Back to Search
Start Over
An improved high yield total synthesis and cytotoxicity study of the marine alkaloid neoamphimedine: an ATP-competitive inhibitor of topoisomerase IIα and potent anticancer agent.
- Source :
-
Marine drugs [Mar Drugs] 2014 Sep 19; Vol. 12 (9), pp. 4833-50. Date of Electronic Publication: 2014 Sep 19. - Publication Year :
- 2014
-
Abstract
- Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC50 values) in all, with significant potency against colorectal cancer (lowest IC50 = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis.
- Subjects :
- Acid Phosphatase metabolism
Antigens, Neoplasm drug effects
Antigens, Neoplasm metabolism
Apoptosis drug effects
Cell Cycle drug effects
Cell Line, Tumor
DNA Topoisomerases, Type II drug effects
DNA Topoisomerases, Type II metabolism
DNA-Binding Proteins drug effects
DNA-Binding Proteins metabolism
G2 Phase drug effects
Humans
Models, Molecular
Rhodamines chemistry
Acridines chemical synthesis
Acridines pharmacology
Antineoplastic Agents chemical synthesis
Antineoplastic Agents pharmacology
Topoisomerase II Inhibitors chemical synthesis
Topoisomerase II Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1660-3397
- Volume :
- 12
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Marine drugs
- Publication Type :
- Academic Journal
- Accession number :
- 25244109
- Full Text :
- https://doi.org/10.3390/md12094833