Synthesis, DNA/RNA-interaction and biological activity of benzo[k,l]xanthene lignans

• Published in: Bioorganic chemistry Vol. 104; pp. 104190 - 104201
• Main Authors: Tumir, Lidija-Marija, Zonjić, Iva, Žuna, Kristina, Brkanac, Sandra Radić, Jukić, Marijana, Huđek, Ana, Durgo, Ksenija, Crnolatac, Ivo, Glavaš-Obrovac, Ljubica, Cardullo, Nunzio, Pulvirenti, Luana, Muccilli, Vera, Tringali, Corrado, Stojković, Marijana Radić
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.11.2020; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative effect; Benzo[k,l]xanthene lignans; Biochemistry & Molecular Biology; Cell Proliferation - drug effects; Chemistry; Chemistry, Organic; Circulating Tumor DNA - chemistry; DNA/RNA recognition; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Escherichia coli K12 - cytology; Escherichia coli K12 - drug effects; G-quadruplex interaction; HSA interaction; Humans; Life Sciences & Biomedicine; Lignans - chemical synthesis; Lignans - chemistry; Lignans - pharmacology; Molecular Structure; Physical Sciences; RNA, Neoplasm - chemistry; Salmonella enterica - cytology; Salmonella enterica - drug effects; Science & Technology; Serum Albumin, Human - chemistry; Staphylococcus aureus - cytology; Staphylococcus aureus - drug effects; Structure-Activity Relationship; Tumor Cells, Cultured; Xanthenes - chemical synthesis; Xanthenes - chemistry; Xanthenes - pharmacology; Benzo[k,l]xanthene lignans; HSA interaction; Antiproliferative effect; G-quadruplex interaction; DNA/RNA recognition; OUTER-MEMBRANE; ACID; PROTEIN; STABILITY; DRUG BINDING-SITES; ANTIOXIDANT ACTIVITY RELATIONSHIPS; EQUILIBRIUM; SEQUENCE; DERIVATIVES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104190

[Display omitted] •Small changes in benzoxanthene (BXLs) structure influenced the DNA/RNA recognition.•BXLs with unsubstituted phenyl ring: the best stabilization effect of G-quadruplex.•Circular dichroism (CD) spectroscopy results suggest mixed binding mode to DNA/RNA.•BXLs: micromolar binding affinities toward HSA, increased protein thermal stability.•BXLs showed strong growth inhibition of Staphylococcus aureus.•Moderate to strong antiproliferative activity of BXLs. Interactions of two newly synthesized and six previously reported benzoxanthene lignans (BXLs), analogues of rare natural products, with DNA/RNA, G-quadruplex and HSA were evaluated by a set of spectrophotometric methods. Presence/absence of methoxy and hydroxy groups on the benzoxanthene core and minor modifications at C-1/C-2 side pendants – presence/absence of phenyl ring and presence/absence of methoxy and hydroxy groups on phenyl ring – influenced the fluorescence changes and the binding strength to double-stranded (ds-) and G-quadruplex structures. In general, compounds without phenyl ring showed stronger fluorescence changes upon binding than phenyl-substituted BXLs. On the other hand, BXLs with an unsubstituted phenyl ring showed the best stabilization effects of G-quadruplex. Circular dichroism spectroscopy results suggest mixed binding mode, groove binding and partial intercalation, to ds-DNA/RNA and end-stacking to top or bottom G-tetrads as the main binding modes of BXLs to those targets. All compounds exhibited micromolar binding affinities toward HSA and an increased protein thermal stability. Moderate to strong antiradical scavenging activity was observed for all BXLs with hydroxy groups at C-6, C-9 and C-10 positions of the benzoxanthene core, except for derivative bearing methoxy groups at these positions. BXLs with unsubstituted or low-substituted phenyl ring and one derivative without phenyl ring showed strong growth inhibition of Gram-positive Staphylococcus aureus. All compounds showed moderate to strong tumor cell growth-inhibitory activity and cytotoxicity.