ABSTRACT
Bioassay-guided fractionation of two marine cyanobacterial extracts using the H-460 human lung cancer cell line and the OVC-5 human ovarian cancer cell line led to the isolation of three related α-methoxy-ß, ß'-dimethyl-γ-pyrones each containing a modified alkyl chain, one of which was identified as the previously reported kalkipyrone and designated kalkipyrone A. The second compound was an analog designated kalkipyrone B. The third was identified as the recently reported yoshinone A, also isolated from a marine cyanobacterium. Kalkipyrone A and B were obtained from a field-collection of the cyanobacterium Leptolyngbya sp. from Fagasa Bay, American Samoa, while yoshinone A was isolated from a field-collection of cyanobacteria (cf. Schizothrix sp.) from Panama. One-dimensional and two-dimensional NMR experiments were used to determine the overall structures and relative configurations of the kalkipyrones, and the absolute configuration of kalkipyrone B was determined by (1)H NMR analysis of diastereomeric Mosher's esters. Kalkipyrone A showed good cytotoxicity to H-460 human lung cancer cells (EC50=0.9µM), while kalkipyrone B and yoshinone A were less active (EC50=9.0µM and >10µM, respectively). Both kalkipyrone A and B showed moderate toxicity to Saccharomyces cerevisiae ABC16-Monster strain (IC50=14.6 and 13.4µM, respectively), whereas yoshinone A was of low toxicity to this yeast strain (IC50=63.8µM).
Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Cyanobacteria/chemistry , Pyrones/isolation & purification , Pyrones/pharmacology , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , Female , Humans , Marine Biology , Molecular Structure , Panama , Pyrones/chemistryABSTRACT
The tumor-associated carbohydrate antigen/hapten Thomsen-nouveau (Tn; a-D-GalpNAc-ONH2) was conjugated to a zwitterionic capsular polysaccharide, PS A1, from commensal anaerobe Bacteroides fragilis ATCC 25285/NCTC 9343 for the development of an entirely carbohydrate cancer vaccine construct and probed for immunogenicity. This communication discloses that murine anti-Tn IgG3 antibodies both bind to and recognize human tumor cells that display the Tn hapten. Furthermore, the sera from immunization of mice with Tn-PS A1 contain cytokine interleukin 17 (IL-17A), which is known to possess anti-tumor function and represents a striking difference to an IL-2, and IL-6 profile obtained with anti-PS A1 sera.
Subject(s)
Antigens, Neoplasm/immunology , Antigens, Tumor-Associated, Carbohydrate/immunology , Bacteroides fragilis/immunology , Breast Neoplasms/immunology , Cancer Vaccines/immunology , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Carbohydrates/chemistry , Carbohydrates/immunology , Cell Line, Tumor , Female , Humans , Immune Sera/immunology , Immunity , Immunization , Immunoglobulin G/metabolism , Interleukin-17/metabolism , Mice , Mice, Inbred C57BL , Polysaccharides, Bacterial/administration & dosage , Polysaccharides, Bacterial/chemistry , Polysaccharides, Bacterial/genetics , Polysaccharides, Bacterial/immunologyABSTRACT
Bioassay-guided fractionation of two cyanobacterial extracts from Papua New Guinea has yielded hoiamide D in both its carboxylic acid and conjugate base forms. Hoiamide D is a polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS)-derived natural product that features two consecutive thiazolines and a thiazole, as well as a modified isoleucine residue. Hoiamide D displayed inhibitory activity against p53/MDM2 interaction (EC(50)=4.5 µM), an attractive target for anticancer drug development.
Subject(s)
Cyanobacteria/metabolism , Depsipeptides/pharmacology , Neoplasms/drug therapy , Proto-Oncogene Proteins c-mdm2/metabolism , Thiazoles/chemical synthesis , Thiazolidines/chemical synthesis , Tumor Suppressor Protein p53/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Isoleucine/chemistry , Magnetic Resonance Spectroscopy/methods , Models, Chemical , Ribosomes/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Thiazolidines/pharmacologyABSTRACT
A collection of Lyngbya bouillonii from Palmyra Atoll in the Central Pacific, a site several thousand kilometers distant from all previous collections of this chemically prolific species of cyanobacterium, was found to contain two new cancer cell cytotoxins of the apratoxin family. The structures of the new compounds, apratoxins F and G, were determined by 1D and 2D NMR techniques in combination with mass spectrometric methods. Stereochemistry was explored by using chromatographic analyses of the hydrolytically released fragments in combination with NMR and optical rotation comparisons with known members of the apratoxin family. Apratoxins F and G add fresh insights into the SAR of this family because they incorporate an N-methyl alanine residue at a position where all prior apratoxins have possessed a proline unit, yet they retain high potency as cytotoxins to H-460 cancer cells with IC(50) values of 2 and 14 nM, respectively. Additional assays using zone inhibition of cancer cells and clonogenic cells give a comparison of the activities of apratoxin F to apratoxin A. Additionally, the clonogenic studies in combination with maximum tolerated dose (MTD) studies provided insights as to dosing schedules that should be used for in vivo studies, and preliminary in vivo evaluation validated the predicted in vivo efficacy for apratoxin A. These new apratoxins are illustrative of a mechanism (the modification of an NRPS adenylation domain specificity pocket) for evolving a biosynthetic pathway so as to diversify the suite of expressed secondary metabolites.
