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Correlation between the Effects of Polyamine Analogues on DNA Conformation and Cell Growth¹

Brain Tumor Research Center of the Department of Neurological Surgery [H. S. B., D. F. D., W. P. L., L. J. M.], and the Departments of Laboratory Medicine [B. G. F., L. J. M.], Pediatrics [B. G. F.], and Radiation Oncology [D. F. D.], School of Medicine, University of California, San Francisco, California 94143; Department of Medicinal Chemistry [R. J. B], University of Florida, Gainesville, Florida 32610; and the Faculty of Pharmaceutical Sciences [K. S.], Josai University, Sakado, Saitama 350-02, Japan

Effects of a number of synthetic analogues of the natural polyamines on the B-Z transition of poly(dG-me⁵dC) and on the aggregation of calf thymus DNA in solution were studied using circular dichroic and UV spectroscopy. The efficiency of induction of the B-Z transition decreased with a decrease in the length of the central alkyl chain of the analogues, and the ability of analogues to aggregate DNA was markedly reduced for compounds ethylated at the terminal amines. Both structural variations appear to have important effects on the biological functions of polyamines. Most analogues studied depleted intracellular levels of natural polyamines, but only those that did not readily induce the B-Z transition and/or aggregate DNA were good inhibitors of cell growth. All but one of the analogues studied were able to rescue cells—at least in part—from the growth-inhibitory effects of -difluoromethylornithine. The single analogue that was unable to effect rescue also failed to induce both the B-Z transition and the aggregation of DNA.

¹ Supported by NIH National Cooperative Drug Discovery Grant CA-37606 (to L. J. M.), NIH Program Project Grant CA-13525, NIH Grant CA-41757 (to B. G. F.), and the Phi Beta Psi Sorority.

² To whom requests for reprints should be addressed, c/o The Editorial Office, 1360 Ninth Avenue, Suite 210, San Francisco, CA 94122.

Received 11/ 2/88. Revised 5/ 1/89. Revised 7/ 7/89. Accepted 7/18/89.

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