Synthesis of polyamine-linked bis-daunomycin hydrazones and their interaction with DNA.
A series of bis-anthracycline hydrazones were prepared, compounds 9, containing either two or three secondary amines in the linker chain as well as the corresponding acetyl (10), or benzoyl (11) protected derivatives. Compounds 9 could not be isolated in pure form as they decomposed during semi-preparative h.p.l.c. Compounds 10a-g and 11b were characterized by f.a.b. mass spectrometry. All compounds bis-intercalated into DNA as judged by viscometric lengthening of DNA and by decreased dissociation kinetics from DNA under conditions of SDS sequestration. The secondary amine containing derivatives (9) exhibited dissociation rates less than 10(-5) that of daunomycin. The apparent affinity of these compounds was so great that the dissociation constants could not be quantitated, and they were only liberated from DNA to monomeric species by a slow hydrolysis process of the hydrazone links. Protection of those derivatives containing two amines in the linker by acetyl (10) and benzoyl (11) groups, decreased the dissociation time constant to 490-2900 s (1400-8000 fold slower than daunomycin) with maximal DNA residence time corresponding to a linker length of 14 atoms (approximately 14 A). Addition of a third protected amine in the linker, compound 10g, enhanced the DNA residence time a further three-fold. In vitro inhibition of transcription analysis showed that all of the bis-anthracyclines exhibited a DNA sequence specificity for 5'-CpA-3' sites, with adjacent intercalation sites decreasing in the order CA greater than AC, TC greater than CT greater than GC, CG, CC, TA, and it is apparent that the presence of the basic amino functions in the bridging chain provides for greatly enhanced formation of the drug-DNA complex.
Hook
R J
RJ
Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia.
Phillips
D R
DR
Reiss
J A
JA
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001483:Base Sequence; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA; D015195:Drug Design; D006835:Hydrazones; D066298:In Vitro Techniques; D007364:Intercalating Agents; D013058:Mass Spectrometry; D011073:Polyamines; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014783:Viscosity
D000903:Antibiotics, Antineoplastic; D006835:Hydrazones; D007364:Intercalating Agents; D011073:Polyamines; D004247:DNA