Over the past decade, there has been a change in the epidemiology of oral cavity squamous cell cancer (OC‐SCC). Many new cases of OC‐SCC lack the recognized risk factors of smoking, alcohol and human papilloma virus. The aim of this study was to determine if the oral microbiome may be associated with OC‐SCC in nonsmoking HPV negative patients. We compared the oral microbiome of HPV‐negative nonsmoker OC‐SCC(n = 18), premalignant lesions(PML) (n = 8) and normal control patients (n = 12). Their oral microbiome was sampled by oral wash and defined by 16S rRNA gene sequencing. We report that the periodontal pathogens Fusobacterium, Prevotella, Alloprevotella were enriched while commensal Streptococcus depleted in OC‐SCC. Based on the four genera plus a marker genus Veillonella for PML, we classified the oral microbiome into two types. Gene/pathway analysis revealed a progressive increase of genes encoding HSP90 and ligands for TLRs 1, 2 and 4 along the controls→PML → OC‐SCC progression sequence. Our findings suggest an association between periodontal pathogens and OC‐SCC in non smoking HPV negative patients.
Three diterpene-benzoate natural products, with novel carbon skeletons and an unusual proposed biosynthesis, were isolated from extracts of the Fijian red alga Callophycus serratus and identified by a combination of X-ray crystallographic, NMR, and mass spectral analyses. Bromophycolide A (1) displayed cytotoxicity against several human tumor cell lines via specific apoptotic cell death. This represents the first discovery of natural products incorporating a diterpene and benzoate skeleton into a macrolide system.The discovery of novel carbon skeletons in natural products research is uncommon, providing new targets for synthetic chemists and pharmacologists, and leading to testable hypotheses regarding biosynthetic mechanisms and ecological function. Red macroalgae are well-known for the production of brominated metabolites, including terpenoids and phenols, yet some taxa within the Rhodophyta remain relatively unstudied. Only six secondary metabolites, one oxylipin and five bromophenols, have been previously characterized from the red algal family Solieriaceae. 1,2 Herein, we report the discovery of a unique structural class of macrolides from Callophycus serratus, an understudied member of the Solieriaceae.We used bioassay-guided fractionation followed by spectroscopic and X-ray crystallographic analyses to identify three novel natural products (1-3) of unusual biosynthetic origin and possessing promising antineoplastic and antimicrobial activities. Supporting Information Available: Additional acknowledgments, experimental details, 2D NMR data (COSY, HSQC, HMBC, NOESY, ROESY), 1 H NMR spectra for 1-3, and X-ray crystallographic data (tables and CIF files) for 1 and 2. This material is available free of charge via the Internet at http://pubs.acs.org. The most abundant natural product from C. serratus, bromophycolide A (1), displayed an [M -H] − molecular ion with m/z 661.0194 and characteristic tribrominated isotopic pattern, suitable for a molecular formula of C 27 H 37 O 4 Br 3 . X-ray diffraction analysis of 1 revealed a 15-membered macrolide within a diterpene-benzoate framework (Figures 1 and 2). The bromine atom within the isopropyl appendage was disordered with respect to the isopropyl methyls over two primary positions, with 70% and 30% occupancies. The Flack parameter was refined to be −0.002(16), indicating that the geometry shown is the absolute configuration. NIH Public AccessThe NMR spectral data of 1 supported the structure derived from X-ray diffraction analysis (Table 1; Supporting Information). HMBC correlations from the methyl groups anchored the carbon skeleton, enabling assignments of all quaternary carbons. COSY and additional HMBC correlations provided the connectivity within spin systems (Supporting Information).From high-resolution mass spectral data, bromophycolide B (2) appeared to be an isomer of 1, with a parent ion with m/z 661.0191. X-ray diffraction analysis of 2 indicated a 16-membered macrolide with absolute stereochemistry predicted as in Figures 1 and 2. Chemical shift...
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