ABSTRACT
A high throughput in vitro screen has been developed to identify substances that induce expression of C/EBPα in tumor cells. An extract of the fruit of Gyrocarpus jacquinii showed induction of C/EBPα activity that was attributed to the bisbenzylisoquinoline (BBIQ) alkaloid pheanthine (13) by dereplication analysis. The research project was broadened to assess the effect of other natural BBIQ structural types occurring outside the genus Gyrocarpus. Several of the 28 compounds assayed showed enhancement of C/EBPα induction in U937 cells. The results of this study should encourage future efforts toward obtaining and screening a larger set of both natural and synthetic analogs of this interesting group of alkaloids.
Subject(s)
Antineoplastic Agents/pharmacology , Benzylisoquinolines/pharmacology , CCAAT-Enhancer-Binding Protein-alpha/antagonists & inhibitors , Drug Discovery , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Benzylisoquinolines/chemistry , Benzylisoquinolines/isolation & purification , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Fruit/chemistry , Hernandiaceae/chemistry , High-Throughput Screening Assays , Humans , Molecular Structure , Plant Extracts/chemistry , Stereoisomerism , Structure-Activity Relationship , U937 CellsABSTRACT
Two novel, highly potent, cytotoxic macrolides, salicylihalamides A (1) and B (2), were isolated from the sponge Haliclona sp. This new macrolide class incorporates salicylic acid, a 12-membered lactone ring, and an enamide side chain. COMPARE pattern-recognition analyses of the NCI 60-cell mean graph screening profiles of 1 did not reveal any significant correlations to the profiles of known antitumor compounds in the NCI's "standard agent database", thus supporting the conclusion that the salicylihalamides represent a potentially important new class for antitumor lead optimization and in vivo investigations.
