The objectives of the proposed work are to study the effect of the distribution of surface positive charges of polyamines on the interactions with nucleic acids and to use these results to design and synthesize polyamine analogs with modified charge distributions that may have different affinities for nucleic acids than the naturally-occurring polyamines. The analogs should physically replace natural polyamines without duplicating at least some of their biological functions.
The specific aims are: 1) to measure the association constants of naturally-occurring polyamines and synthetic polyamine analogs with DNA and polynucleotides using Spectroscopic methods; 2) to determine whether polyamine analogs will mimic the condensation of DNA and/or the induction of the B to Z transition of specific polynucleotides caused by naturally-occurring polyamines; 3) to test the effects of specific analogs on the growth and viability of cultured human and rodent brain tumor cells; 4) to study the effects on the cytotoxicity of CENUs and Cis-Pt caused by replacement of naturally- occurring polyamines with effective analogs previously identified: and, 5) to assist the effects of analogs on DNA crosslinking caused by CENU and cis- Pt. Results obtained in Aims 1 and 2 will be used to choose and design effective analogs, and results from Aims 3-5 will allow evaluation of the effects of analogs on living cells that may lead to the design of therapeutically important anticancer agents.
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