PubMed · 4161073
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M Stastny. 1965. Precipitation methods and large-scale methods.. https://pubmed.ncbi.nlm.nih.gov/4161073/
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Fractionation of the crude methanol extract of the ascidian Cystodytes dellechiajei collected in Brazil yielded two novel alkaloids, sebastianine A (1) and sebastianine B (2). The structures of both 1 and 2 were established by analysis of spectroscopic data, indicating an unprecedented ring system for both compounds, comprising a pyridoacridine system fused with a pyrrole unit in sebastianine A (1) and a pyridoacridine system fused with a pyrrolidine system condensed with alpha-hydroxyisovaleric acid in sebastianine B (2). Both alkaloids displayed a cytotoxic profile against a panel of HCT-116 colon carcinoma cells indicative of a p53 dependent mechanism.
[reaction: see text] A novel high-yielding method for the solid-phase synthesis of 3,6-bispeptide-acridone conjugates is reported. It involves initial coupling of bifunctionalized acridone to a resin-bound peptide followed by an on-bead site-site reaction to couple the second peptide. This method leads to clean symmetrical bispeptide derivatives and appears to be general. This strategy will enable the generation of a library of 3,6-bispeptide-acridones to be screened for selective binding to telomeric G-quadruplex DNA.
The DNA binding of two novel acridinylthioureas, ACR-NH-(CH(2))(2)-C(S)-NHCH(3) (1) and ACR-N(CH(3))-C(S)-NHCH(3) (3), and their platinum conjugates 4 and 5-derived from [PtCl(2)(en)]-was studied in cell-free model systems using various physico-chemical and biophysical methods. These included: spectrophotometric drug-DNA titrations, ethidium-DNA fluorescence quenching, competitive drug displacement, high-resolution NMR spectroscopy, and unwinding of plasmid DNA monitored by agarose gel electrophoresis. The acridinium cation of 1 showed strong binding to native DNA with K(i)=1.5 x 10(6)M(-1) and an excluded site size (n) of 2bp (McGhee-von Hippel fits of absorbance data). Compound 3 showed no measurable association with DNA. Binding of 1 was an order of magnitude stronger than that of simple 9-methylaminoacridine (2). In alternating copolymers, 1 exhibited slight AT preference. In poly(dA-dT)(2), enhanced association was accompanied by an increased binding site (approximately 3bp), while parameters in poly(dG-dC)(2) were consistent with classical intercalation. Displacement of 1 by distamycin from calf thymus DNA was suggestive of non-intercalating thiourea in 1 being located in the minor groove of the duplex. 1H NMR data of d(GGAGCTCC)(2) modified with 1 indicated intercalative binding of planar acridine, based on upfield shifts of aromatic proton signals relative to those in unbound 1 (Deltadelta approximately equal to -0.5 to -1ppm). Finally, 4 and 5 were found to unwind negatively supercoiled pUC19 plasmid by 21 degrees and 7 degrees per adduct, respectively (electrophoretic gel mobility assays). The difference in DNA binding modes of 4 and 5 is discussed as the ultimate source of the distinctly different biological activities of the conjugates.