Total synthesis and biological evaluation of Amaryllidaceae alkaloids: narciclasine, ent-7-deoxypancratistatin, regioisomer of 7-deoxypancratistatin, 10b-epi-deoxypancratistatin, and truncated derivatives.
Biocatalytic approaches have yielded efficient total syntheses of the major Amaryllidaceae alkaloids, all based on the key enzymatic dioxygenation of suitable aromatic precursors. This paper discusses the logic of general synthetic design for lycoricidine, narciclasine, pancratistatin, and 7-deoxypancratistatin. Experimental details are provided for the recently accomplished syntheses of narciclasine, ent-7-deoxypancratistatin, and 10b-epi-deoxypancratistatin via a new and selective opening of a cyclic sulfate over aziridines followed by aza-Payne rearrangement. The structural core of 7-deoxypancratistatin has also been degraded to a series of intermediates in which the amino inositol unit is cleaved and deoxygenated in a homologous fashion. These truncated derivatives and the compounds from the synthesis of the unnatural derivatives have been tested against six important human cancer cell lines in an effort to further develop the understanding of the mode of action for the most active congener in this group, pancratistatin. The results of the biological activity testing as well as experimental, spectral, and analytical data are provided in this manuscript for all relevant compounds.
Hudlicky
Tomas
T
Department of Chemistry, University of Florida, Gainesville 32611-7200, USA.
Rinner
Uwe
U
Gonzalez
David
D
Akgun
Hulya
H
Schilling
Stefan
S
Siengalewicz
Peter
P
Martinot
Theodore A
TA
Pettit
George R
GR
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047151:Amaryllidaceae Alkaloids; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007941:Leukemia P388; D019684:Magnoliopsida / Q000737:chemistry; D051379:Mice; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010617:Phenanthridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
C473585:10b-epi-deoxypancratistatin; C418326:7-deoxypancratistatin; D000470:Alkaloids; D047151:Amaryllidaceae Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D007546:Isoquinolines; D010617:Phenanthridines; C010753:narciclasine; C044997:pancratistatin; C015330:lycorine