Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aldehydes / chemistry
-
Amaryllidaceae Alkaloids / chemical synthesis*
-
Amaryllidaceae Alkaloids / chemistry
-
Amaryllidaceae Alkaloids / pharmacology
-
Antineoplastic Agents, Phytogenic / chemical synthesis*
-
Antineoplastic Agents, Phytogenic / chemistry
-
Antineoplastic Agents, Phytogenic / pharmacology
-
Apoptosis / drug effects
-
Aziridines / chemistry
-
Catalysis
-
Cell Line, Tumor
-
Cyclization
-
Drug Screening Assays, Antitumor
-
Epoxy Compounds / chemistry
-
Humans
-
Isoquinolines / chemical synthesis*
-
Isoquinolines / chemistry
-
Isoquinolines / pharmacology
-
Molecular Structure
-
Oxidation-Reduction
-
Phenanthrenes / chemistry
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
7-deoxypancratistatin
-
Aldehydes
-
Amaryllidaceae Alkaloids
-
Antineoplastic Agents, Phytogenic
-
Aziridines
-
Epoxy Compounds
-
Isoquinolines
-
Phenanthrenes
-
trans-dihydrolycoricidine
-
phenanthrene
-
aziridine