Antiviral and anticancer optimization studies of the DNA-binding marine natural product aaptamine.
Aaptamine has potent cytotoxicity that may be explained by its ability to intercalate DNA. Aaptamine was evaluated for its ability to bind to DNA to validate DNA binding as the primary mechanism of cytotoxicity. Based on UV-vis absorbance titration data, the K(obs) for aaptamine was 4.0 (+/-0.2) x 10(3) which was essentially equivalent to the known DNA intercalator N-[2-(diethylamino)ethyl]-9-aminoacridine-4-carboxamide. Semi-synthetic core modifications were performed to improve the general structural diversity of known aaptamine analogs and vary its absorption characteristics. Overall, 26 aaptamine derivatives were synthesized which consisted of a simple homologous range of mono and di-N-alkylations as well as some 9-O-sulfonylation and bis-O-isoaaptamine dimer products. Each product was evaluated for activity in a variety of whole cell and viral assays including a unique solid tumor disk diffusion assay. Details of aaptamine's DNA-binding activity and its derivatives' whole cell and viral assay results are discussed.
Bowling
John J
JJ
Department of Pharmacognosy, School of Pharmacy and The University of Mississippi, University, MS 38677, USA.
Pennaka
Hari K
HK
Ivey
Kelly
K
Wahyuono
Subagus
S
Kelly
Michelle
M
Schinazi
Raymond F
RF
Valeriote
Frederick A
FA
Graves
David E
DE
Hamann
Mark T
MT
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D008386:Marine Biology; D009287:Naphthyridines / Q000378:metabolism / Q000494:pharmacology*; D011161:Porifera / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001688:Biological Products; D009287:Naphthyridines; D004247:DNA; C043986:aaptamine