In vitro cytotoxic activity of phenanthroindolizidine alkaloids from Cynanchum vincetoxicum and Tylophora tanakae against drug-sensitive and multidrug-resistant cancer cells.
Two known phenanthroindolizidine alkaloids, (-)-(R)-13aalpha-antofine (1) and (-)-(R)-13aalpha-6-O-desmethylantofine (2), and two new natural products, (-)-(R)-13aalpha-secoantofine (3) and (-)-(R)-13aalpha-6-O-desmethylsecoantofine (4), were isolated from Cynanchum vincetoxicum. The structures of all compounds were established by means of NMR methods including COSY, NOESY, HSQC, and HMBC experiments, supported by HRMS and optical rotation data. Cytotoxic activity of the isolated alkaloids, and of three other alkaloids previously isolated from Tylophora tanakae, (-)-(R)-13aalpha-tylophorine (5), (-)-(R)-13aalpha-7-O-desmethyltylophorine (6), and (+)-(S)-13abeta-isotylocrebrine (7), was assessed in vitro using a drug-sensitive KB-3-1 and a multidrug-resistant KB-V1 cancer cell line. Structure-activity relationships in this series of alkaloids are discussed. The IC(50) values of some of the alkaloids are in the low nanomolar range, being thus comparable to the activity of clinically used cytotoxic drugs. Previously reported adverse side effects of these alkaloids could possibly be overcome by modern tissue-specific drug targeting techniques.
D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D031105:Cynanchum / Q000737:chemistry*; D003718:Denmark; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010616:Phenanthrenes; D018515:Plant Leaves / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms; D014747:Vinblastine / Q000494:pharmacology
C470362:13a-6-O-desmethylantofine; C470361:13a-antofine; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D007546:Isoquinolines; D010616:Phenanthrenes; D014747:Vinblastine