Flavonoids isolated from citrus were evaluated for their ability to affect the inflammation response through suppression of cytokine expression by human monocytes. Several polymethoxylated flavones inhibited lipopolysaccharide-induced monocyte expression of tumor necrosis factor (TNFalpha). Subsequent studies centered on the compound 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) which produced the highest inhibition (IC50 = 5 microM). HMF was also a potent inhibitor of macrophage inflammatory protein-1alpha (MIP-1alpha) and interleukin-10 (IL-10) production, but not of IL-1beta, IL-6, or IL-8 production. Suppression of TNFalpha production was at the level of mRNA induction as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). HMF was also a potent inhibitor of human phosphodiesterase activity and was shown to induce a substantial elevation of cAMP levels in monocytes. The similarity of these results to the inhibition profile of the known phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, suggests that the polymethoxylated flavones inhibit cytokine production in part by suppression of phosphodiesterase activity. The ability of HMF to also inhibit IL-10 production suggests the additional existence of a phosphodiesterase-independent mechanism for this compound.

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The biosynthesis of chromomycin A3 was investigated using 1 3C-labeled acetates, methionine and glucose, and 13C,18O-labeled acetate. 13C NMRspectral analysis demonstrated that: Aglycone assembly occurs by combining at least two polyketide chains; three of nine oxygen atoms of the aglyconeoriginate fromacetate precursor oxygenatoms;carbon methylationson the aromatic ring at C-7, on the chromose B sugar, and two O-methylations appear to be carried out by 5-adenosyl-methionine requiring methyl transferases; and glucose is the precursor for all of the sugars.ChromomycinA3 (Fig. 1) is an antitumor active1} memberof the aureolic acid family of antibiotics produced by strains of Streptomyces griseus2~4\ Chromomycinone is the highly functionalized aglycone which is substituted at positions-2 and 6 with tri-and disaccharide moieties comprised of 2,6-dideoxy sugars. Early biogenesis studies using 14C-labeled precursors identified methionine, acetate and malonate