Reactions of the Double‐Stranded Oligonucleotide d(TTGGCCAA)₂withcis‐[Pt(NH₃)₂(H₂O)₂]²⁺and [Pt(NH₃)₃(H₂O)]²⁺

Abstract

The kinetics of the reactions between the GGcontaining double-stranded oligonucleotide d(TTGGCCAA), (II) and the platinum complexes cis-[Pt-(Hz0)lz+ (2) were studied and compared with those already determined for the reactions of the single-stranded octanucleotide d(CTGGCTCA) (I).['] The results were as follows: i) Complex 1 reacted faster than 2 with both I and 11. ii) Both complexes 1 and 2 reacted faster with I1 than with I. This acceleration was greater for 1 ( x 13) than for 2 ( x 4) and only due to the increase of the platination rate of the 5'-G of the GG sequence. iii) For both I and 11, the first platination by 1 and ( N H~) Z ( H Z~) Z~~~(1) and [Pt(NH3)3-2 was faster on the 5'-G than on the 3'43. This difference was more significant for the platination of I1 (ks,/k3, = 12 for 1 and 5 for 2) than of I (ks,/k3, 5 2). iv) The cyclization reaction of the monoadducts (G*) of 1 to yield the GG cis-Pt(NH,)$+ chelate (G*G*) was considerably slowed down in the duplex. This rate decrease was significantly larger for the chelation of the 5'-G* (factor of 16) than of the 3'-G* (factor of 4) monoadducts. v) The intrastrand chelation of the 3'-G* monoadducts (k3J was faster than that of the 5'-G* monoadducts ( k 5 J , both for I and I1 (k38c/ks,c = 3 and 13, respectively). vi) In addition to the intrastrand G*G* crosslink, we also observed the interstrand crosslink d(GG*CC)-d(GG*CC) between the two 3'43s of the central tetranucleotide. The rate constant for the interstrand crosslinking (k3,i) was half that of the intrastrand chelation (k3,c).vii) The 5' monoadduct, which was formed faster (ks. > k3.) and was chelated more slowly (k5,c @ k,.i c k3.c), exhibited a half-life of 3.2 h under our experimental conditions.

Cisplatin Adducts on a GGG Sequence within a DNA Duplex Studied by NMR Spectroscopy and Molecular Dynamics Simulations

“…[39] The hairpin-forming monoadducts subsequently react to form preferential crosslinks with the 3'-guanine. [38] In contrast, monoadducts within intact duplex DNA form cross-links predominantly with the 5'-G. [41] We have found in this work that the 1,2-G*G* adduct forms faster than the 2,3-G*G* adduct also in the single strand d(GCCGGGTCGC), thereby exceeding the formation of the latter by a factor of approximately 2. Surprisingly, the purified 1,2-G*G* adduct was, after hybridization with the complementary strand, unstable and rearranged reversibly to the 2,3-G*G* adduct to finally yield a mixture of the 1,2-G*G* (dsCG*G*G) and 2,3-G*G* (dsGG*G*T) adducts in a ratio of approximately 40:60.…”

Metals in Medicine

“…[98,99] For the double-stranded oligonucleotide d(TTGGCCAA) 2 the formation of the 5'-G monoaqua adduct is faster than that of the 3'-G monoadduct, and macrochelate ring closure of the 5'-G monoaqua to give the bifunctional adduct (half-life of 3.2 h at 293 K) is much slower than that of the 3'-G monoadduct. The biological significance of long-lived monofunctional adducts on DNA remains to be determined, but these alone may be sufficient to kill cells if they are not repaired, which seems to be the case for the active trans iminoether complex 33 (see Section 3.4).…”

Ruthenation of Duplex and Single‐Stranded d(CGGCCG) by Organometallic Anticancer Complexes

“…This has often been observed for reactions of duplex DNA with platinum anticancer complexes. [17] For example, 3'-G and 5'-G platinated single-strand monoadducts and the GG-chelate adducts have been separated on a C18 reverse-phase column from the 1:1 reaction mixture of the duplex dA C H T U N G T R E N N U N G (TTGGCCAA) 2 with cis-…”