Actinoplanic acid

Actinoplanic acids A and B (Figure 15) are structurally complex polyketide-derived polycarboxylic acids isolated from the unicellular organism Actinoplanes sp. These compounds were efficiently isolated [86,87] by two-step processes employing gel filtration and reverse phase HPLC. The structure elucidation of these complex molecules required the use of a battery of 2D NMR methods. The HMBC correlations of the methyl groups to the respective carbons were most helpful in delineation of the carbon framework. 

Structurally, both compounds contain a 30-carbon straight chain tri and tetrahydroxy carboxylic acid. The alkyl chain in each compound is substituted with an ethyl and a number of methyl groups and two of the hydroxy groups are esterified with two units of tricarballylic acid. One of the methyl groups in actinoplanic acid A is oxidized to an hydroxy methyl group that, in turn, forms a 20-membered 6w-lactone ring with the free carboxy group of one of the tricarballylic acids [86,87]. 

Actinoplanic acids A and B exhibited IC50 values of 230 and 50 nM, respectively, against rHFPTase. Both compounds are competitive with FPP and displayed Kj values of 98 and 8 nM, respectively. The inhibition profile of these compounds was uncompetitive with respective to the Ras peptide substrate. The inhibition of FPTase by actinoplanic acids is selective and reversible and these compounds did not inhibit the human squalene synthase and bovine brain GGPTase (ICso s > 1 jjM) [87,88]. Similar to other examples of inhibitors that are competitive with respect to FPP, esterification of the carboxy groups of actinoplanic acids completely eliminated inhibitory activity. The increased potency of actinoplanic acid B is associated with the increased number of negative charges when compared with acid A [87,88]. 

Zmijewski, M., Gillespie, T.A., Jackson, D.A. etal. (2006) Application of biocatalysis to drug metabolism preparation of mammalian metabolites of a biaryl-bis-sulfonamide AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor potentiator using Actinoplanes missouriensis. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34, 925—931. 

LD Boeck, DS Fukuda, BJ Abbott, M Debono. Deacylation of A21978C, an acidic lipopeptide antiobiotic complex, by Actinoplanes utahensis. J Antibiot 41 1085-1092, 1988. 

Corn steep liquor Sulfuric acid Actinoplanes sp... 

Actinoplanes garbadinensis ATCC 31049 Calcium carbonate Hydrochloric acid Sodium chloride... 

Initial modification of the acyl side chain yielded FR131535.11 The synthesis of this novel echinocandin-like lipopeptide is outlined in Figure 15.5. The palmitoyl group was removed from FR901379 by treating it with acylase from Actinoplanes utahensis, which yielded FR179642. A new acyl side chain was prepared starting with 1-bromooctane and 4-hydroxybenzoic acid. 

A Malabarba, P Strazzolini, A Depaoli, M Landi, M Berti, B Cavalleri. Teicoplanin, antibiotics from Actinoplanes teichomyceticus nov. sp. VI. Chemical degradation physicochemical and biological properties of acid hydrolysis products. J Antibiot 37 988-999, 1984. 

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