Specific inhibition of tetrapyrrole biosynthesis by 3-amino 2,3-dihydrobenzoic acid (gabaculin) in the cyanobacteriumSynechococcus 6301

Gabaculin (3-amino 2,3-dihydrobenzoic acid) inhibited the growth of cyanobacteria but not of other prokaryotes. Exposure of growing cultures ofSynechococcus 6301 to 50 M gabaculin resulted in an immediate and complete inhibition of the synthesis of chlorophylla and phycocyanin. With 8 M gabaculin, tetrapyrrole synthesis was suppressed for approximately 10 h and then resumed at a lower rate than in untreated organisms. The effect of 50 M gabaculin was reversed by transferring organisms to inhibitor-free medium; chlorophylla synthesis began within 5 h and exponential growth was re-established after about 25 h. Compared with 4,6-dioxoheptanoic acid (DA) and laevulinic acid (LA), gabaculin was a much more potent inhibitor of tetrapyrrole synthesis inSynechococcus 6301. The catalytic activity of -aminolaevulinic acid (ALA) dehydratase in vitro was inhibited by DA and LA but not by 1 mM gabaculin. However, the specific activity of the dehydratase was much lower in organisms exposed to the inhibitor for 36 h. Growing cultures and cell suspensions ofSynechococcus 6301 exposed to DA excreted appreciable quantities of ALA. In contrast, relatively small amounts of ALA accumulated in the presence of gabaculin alone and this inhibitor blocked the excretion of ALA caused by DA. This suggests that the primary effect of gabaculin is the specific inhibition of the C₅ pathway for the biosynthesis of ALA.Abbreviations ALA -aminolaevulinic acid - DA 4,6-dioxoheptanoic acid - LA laevulinic acid - GABA -aminobutyric acid     

Inhibition of human neuraminidase 3 (NEU3) by C9-triazole derivatives of 2,3-didehydro-N-acetyl-neuraminic acid

We report the synthesis of a series of C9 and N5Ac modified analogs of 2,3-didehydro-N-acetyl-neuraminic acid (DANA) and their inhibitory potency for the human neuraminidase 3 (NEU3) enzyme. We were able to generate a small library of compounds through the synthesis of azide derivatives of DANA, followed by Cu-catalyzed azide-alkyne cycloaddition (CuAAC) to generate triazole-containing inhibitors. Our results suggest that NEU3 can tolerate large hydrophobic groups at the C9 position; however, none of the derivatives made at the N5Ac side-chain were active. We identify three new inhibitors that have comparable potency to the best reported inhibitors of the enzyme.     

Inhibition of chlorophyll synthesis by kinetin in Cucumis cotyledons

Kinetin is shown to inhibit the synthesis of chlorophyll inlight while causing expansion of isolated cotyledons of Cucumis.The inhibitory effect is more marked at higher concentrationsof kinetin. It has been suggested that specific kinins may beinvolved in different tissues for stimulating chlorophyll synthesis. (Received August 14, 1969; )     

Inhibition of fatty acid synthesis by RMI 14,514 (5-tetradecyloxy-2-furoic acid)

RMI 14,514 strongly inhibited the incorporation of label from [1-¹⁴C]acetyl-CoA into fatty acids by rat liver homogenates. No inhibition was observed when [2-¹⁴C]malonyl-CoA was used as the labeled fatty acid precursor. These results suggest that the drug inhibits $\text{de novo}$ fatty acid biosynthesis at the step mediated by acetyl-CoA carboxylase. The data presented in this communication support earlier reports that RMI 14,514 probablyexerts its hypolipidemic effects by inhibition of fatty acid biosynthesis.     

Inhibition of dinoflagellate growth by extracts of barley straw (Hordeum vulgare)

Growth of dinoflagellates representing three orders, the Gymnodiniales,Peridiniales, and the Prorocentrales was examined following treatment withbarley straw extract. Selected dinoflagellate taxa showed growth responsessimilar to those reported for freshwater algae including: inhibition(Gyrodinium galatheanum, Gymnodiniumsanguineum, Heterocapsa triquetra andH. pygmaea); stimulation (Gyrodinium instriatum,Prorocentrum minimum and P. micans); and no effect(Gyrodinium estuariale, G. uncatenum,Ceratium furca, Peridinium sp.).Although barley straw extracts do not appear to have value as a universalmanagement tool for dinoflagellates, they may have potential in management ofspecific taxa and possibly taxonomic groups.     

