Characteristics of Anti-helicase Action of Anthracyclines1
The helicases are the class of enzymes responsible for the dissociation of duplex DNA into DNA single strands. This requires energy from ATP hydrolysis - about two molecules of ATP are consumed for every base pair that is separated to be used as a template. For DNA replication, as a pre-requisite for RNA transcription, the duplex DNA strands must be separated to expose the DNA single strands for bio-molecular processing2 via DNA polymerase and ligase enzymes. DNA synthesis starts with an RNA (ribonucleic acid) primer that is subsequently erased. At least 15 enzymes (proteins!) are directly responsible in DNA replication.
The activities, specificities and other characteristics of the helicase enzymes vary. It is noteworthy that the rates of unwinding and estimates of activities for the three helicases suggest different kinetic characteristics for these enzymes as well as different sensitivities to intercalating drugs.
In addition to increasing stability, anthracycline intercalation also increases DNA helix rigidity and deforms, lengthens and unwinds the DNA helix. Blockade of helicase activity could result from any of these effects or a combination of them. DNA deformation results from a change in DNA helicity (unwinding angle) and steric factors of the drug blocking the wide and narrow groove. Other factors such as base sequence specificity, the duplex DNA base to drug ratio and structural characteristics of the intercalating agents themselves must also be considered. Daunorubicin binding to duplex DNA favours G/C regions. and particularly the triplets 5' A/T CG or 5' A/T GC. N-acylation of the daunosamine sugar decreases binding affinity of these analogs and eliminates anti-helicase activity of these N-acylated compounds. N-alkylated analogues retain potent anti-helicase activity.
1. N. R. Bachur, R. Johnson, F. Yu, R. Hickey and L. Malkas, Anthracycline Antihelicase Action- New Mechanism with Implications Guanosine-Cytidine Intercalation Specificity, Chapter 13, pp. 204-221 in "Anthracycline Antibiotics - New Analogues, Methods of Delivery and Mechanisms of Action", Ed. W Priebe, ACS Symposium Series 574, 1995. ISBN 0 8412 3040 4.
2. J. H. Matson, K. A. Kaiser-Rogers, Ann. Rev. Biochem., 1990, 59, 289.