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Combinations of structural elements found in (methoxyalkyl)thiazole 1a and methoxytetrahydropyran 2a with a naphthalenic lignan lactone produce the potent 5-lipoxygenase (5-LO) inhibitors 3 and 4. While the nature of link Y-Z has a major effect on the in vitro activity of compounds 1 and 2, inhibitors 3 and 4 retain their potencies with either an oxymethylene (Y = O, Z = CH2) or a methyleneoxy (Y = CH2, Z = O) link. Compound 4b inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 14 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 1.5 nM) as well as in human whole blood (IC50 = 50 nM). Compound 4b is a selective 5-LO inhibitor showing no significant inhibition of human 15-lipoxygenase or porcine 12-lipoxygenase or binding to human 5-lipoxygenase-activating protein up to 10 microM and inhibits leukotriene biosynthesis by a direct, nonredox interaction with 5-LO. Compound 15, the open form of lactone 4b, is well absorbed in the rat and is transformed into the active species 4b. In addition, 15 is orally active in the rat pleurisy model (ED50 = 0.6 mg/kg) and in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.3 mg/kg).

The synthesis, cell growth-inhibitory activity, in vivo antileukemic activity, and extent of DNA binding of the alpha- and beta-anomeric 7-O-(3-amino-3,5-dideoxy-D-ribofuranosyl)daunomycinones and their trifluoroacetamides are described. These compounds are unique in that they are the first reported furanoside analogues of the antitumor antibiotics daunorubicin and adriamycin. Continuing analysis of structure-activity relationships amongst natural and semisynthetic anthracyclines fails to reveal a predictable relationship between in vivo antitumor activity and the in vitro properties of DNA complexation and cell growth inhibition.

Arylacetic acid antiinflammatory drugs can be metabolically produced by beta-oxidation of a 6-arylhex-5-enoic acid side chain. Such a mechanism provides for an in vivo sustained release of the active principle indomethacin from 6-[N-(p-chlorobenzoyl)-2-methylindol-3-yl]hex-5-enoic acid (7). Similarly, biphenylacetic acid was produced from both 6-(4'-biphenylyl)hex-5-enoic acid and its lower even homologue, 4-(4'-biphenylyl)but-3-enoic acid. The indole derivative produced sustained analgesia in a yeast-induced hyperalgesia model over a 12-h period. Indomethacin plasma levels of 2 micrograms/mL were observed for up to 24 h. Such levels were less than those achieved for the analogous case in which biphenylacetic acid was produced from biphenylylhex-5-enoic acid, suggesting metabolic discrimination between hex-5-enoic substrates. When indomethacin was dosed in equipotent analgesic levels, the level of circulating drug was considerably higher than that seen for metabolically derived drug. Hence 6-hex-5-enoic acid derivatives of indomethacin are metabolized to indomethacin in vivo to give sustained analgesia at low apparent circulating plasma levels of free drug. The possibility of tissue compartmentalization enhancing biological efficacy is suggested by these observations.