Carotenoid composition in milo (Sorghum vulgare) shoots as affected by phytochrome and chlorophyll

The composition of coloured carotenoids in the milo shoot was investigated quantitatively (high performance liquid chromatography) during light-mediated plastidogenesis, including the time span of photodelay as caused by medium and high light fluxes. It was found that as long as only the far-red-absorbing form of phytochrome operates, the carotenoid pattern remains virtually the same as in complete darkness (violaxanthin and lutein as major constituents, traces of -carotene). On the other hand, the pattern changes dramatically in white or red light with increasing amounts of chlorophyll (lutein and -carotene dominate, -carotene showing the strongest relative increase). Photodelay during the early phase of plastidogenesis affects the carotenoid composition strongly. Increase of neoxanthin, violaxanthin and -carotene contents are diminished while lutein accumulation proves resistant towards chlorophyll-mediated photoinhibition. The photodelay can be diminished by an appropriate light pretreatment. The data indicate that light-mediated control over carotenoid accumulation is exerted at three levels: i) a coarse control through phytochrome, ii) fine tuning in connection with chlorophyll accumulation, iii) stabilization of holocomplexes against photodecomposition.Abbreviations GG14 high fluence rate green-yellow light - HPLC high-performance liquid chromatography - Chl chlorophyll - WL_w weak white light (1200 lx) - WL_m medium flux white light (12000 lx)     

New sialyl Lewis(x) mimic containing an alpha-substituted beta(3)-amino acid spacer

A highly convergent and efficient synthesis of a new sialyl Lewis(x) (sLe(x)) mimic, which was predicted by computational studies to fulfil the spacial requirements for a selectin antagonist, has been developed. With a beta(2,3)-amino acid residue l-galactose (bioisostere of the l-fucose moiety present in the natural sLe(x)) and succinate are linked, leading to a mimic of sLe(x) that contains all the required pharmacophores, namely the 3- and 4-hydroxy group of l-fucose, the 4- and 6-hydroxy group of d-galactose and the carboxylic acid of N-acetylneuraminic acid. The key step of the synthesis involves a tandem reaction consisting of a N-deprotection and a suitable O-->N intramolecular acyl migration reaction which is promoted by cerium ammonium nitrate (CAN). Finally, the new sialyl Lewis(x) mimic was biologically evaluated in a competitive binding assay.     

N-(3-(4-Hydroxyphenyl)-propenoyl)-amino acid tryptamides as SIRT2 inhibitors

A series of N-(3-(4-hydroxyphenyl)-propenoyl)-amino acid tryptamides was based on a previously reported new SIRT2 inhibitor from our group, and it was designed to study if the molecular size of the compound could be reduced. The most potent compounds, N-(3-(4-hydroxyphenyl)-propenoyl)-2-aminoisobutyric acid tryptamide and N-(3-(4-hydroxyphenyl)-propenoyl)-L-alanine tryptamide, were equipotent, 30% smaller in molecular weight, and slightly more selective (SIRT2/SIRT1) than the parent compound.     

Inhibition of nucleic acid synthesis by maleic hydrazide

Maleic hydrazide (MH), which causes chromosome breakage, inhibitionof cell division and retardation of plant growth, inhibits nucleicacid synthesis in corn and pea seedling roots. DNA synthesisin corn roots is affected sooner than RNA synthesis; the lagtimes for inhibition are 4 hr and 8–12 hr respectively.MH inhibits nucleic acid synthesis in the root apices most rapidly,while it acts on the subapical portions only after a much longerdelay and sometimes not at all. Likewise, certain fractionsof RNA synthesis are inhibited preferentially (ribosomal RNA),and others are relatively unaffected (transfer RNA). Proteinsynthesis is not affected during the early stages of MH treatment;however, it too may be reduced after a long exposure. Since0.2% colchicine does not inhibit DNA synthesis in corn rootswithin 24 hr, it seems unlikely that MH inhibits DNA synthesisindirectly through an effect on cell division. Although MH mayalso interfere with solute uptake, there is evidence that itis fairly selective in its action, i.e. it does not inhibitrespiration or cell expansion in corn roots. (Received February 22, 1972; )     

Some observations on chlorophyll(ide) synthesis by isolated etioplasts.

1. A modified procedure for the isolation of etioplasts from dark-grown barley is described and the regeneration of phototransformable protchlorophyll(ide) was demonstrated in the isolated plastids. 2. On exposure of the etioplasts to a long-term flash illumination, chlorophyll(ide) synthesis from a precursor pool, which includes all the protochlorophyllide, was demonstrated. 3. Added delta-aminolaevulinic acid failed to be significantly incorporated into chlorophyll(ide) in the etioplasts despite its extensive incorporation into porphyrin precursors of chlorophyll and haem compounds. The findings are discussed in terms of the inability of etioplasts to carry out the metal-insertion step in chlorophyll synthesis. 4. An elevated chlorophyll(ide) concentration was attained in the etioplasts by increasing the size of the utilizable precursor pool by pre-feeding whole plants with delta-aminolaevulinic acid, isolating the etioplasts and subjecting them to the flash illumination.     

Inhibition of plant fatty acid synthesis by nitroimidazoles.

1. The effect of the addition of a number of nitroimidazoles was tested on fatty acid synthesis by germinating pea seeds, isolated lettuce chloroplasts and a soluble fraction from pea seeds. 2. All the compounds tested had a marked inhibition on stearate desaturation by lettuce chloroplasts and on the synthesis of very-long-chain fatty acids by pea seeds. 3. In contrast, the effect of the drugs on total fatty acid synthesis from [14C]acetate in chloroplasts was related to the compound's electron reduction potentials. 4. Of the compounds used, only metronidazole had a marked inhibition on palmitate elongation in the systems tested. 5. The mechanism of inhibition of plant fatty acid synthesis by nitroimidazoles is discussed and the possible relevance of these findings to their neurotoxicity is suggested.