Isolation and structural modification of 7-deoxynarciclasine and 7-deoxy-trans-dihydronarciclasine.
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.
Pettit
George R
GR
Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-2404, USA. bpettit@asu.edu
Eastham
Stephen A
SA
Melody
Noeleen
N
Orr
Brian
B
Herald
Delbert L
DL
McGregor
Jane
J
Knight
John C
JC
Doubek
Dennis L
DL
Pettit
George R
GR
Garner
Lynnette C
LC
Bell
Joy A
JA
D047151:Amaryllidaceae Alkaloids; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology; D007941:Leukemia P388; D051379:Mice; D015394:Molecular Structure; D031427:Narcissus / Q000737:chemistry*; D010946:Plants, Medicinal / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C508325:7-deoxy-trans-dihydronarciclasine; C445686:7-deoxynarciclasine; D047151:Amaryllidaceae Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D007546:Isoquinolines; C044997:pancratistatin