No abstract

SKI 0 4TGNectria coccinea produces antibiotics LL-Z1272-p (1 b), -y (ascochlorin) (Za), -8 (3a). and -E (3b) together with a new metabolite for which the name chloronectrin and structure (3c) (based on 3-[5-(3-oxocyclohexyl)pent-2enyl]-5-chloro-orseliinaldehyde) are proposed. In the presence of bromide in place of chloride, N. coccinea produces an analogous 3-(penta-2,4-dienyl) -5-bromo-compound (2c). Several new derivatives in the series are reported.ANTIBIOTICS LL-21272 [a (la), p (1 b) , y (2a), 8 (3a), E (3b), and < (2b)l have been isolated from an unidentified Fusarium sp.l Antibiotic LL-21272 y (2a) (ascochlorin) published data it seems likely that ilicicolin A is identical with antibiotic LL-Z1272-a, B with -PI C with -6, D with -7, and F with -<, though no reference was made in ref. 4 to the work of Ellestad et a1.l We report here the isolation from Nectria coccinea of OR^ 0 R1 R2 R3 R4 a ; C1

Examples of a novel series of phenanthrolinones are shown to be potent competitive inhibitors of avian prolyl 4-hydroxylase, and of collagen hydroxylation, in embryonic chick tendon cells and human foreskin fibroblasts in vitro and in the oestradiol-stimulated rat uterus in vivo. Two compounds, Compound 1 (1,4-dihydrophenanthrolin-4-one-3-carboxylic acid) and Compound 5 [8-(N-butyl-N-ethylcarbamoyl)-1,4-dihydrophenathrolin-4-one-3-carboxylic acid], with comparable potencies in vivo, were chosen to investigate the effect of the inhibition of the hydroxylation of newly synthesized uterine collagen on the turnover of this protein in vivo. Inhibition of hydroxylation by more than 50% for approx. 8 h following single oral doses of the compounds was associated with significant losses of radiolabelled proline and 4-hydroxyproline from collagen during this period. Progressive hydroxylation of collagen over 48 h, as the inhibitory action of the compounds declined, was accompanied by a decreased loss of radiolabel from the uterine collagen. Earlier reports indicated that underhydroxylated collagen, accumulating within the endoplasmic reticulum in cells where prolyl 4-hydroxylase is inactivated, is slowly degraded, but is then rapidly hydroxylated and secreted when the activity of prolyl 4-hydroxylase is restored. Taken with the present results, this suggests that the potential use of inhibitors of prolyl 4-hydroxylase to control excessive collagen deposition in pathological fibrosis may be limited by the need to maintain continuous inhibition of collagen hydroxylation so as to facilitate intracellular degradation of the accumulated protein.

Examples of a novel series of phenanthrolinones are shown to be potent competitive inhibitors of avian prolyl 4-hydroxylase, and of collagen hydroxylation, in embryonic chick tendon cells and human foreskin fibroblasts in vitro and in the oestradiol-stimulated rat uterus in vivo. Two compounds, Compound 1 (1,4-dihydrophenanthrolin-4-one-3-carboxylic acid) and Compound 5 [8-(N-butyl-N-ethylcarbamoyl)-1,4-dihydrophenathrolin-4-one-3-carboxylic acid], with comparable potencies in vivo, were chosen to investigate the effect of the inhibition of the hydroxylation of newly synthesized uterine collagen on the turnover of this protein in vivo. Inhibition of hydroxylation by more than 50% for approx. 8h following single oral doses of the compounds was associated with significant losses of radiolabelled proline and 4-hydroxyproline from collagen during this period. Progressive hydroxylation of collagen over 48h, as the inhibitory action of the compounds declined, was accompanied by a decreased loss of radiolabel from the uterine collagen. Earlier reports indicated that underhydroxylated collagen, accumulating within the endoplasmic reticulum in cells where prolyl 4-hydroxylase is inactivated, is slowly degraded, but is then rapidly hydroxylated and secreted when the activity of prolyl 4-hydroxylase is restored. Taken with the present results, this suggests that the potential use of inhibitors of prolyl 4-hydroxylase to control excessive collagen deposition in pathological fibrosis may be limited by the need to maintain continuous inhibition of collagen hydroxylation so as to facilitate intracellular degradation of the accumulated protein.

The synthesis of a series of derivatives of 1-phenyl-2-[[(substituted amido)alkyl]amino]ethanols is described. The compounds were investigated for beta-adrenoceptor blocking properties, and many showed a surprising degree of potency and beta 1-cardioselectivity when tested in vivo in anesthetized cats. The structure-activity relationships shown by this series of compounds are discussed and related to known beta-adrenergic blocking agents.