Human DNA topoisomerase I inhibitory activities of synthetic polyamines: Relation to DNA aggregation

DNA aggregation by polyamines has acquired importance as a prerequisite for the cellular uptake of DNA for gene therapy. Intracellular polyamines are constitutive components of mammalian cells and their availability is critic al for cell proliferation. Interference of polyamine biosynthesis by synthe tic polyamines leads to cytotoxicity. Optimization of the polyamine structu ral parameters is necessary to control their DNA aggregation, cytotoxic or enzyme inhibitory activities. We designed two series of tetra- and hexamine s and compared their human DNA topoisomerase I (top1) inhibitory effects wi th the DNA aggregation properties. We show that hexamines are more efficien t inhibitors of DNA relaxation by top1 than tetramines and that they suppre ss the top1-mediated DNA cleavage while tetramines do not. The DNA aggregat ion abilities within two series of polyamines correlate with the length of their central methylene chain. By contrast, the top1 inhibition within two series does not show the same correlation but demonstrates a threshold inhi bitory effect on going from the (CH2)(12) to the (CH2)(14) central chain. W e show further that the structures of DNA aggregates formed by polyamines w ith the (CH2)(10-12) or with the (CH2)(14-16) chains are very different. Th e first are a fluid cholesteric-type phases, whereas the second are well-st ructured aggregates similar to columnar liquid crystals with high packing d ensity of DNA duplexes. The structures of polyamines-induced DNA aggregates are proposed to be crucial for top1 catalysis. The structure-function corr elation described here may serve as a guide for rational design of polyamin es with desired DNA-aggregation or anti-top1 activities. (C) 2001 Elsevier Science Ltd. All rights reserved.