible through a unique Fe­(III)/NaBH₄-mediated alkene functionalization reaction of anhydrovinblastine. Three analogues were examined across a panel of 15 human tumor cell lines, displaying remarkably potent cell growth inhibition activity (avg. IC₅₀ = 200–300 pM), being 10–200-fold more potent than vinblastine (avg. IC₅₀ = 6.1 nM). Significantly, the analogues also display further improved activity against the vinblastine-resistant HCT116/VM46 cell line that bears the clinically relevant overexpression of Pgp, exhibiting IC₅₀ values on par with that of vinblastine against the sensitive HCT116 cell line, 100–200-fold greater than the activity of vinblastine against the resistant HCT116/VM46 cell line, and display a reduced 10–20-fold activity differential between the matched sensitive and resistant cell lines (vs 100-fold for vinblastine)

Cottoquinazoline A and Cotteslosins A and B, metabolites from an australian marine-derived strain of aspergillus versicolor

An Australian marine-derived isolate of Aspergillus versicolor (MST-MF495) yielded the known fungal metabolites sterigmatocystin, violaceol I, violaceol II, diorcinol, (−)-cyclopenol, and viridicatol, along with a new alkaloid, cottoquinazoline A (1), and two new cyclopentapeptides, cotteslosins A (2) and B (3). Structures for 1−3 and the known compounds were determined by spectroscopic analysis. The absolute configurations of 1−3 were addressed by chemical degradation and application of the C3 Marfey’s method. The use of “cellophane raft” high-nutrient media as a device for up-regulating secondary metabolite diversity in marine-derived fungi is discussed. The antibacterial properties displayed by A. versicolor (MST-MF495) were attributed to the phenols violaceol I, violaceol II, and diorcinol, while cotteslosins 2 and 3 were identified as weak cytotoxic agents