Subsidiary hydrogen bonding of intercalated anthraquinonic anticancer drugs to DNA phosphate.
Several anthraquinone derivatives are active against different kinds of human cancer. The cancerostatic activity has been mainly attributed to their ability to bind strongly to DNA by intercalation. Here, infrared spectroscopy was used to detect further, more specific DNA interactions with the prominent anticancer drugs daunomycin, adriamycin, aclacinomycin A and mitoxantrone as well as with the cytotoxic violamycin BI. The most striking result was a significant decrease in wave number of the band arising from antisymmetric stretching vibration of the PO2- groups of DNA upon complexation with adriamycin, aclacinomycin A, violamycin BI and mitoxantrone. This became evident after separation of the contributions from conformational changes of DNA to the influence on the wave number of that band. The drug-induced shift was interpreted in terms of the formation of a hydrogen bond between the intercalated drug molecules and the PO2- moiety of DNA via the following terminal hydroxyl groups: C14-OH for adriamycin, C4-OH for both aclacinomycin A and violamycin BI and, more tentatively, the external side-chain OH of mitoxantrone. Theoretical considerations, consisting of semi-empirical CNDO/2 calculations as well as normal coordinate analyses performed with molecular model fragments, provided results confirming and rationalising the experimental findings. The capacities of the anthracyclines for restriction of the conformational flexibility of DNA differ, presumably due to variations in the spatial dimensions of the sugar moieties of the drugs. The compatibility of the present results with data obtained from current geometrical models, especially those for the DNA-daunomycin and DNA-adriamycin complexes, is discussed in detail.
Central Institute of Microbiology and Experimental Therapy, Academy of Sciences of the G.D.R., Jena.
W
W
Pohle
M
M
Bohl
J
J
Flemming
H
H
Böhlig
D000880:Anthraquinones / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004273:DNA, Neoplasm / Q000187:drug effects*; D006813:Humidity; D006860:Hydrogen Bonding; D008962:Models, Theoretical; D008968:Molecular Conformation; D013055:Spectrophotometry, Infrared
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm