Chemoenzymatic synthesis of Amaryllidaceae constituents and biological evaluation of their C-1 analogues. The next generation synthesis of 7-deoxypancratistatin and trans-dihydrolycoricidine.
An efficient synthesis of C-1 derivatives of 7-deoxypancratistatin is reported. The key steps include the following: selective opening of an epoxide with aluminum acetylide in the presence of an aziridine; solid-state silica-gel-catalyzed opening of an aziridine; and oxidative cleavage of a phenanthrene core and its recyclization to phenanthridone to provide the key C-1 aldehyde 22. The conversion of this aldehyde to C-1 acetoxymethyl and C-1 hydroxymethyl derivatives is described along with the evaluation of their biological activity against several cancer cell lines and in an apoptosis study. The C-1 acetoxymethyl derivative has shown promising activity comparable to that of the natural product. In addition, a total synthesis of trans-dihydrolycoricidine and a formal total synthesis of 7-deoxypancratistatin are reported from aldehyde 22. Detailed experimental and spectral data are provided for all new compounds.
Collins
Jonathan
J
Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada.
Rinner
Uwe
U
Moser
Michael
M
Hudlicky
Tomas
T
Ghiviriga
Ion
I
Romero
Anntherese E
AE
Kornienko
Alexander
A
Ma
Dennis
D
Griffin
Carly
C
Pandey
Siyaram
S
D000447:Aldehydes / Q000737:chemistry; D047151:Amaryllidaceae Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001388:Aziridines / Q000737:chemistry; D002384:Catalysis; D045744:Cell Line, Tumor; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000737:chemistry; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010616:Phenanthrenes / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C418326:7-deoxypancratistatin; D000447:Aldehydes; D047151:Amaryllidaceae Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D001388:Aziridines; D004852:Epoxy Compounds; D007546:Isoquinolines; D010616:Phenanthrenes; C551128:trans-dihydrolycoricidine; C031181:phenanthrene; C033132:aziridine