Bis-substituted hydroxy-anthracenediones: DNA binding and biological activity.
Three new hydroxy-9,10-anthracenedione derivatives (compounds 1-3 in Figure 1), bearing two charged or polar side chains at positions 2 and 4/5 of the tricyclic system, have been investigated for their DNA binding, cytotoxic and genotoxic activity. The interaction mode with nucleic acids is intercalative for compounds 1 and 2, while external and intercalative binding probably coexist for compound 3. Complexation of the nucleic acid occurs in all cases in a cooperative manner, so that drug binding favours further binding to double helical DNA. The scale of the intrinsic binding constant is discussed in terms of the nature and position of the side chain. Cell growth and DNA synthesis inhibition data match quite well with DNA affinity. Alkaline elution experiments show a correlation between drug cytotoxicity and DNA damage. Our results indicate that the position and number of OH groups, as well as of charged side chains, play an important role in modulating drug affinity for DNA and the consequent biological effects.
Palumbo
M
M
Department of Organic Chemistry, Biopolymer Research Centre, Padova, Italy.
Palù
G
G
Gia
O
O
Ferrazzi
E
E
Gastaldi
S
S
Antonello
C
C
Meloni
G A
GA
D000880:Anthraquinones / Q000378:metabolism* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004247:DNA