Isolation and structural modification of 7-deoxynarciclasine and 7-deoxy-trans-dihydronarciclasine

• Published in: Journal of natural products (Washington, D.C.) Vol. 69; no. 1; pp. 7 - 13
• Main Authors: Pettit, G.R, Eastham, S.A, Melody, N, Orr, B, Herald, D.L, McGregor, J, Knight, J.C, Doubek, D.L, Pettit, G.R. III, Garner, L.C
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Pharmacognosy 2006; Glendale, AZ American Chemical Society
• Subjects: 7-deoxy-trans-dihydronarciclasine; 7-deoxynarciclasine; Amaryllidaceae Alkaloids; Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; chemical structure; crystal structure; Crystallography, X-Ray; Drug Screening Assays, Antitumor; General aspects; General pharmacology; Humans; Hymenocallis; Hymenocallis littoralis; isoquinolines; Isoquinolines - chemistry; Isoquinolines - isolation & purification; Isoquinolines - pharmacology; Leukemia P388; Medical sciences; medicinal plants; Mice; Molecular Structure; Narcissus - chemistry; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Plants, Medicinal - chemistry; Stereoisomerism; Structure-Activity Relationship; structure-activity relationships; traditional medicine; Antineoplastic agent; Monocotyledones; Lactam; P388-Leukemia; Cytotoxicity; Medicinal plant; Alkaloid; Structure activity relation; Angiospermae; Aromatic compound; Secondary alcohol; Chemical synthesis; Tumor cell; Oxygen nitrogen heterocycle; Human; Pharmacognosy; Rodentia; Tetracyclic compound; X ray diffraction; In vitro; Vertebrata; Mammalia; Cell line; Mouse; Animal; Plant origin; Isolation; Spermatophyta; Amaryllidaceae; Triol; Structural analysis; Crystalline structure
• DOI: 10.1021/np058068l
• EISSN: 1520-6025
• ISSN: 0163-3864

As an extension of structure-activity relationship studies of pancratistatin (1), various techniques were first evaluated for separating the mixtures of 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a) isolated from Hymenocallis littoralis. An efficient solution for that otherwise difficult separation then allowed the lactam carbonyl group of protected (4c and 5c) alcohols 2b and 3a to be reduced employing lithium aluminum hydride. Cleavage (TBAF followed by H2SO4) of the silyl ester/acetonide protected 6a gave amine 8. X-ray crystal structure determinations were employed to confirm the structures of 3,4-acetonide-5-aza-6-deoxynarciclasine (6b), 5-aza-6-deoxynarciclasine (8a), and 5-aza-6-deoxy-trans-dihydronarciclasine (9a, 9b). Against the murine P388 lymphocytic leukemia and a panel of human cancer cell lines, the parent natural products, 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a), were found to generally be more cancer cell growth inhibitory (GI50 0.1 to <0.01 microg/mL) than the compounds with structural modifications such as amine 8 by a factor of 10 or more. The trans ring juncture of isocarbostyril 3a proved to be an important modification of narciclasine (2a) for improving cancer cell growth inhibition in this series.