the corresponding tocotrienols ( ␣ TE, ␤ TE, ␥ TE, and ␦ TE) ( Fig. 1 ). Among the members of the vitamin E family, ␣ T is the predominant form in tissues and is preferentially bound to a tocopherol transport protein that prevents ␣ T from being extensively metabolized ( 1 ). In contrast, other vitamin E forms are largely metabolized in the liver via -hydroxylation and oxidation to generate 13 ′ -hydroxychromanol (13 ′ -OH) and 13 ′ -carboxychromanol (13 ′ -COOH), the latter of which is subsequently metabolized via ␤ -oxidation to various shorter-chain carboxychromanols including the terminal metabolite observed in urine, 3 ′ -COOH [or 2-( ␤ -carboxyethyl)-6-hydroxychroman (CEHC)] ( Fig. 2 ) ( 1-3 ). In parallel with ␤ -oxidation, long-chain carboxychromanols and CEHCs appear to be conjugated via sulfation to form conjugated carboxychromanols ( Fig. 2 ) ( 4,5 ). The terminal metabolite CEHCs and their conjugated forms are found in the urine ( 6-11 ). On the other hand, unconjugated short-, mid-, and long-chain carboxychromanols have recently been detected in feces after supplementation of ␥ T or ␦ T ( 12-14 ).Although research on vitamin E has predominantly focused on tocopherols and tocotrienols, their metabolites have been shown to have biological activities that are stronger than or differ from the unmetabolized vitamins. For instance, ␥ -CEHC has been reported to have natriuratic activity in vitro and in animals ( 15 ). Recent studies including ours have demonstrated that long-chain carboxychromanols appear to have unique anti-infl ammatory effects by inhibition of cyclooxygenases and 5-lipoxygenase and induced apoptosis in cancer cells (16)(17)(18). For these activities, long-chain carboxychromanols are much stronger than tocopherols or shorter-chain carboxychromanols. Despite these interesting fi ndings of vitamin E metabolites, Abstract Tocopherols and tocotrienols are metabolized via hydroxylation and oxidation of their hydrophobic side chain to generate 13 ′ -hydroxychromanols (13 ′ -OHs) and various carboxychromanols, which can be further metabolized by conjugation including sulfation. Recent studies indicate that long-chain carboxychromanols, especially 13 ′ -carboxychromanol (13 ′ -COOH), appear to be more bioactive than tocopherols in anti-infl ammatory and anticancer actions. To understand the potential contribution of metabolites to vitamin E-mediated effects, an accurate assay is needed to evaluate bioavailability of these metabolites. Here we describe an LC/MS/MS assay for quantifying vitamin E metabolites using negative polarity ESI. This assay includes a reliable sample extraction procedure with effi cacy of Ն 89% and interday/intraday variation of 3-11% for major metabolites. To ensure accurate quantifi cation, short-chain, long-chain, and sulfated carboxychromanols are included as external/ internal standards. Using this assay, we observed that sulfated carboxychromanols are the primary metabolites in the plasma of rodents fed with ␥ -tocopherol or ␦ -tocopherol. Although plasma levels of 13...

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.

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Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.

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