ABSTRACT
A novel series of benzo[6,7]indolo[3,4-c]isoquinolines 3a-3f was designed by scaffold hopping of topoisomerase I inhibitor benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), which were developed by structural modification of the natural marine product lamellarin. The unconventional pentacycle was constructed by Bischler-Napieralski-type condensation of amide 11 and subsequent intramolecular Heck reaction. In vitro anticancer activity of the synthesized benzo[6,7]indolo[3,4-c]isoquinolines was evaluated on a panel of 39 human cancer cell lines (JFCR39). Among the compounds tested, N-(3-morpholinopropyl) derivative 3e showed the most potent antiproliferative activity, with a mean GI50 value of 39 nM. This compound inhibited topoisomerase I activity by stabilizing the enzyme-DNA complex.
Subject(s)
Antineoplastic Agents , Coumarins , Heterocyclic Compounds, 4 or More Rings , Isoquinolines , Topoisomerase I Inhibitors , Humans , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Topoisomerases, Type I/metabolism , Drug Screening Assays, Antitumor , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Isoquinolines/pharmacology , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/pharmacology , Drug Design , Coumarins/chemical synthesis , Coumarins/chemistry , Coumarins/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacologyABSTRACT
Nuclear import, mediated in part by karyopherin-α (KPNA)/importin-α subtypes, regulates transcription factor access to the genome and determines cell fate. However, the cancer-specific changes of KPNA subtypes and the relevancy in cancer biology remain largely unknown. Here, we report that KPNA4, encoding karyopherin-α4 (KPNA4), is exclusively amplified and overexpressed in head and neck of squamous cell carcinoma (HNSCC). Depletion of KPNA4 attenuated nuclear localization signal-dependent transport activity and suppressed malignant phenotypes and induced epidermal differentiation. Mechanistically, KPNA4-mediated nuclear transport of Ras-responsive element-binding protein (RREB1), which sustains Ras/ERK pathway signaling through repressing miR-143/145 expression. Notably, MAPK signaling enhanced trafficking activity of KPNA4 via phosphorylation of KPNA4 at Ser60. These data reveal that KPNA4 establishes a feed-forward cascade that potentiates Ras/ERK signaling in HNSCC.
Subject(s)
Carcinogenesis , DNA-Binding Proteins/metabolism , Gene Amplification , Squamous Cell Carcinoma of Head and Neck/metabolism , Transcription Factors/metabolism , alpha Karyopherins/genetics , Active Transport, Cell Nucleus , Amino Acid Sequence , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , MicroRNAs/genetics , Nuclear Localization Signals , Phosphorylation , Protein Processing, Post-Translational , Protein Transport , Sequence Alignment , Signal Transduction , Squamous Cell Carcinoma of Head and Neck/genetics , alpha Karyopherins/chemistry , alpha Karyopherins/metabolismABSTRACT
Bioassay-guided fractionation of a methanol extract of the brown alga, Dictyopteris undulata, led to the isolation of a novel sesquiterpene hydroquinone named zonarenone, together with seven known sesquiterpene hydroquinones, zonarol, isozonarol, yahazunol, zonaroic acid, chromazonarol, isochromazonarol, and 2-(3,7,11-trimethyl-2,6,10-dodecatrienyl)hydroquinone. The structure of zonarenone was elucidated on the basis of spectroscopic information. The isolated compounds, excepting zonaroic acid, showed moderate to high cell lysis activity against the red tide microalgal species, Heterosigma akashiwo and Heterocapsa circularisquama, at a concentration of 1 µg/mL.
