Authors: Jayati Roy Choudhury Lu Rao Ulrich Bierbach
Publish Date: 2010/11/18
Volume: 16, Issue: 3, Pages: 373-380
Abstract
A restriction enzyme cleavage inhibition assay was designed to determine the rates of DNA platination by four noncrosslinking platinum–acridine agents represented by the formula Ptam2LClNO32 where am is a diamine nonleaving group and L is an acridine derived from the intercalator 12acridin9ylaminoethyl13dimethylthiourea ACRAMTU The formation of monofunctional adducts in the target sequence 5′CGA was studied in a 40basepair probe containing the EcoRI restriction site GAATTC The time dependence of endonuclease inhibition was quantitatively analyzed by polyacrylamide gel electrophoresis The formation of monoadducts is approximately 3 times faster with doublestranded DNA than with simple nucleic acid fragments Compound 1 am2 is ethane12diamine L is ACRAMTU reacts with a firstorder rate constant of k obs = 14 ± 037 × 10−4 s−1 t 1/2 = 83 ± 22 min Replacement of the thiourea group in ACRAMTU with an amidine group compound 2 accelerates the rate by fourfold k obs = 57 ± 058 × 10−4 s−1 t 1/2 = 21 ± 2 min and introduction of a propane13diamine nonleaving group results in a 15fold enhancement in reactivity compound 3 k obs = 21 ± 040 × 10−4 s−1 t 1/2 = 55 ± 10 min compared with the prototype Derivative 4 containing a 49disubstituted acridine threading intercalator was the least reactive compound in the series k obs = 11 ± 040 × 10−4 s−1 t 1/2 = 104 ± 38 min The data suggest a correlation may exist between the binding rates and the biological activity of the compounds Potential pharmacological advantages of rapid formation of cytotoxic monofunctional adducts over the common purine–purine crosslinks are discussed
Keywords: