RESUMO
Bioassay-guided fractionation of the methanolic extract of the roots of Rhaphiolepis indica var. tashiroi afforded four new dibenzofurans, 2-hydroxy-3,4,6-trimethoxydibenzofuran (1), 2-hydroxy-3,4,9-trimethoxydibenzofuran (2), 2-hydroxy-3,4,6,9-tetramethoxydibenzofuran (3), and 1,2-methylenedioxy-3,4,6-trimethoxydibenzofuran (4), two new biphenyls, 3-hydroxy-2',5-dimethoxybiphenyl (5) and 2',3-dihydroxy-5-methoxybiphenyl (6), and 3-hydroxy-5-methoxybiphenyl (7). Among the isolates, 3, 5, and 6 exhibited inhibitory effects on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide production, with in vitro IC50 values < 8.36 µM.
Assuntos
Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Benzofuranos/isolamento & purificação , Benzofuranos/farmacologia , Compostos de Bifenilo/isolamento & purificação , Compostos de Bifenilo/farmacologia , Rosaceae/química , Anti-Inflamatórios/química , Benzofuranos/química , Compostos de Bifenilo/química , Humanos , Concentração Inibidora 50 , Estrutura Molecular , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Raízes de Plantas/química , Superóxidos , TaiwanRESUMO
A series of new, water-soluble phenyl N-mustard-benzenealkylamide conjugates containing hydrophilic ω-dialkylaminoalkylamide or ω-cyclic aminoalkylamide moieties were synthesized via a bioisostere approach. These compounds have a broad spectrum of antitumor activity against a panel of human tumor cell lines. Of these derivatives, compound 18b effectively suppressed the growth of colon cancer (HCT-116), prostate cancer (PC3), and lung cancer (H460) xenografts. The growth of HCT-116 xenografts was almost completely suppressed when co-treated with compound 18b and 5-fluorouracil. Furthermore, compound 18b can induce DNA cross-linking and cell-cycle arrest at the G2/M phase. Early preclinical studies, including pharmacokinetics in rats, inhibition of the hERG, and 14 days of acute intravenous injection toxicity, suggest that compound 18b is a promising candidate for further preclinical studies.