The total synthesis of the reported structure 2 for yatakemycin, an exceptionally potent, naturally occurring antitumor agent disclosed in 2003, and its lack of correlation with the natural product are detailed. On the basis of spectroscopic distinctions between 2 and yatakemycin, the natural product structure was reformulated as 3, now bearing a thiomethyl ester versus thioacetate in the left-hand subunit. Total synthesis of 3 provided a compound nearly identical to but still subtly distinct from the natural product. A second reformulation of the yatakemycin structure as 1, incorporating the alternatively substituted right-hand subunit as well as the initial thiomethyl ester reformulation, was confirmed by total synthesis of both (+)- and ent-(-)-1 in studies that also unambiguously established the absolute configuration of the natural product.

Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five base-pair AT sequence, eg. 5′-AAAAA), efficiency, relative rate, and reversibility of ent-(−)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nature of the DNA reaction, and comparisons of the cytotoxic activity of the natural product (L1210 IC 50 = 5 pM) with its unnatural enantiomer (IC 50 = 5 pM) and a series of key partial structures including those that probe the role of the C-terminus thiomethyl ester. The only distinguishing features between the enantiomers is that ent-(−)-yatakemycin alkylates DNA at a slower rate (k rel = 0.13) and is reversible, whereas (+)-yatakemycin is not. Nonetheless, even ent-(−)-yatakemycin alkylates DNA at a faster rate and with a greater thermodynamic stability than (+)-duocarmycin SA illustrating the unique characteristics of such "sandwiched" agents.

The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio. KEYWORDS: FAAH, covalent, ethanolamides, enzyme, anandamide T he fatty acid amide hydrolases 1,2 interrupt the actions, through degradation, of a variety of endogenous lipid signaling molecules.3 FAAH rapidly degrades several fatty acid ethanolamides, including FAAH's primary substrate, AEA (N-arachidonyl ethanolamide or anandamide), 4 PEA (N-palmitoyl ethanolamide), 5,6 and OEA (N-oleoyl ethanolamide).7 In contrast, FAAH-2 catabolizes ethanolamides less efficiently, but will hydrolyze long-chain primary amides. The likely source of AEA's analgesic pharmacology is its ability to agonize the cannabinoid receptor CB 1 .8−10 However, AEA is synthesized on demand and then rapidly broken down locally, which mitigates the side-effects observed as a result of systemic CB 1 agonism (e.g., Δ 9 THC pharmacology). As AEA is synthesized in a localized manner, one might hypothesize that inhibiting FAAH could lead to elevated concentrations of AEA in relevant tissues. Indeed, prior reports have described an increase in AEA levels in the plasma and brains 11−14 of rats and in the plasma of humans upon inhibition of FAAH.Small molecule interruption of FAAH activity has been examined in numerous laboratories (Figure 1)

DNA-binding small molecules are an important source of anticancer therapeutics that display a diverse array of mechanisms of action. Synthetic studies on the new DNA-alkylating natural product yatakemycin, detailed in this Highlight, have served to reassign its structure, assign the absolute stereochemistry, and provide access to yatakemycin and a series of structural analogues for biological evaluation. Studies on the DNA alkylation properties of (+)-and ent-(-)-yatakemycin and related analogues have demonstrated the enhanced DNA alkylation properties of this class of agents and provided insight into their interaction with DNA.

The ruthenium(II) cation, [Cp*Ru(NCMe)3]OTf (4), triggers the Bergman cycloaromatization of acyclic endiynes at room temperature in THF solvent. Treatment of 1,2-di(1-alkynynyl)cyclopentenes (13-Me, alkynyl = propynyl; 13-Prn, alkynyl = pentynyl; 13-Bui, alkynyl = 4-methyl-pent-1-ynyl) with 4 in THF solvent at room temperature gives rise to the ruthenium arene complexes: [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-5,6-dialkyl-1H-indene}]OTf (15-Me, alkyl = methyl, 64% yield; 15-Prn, alkyl = n-propyl, 73% yield; 15-Bui, alkyl = 4-methyl-1-pentynyl, 88% yield). In a similar fashion, the room-temperature reaction of 4 with 1-ethynyl-2-(1-propynyl)cyclopentene (11) and [2-(1-propynyl)-1-cyclopenten-1-yl]trimethylsilane (14) leads to the formation of [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-5-methyl-1H-indene}]OTf (12, 92% yield) and [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-6-methyl-1H-inden-5-yl)trimethylsilane}]OTf (16, 77% yield), respectively. The bis(TMS)-substituted enediyne (1-cyclopentene-1,2-diyldi-2,1-ethynediyl)bis(trimethylsilane) (9-TMS) and 4 underwent reaction at 100 degrees C to give [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-1H-inden-5-yl)trimethylsilane}]OTf (10, 69% yield). Deuterium-labeling studies rule out a mechanism that involves a ruthenium-vinylidene intermediate, and provide support for the involvement of a p-benzyne intermediate. In a similar fashion, complex 4 is shown to trigger the cycloaromatization of the conjugated dienyne, 1-ethenyl-2-(1-pentynyl)cyclopentene (19), at room temperature in chloroform-d1 solvent to give [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-5-(1-propyl)-1H-indene}]OTf (20, 96% yield), with no deuterium enrichment. In the absence of ruthenium the thermal cyclization reactions of unsubstituted acyclic enediynes (Bergman cycloaromatization) and acyclic conjugated dienynes (Hopf cyclization) typically require elevated temperatures (150-250 degrees C). Complexes 10 and 15-Prn were characterized structurally by X-ray crystallography.