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A rapid and exhaustive one-step biomass extraction as well as an enrichment and cleanup procedure has been developed for HPLC-UV detection and quantification of closely related [7.7]paracyclophanes and structural derivatives based on a two-phase solvent system. The procedure has been validated using the biomass of the carbamidocyclophane- and cylindrocyclophane-producing cyanobacterium Nostoc sp. CAVN2 and was utilized to perform a screening comprising 102 cyanobacterial strains. As a result, three new cylindrocyclophane-related alkylresorcinols, cylindrofridins A-C (1-3), and known cylindrocyclophanes (4-6) were detected and isolated from Cylindrospermum stagnale PCC 7417. Structures of 1-3 were elucidated by a combination of 1D and 2D NMR experiments, HRMS, and ECD spectroscopy. Cylindrofridin A (1) is the first naturally occurring [7.7]paracyclophane-related monomeric derivative. In contrast, cylindrofridins B (2) and C (3) represent dimers related to 1. Due to chlorination at the alkyl carbon atom in 1-3, the site of [7.7]paracyclophane macrocycle formation, the cylindrofridins represent linearized congeners of the cylindrocyclophanes. Compounds 1-3 were not toxic against nontumorigenic HaCaT cells (IC50 values >25 μM) compared to the respective cylindrocyclophanes, but 1 was the only cylindrofridin showing moderate activity against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae with MIC values of 9 and 17 μM, respectively.

Phytochemical investigation of the leaves of Pittosporum angustifolium resulted in the isolation and structural elucidation of nine new triterpene saponins, named pittangretosides A-I (1-9), together with a known compound (10). Mainly by NMR and HRESIMS experiments, eight compounds were identified as A1-barrigenol glycosides (1-7, 10), whereas two compounds exhibited an unusual 17,22-seco-backbone of oleanolic acid (8, 9). All compounds were evaluated for their in vitro cytotoxicities against human urinary bladder carcinoma cells (5637). Only compounds with an angeloyl-residue at C-22 of the aglycone (1-4 and 10) showed antiproliferative effects with IC50 values of 4.1, 5.2, 2.1, 17.9, and 2.4 µM, respectively.

In preceding papers, we discussed the laccase-catalyzed amination of 2,5-dihydroxybenzoic acid derivatives with aminopenicillins and aminocephalosporins.2,3) The motive for our work was the global issue with resistant pathogenic bacteria, e.g. Streptococcus pneumoniae strains [4][5][6][7] and Staphylococcus strains, against currently available b-lactam antibiotics. [8][9][10][11] Aminated products like 2-(3,6-dioxocyclohexa-1,4-dienylamino)-2-phenyl-acetylamino-penicillanic acids and 2-(3,6-dioxocyclohexa-1,4-dienylamino)-2-phenyl-acetylamino-cephalosporanic acids 2,3) inhibited the growth of several Gram positive bacterial strains and protected mice against an infection with Staphylococcus aureus. After amination the 2,5-dihydroxybenzoic acid derivatives were units of the C-7 substituent of the b-lactam antibiotics.The possibility of utilizing catechol units as an element of the C-7 substituent of penicillins and cephalosporins was investigated for a long time. [12][13][14][15][16][17] Through the tonB dependent iron transport mechanism, 18) the use of catechol substituted b-lactams was known to increase the drug's penetration into the bacterial cell walls. Thus, several catechol-substituted blactams have been synthesized and showed good antimicrobial activities. [19][20][21][22][23] As a consequence of the promising activity of the catechol substituted b-lactams on one hand and the novel laccase-synthesized b-lactams on the other hand, we got interested in laccase-catalyzed amination of catechols with aminopenicillins and aminocephalosporins.In this study, we have employed laccase from Trametes sp. to derivatize amino-b-lactams and to couple them both with catechol and with substituted catechols. The novel b-lactams were structurally characterized as new coupling products inhibiting the growth of several Gram positive bacterial strains in the agar diffusion assay, among them methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. The cytotoxicity of the new compounds and the effectiveness in a "Staphylococcus-infected, immune suppressed mouse" model are discussed. Results and DiscussionBiotransformation of Amino-b b-lactams by LaccasesLaccase-catalyzed reaction between catechols (substrates 1a to 1c) on one hand and the amino-b-lactams cefadroxil 2a, amoxicillin 2b, ampicillin 2c, and the structurally related carbacephem loracarbef 2d on the other hand led to cross coupled products (Table 1). 3-Methylcatechol and amino-b-lactams were consumed after an incubation time of 1.5 h, and monoaminated products (3a to 3d) were detectable by high-performance liquid chromatography (HPLC). If other catechols or longer reaction times were used, monoaminated products were only obtained in low yields and undesirable side reactions produced a number of by-products. Reaction kinetics similar to these findings were described for hybrid dimer formation from 3,4-dichloroaniline and syringic acid 24) or 3-(3,4-dihydroxy-phenyl)-propionic acid and 4-aminobenzoic acid. 25) In contrast, for hybrid dimer form...