Key studies leading to the discovery and definition of the role of endogenous fatty acid amide signaling molecules are summarized.

A summary of the discovery and advancement of inhibitors of fatty acid amide hydrolase (FAAH) is presented.

We report an extensive structure-activity relationship (SAR) of 62 compounds active against two drug-resistant colon cancer cell lines. Our comprehensive evaluation of two generations of compounds utilizes SAR, NMR, and molecular modeling to evaluate the key 3D features of potent compounds. Of the seven most potent compounds reported here, five are second-generation, emphasizing our ability to incorporate potent features found in the first generation and utilize their structures to design potency into the second generation. These analogs share no structural homology to current colon cancer drugs, are cytotoxic at levels on par with existing drugs treating other cancers, and demonstrate selectivity for drug-resistant colon cancer cell lines over noncancerous cell lines. Thus, we have established sansalvamide A as an excellent lead for treating multiple drug-resistant colon cancers.

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 analogs 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 analogs 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).

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