TY - JOUR
T1 - DNA cross-linking patterns induced by an antitumor-active trinuclear platinum complex and comparison with its dinuclear analogue
AU - Zhu, Jianhui
AU - Zhao, Yongmei
AU - Zhu, Yanyan
AU - Wu, Ziyi
AU - Lin, Miaoxin
AU - He, Weijiang
AU - Wang, Yan
AU - Chen, Guangju
AU - Dong, Lei
AU - Zhang, Junfeng
AU - Lu, Yi
AU - Guo, Zijian
PY - 2009/5/18
Y1 - 2009/5/18
N2 - The DNA binding and cross- linking modes of a trinuclear platinum complex [Pt3Cl3(hptab)][ClO4]3 (1. hptab = N,N,N',N',N",N"-hexakis(2-pyr- idylmethyl)-1,3,5-tris(aminomethyl)- benzene) and its dinuclear analogue [Pt2Cl2(m-tpxa)] Cl2 (2. m-tpxa = N,N,N',N'-tetra(2-pyridylmethyl)-m-xy- lylene diamine) are reported and compared. The adducts of 1 and 2 with 18- mer duplex N1,5′-d(GAAGAAGTCA- CAAAATGT)-3′ 5′-d(ACATTTTGT- GACTTCTTC)-3′, have been characterized by means of denaturing poly- acrylamide gels, Maxam-Gilbert sequencing, and MALDI-TOF mass spectrometry combined with enzymatic degradation to obtain insights into structural features responsible for the differences in their antitumor activities. The cytotoxic-active complex 1 readily forms various DNA adducts, such as through 1,3- and 1,4-intrastrand crosslinks, and in particular, the unique and unprecedented interstrand cross-linked triadducts. In contrast, the cytotoxic-in- active complex 2 preferentially forms 1,4-intrastrand rather than 1,3-intra- and -interstrand cross-links. Digestion of the DNA adducts of 1 shows that the cleavage is completely blocked at one nucleotide before the cross-linked guanine residuesontheopposite strand, a feature that appears to be unprecedented in antitumor platinum complexes. In the case of 2, the cleavage bypasses the first platinated gua- nine site and stops at one nucleotide prior to the second platinated site, confirming that very few 1,3-intrastrand cross-links are formed by 2. These results are supported by molecular-modeling studies of intra- and interstrand cross-links of duplex N1 with 1 and 2. The remarkable differences between 1 and 2 in DNA binding and cross-linking provide mechanistic insights into their different cytotoxicity against the tumor cell lines. these insights are useful for designing future antitumor agents..
AB - The DNA binding and cross- linking modes of a trinuclear platinum complex [Pt3Cl3(hptab)][ClO4]3 (1. hptab = N,N,N',N',N",N"-hexakis(2-pyr- idylmethyl)-1,3,5-tris(aminomethyl)- benzene) and its dinuclear analogue [Pt2Cl2(m-tpxa)] Cl2 (2. m-tpxa = N,N,N',N'-tetra(2-pyridylmethyl)-m-xy- lylene diamine) are reported and compared. The adducts of 1 and 2 with 18- mer duplex N1,5′-d(GAAGAAGTCA- CAAAATGT)-3′ 5′-d(ACATTTTGT- GACTTCTTC)-3′, have been characterized by means of denaturing poly- acrylamide gels, Maxam-Gilbert sequencing, and MALDI-TOF mass spectrometry combined with enzymatic degradation to obtain insights into structural features responsible for the differences in their antitumor activities. The cytotoxic-active complex 1 readily forms various DNA adducts, such as through 1,3- and 1,4-intrastrand crosslinks, and in particular, the unique and unprecedented interstrand cross-linked triadducts. In contrast, the cytotoxic-in- active complex 2 preferentially forms 1,4-intrastrand rather than 1,3-intra- and -interstrand cross-links. Digestion of the DNA adducts of 1 shows that the cleavage is completely blocked at one nucleotide before the cross-linked guanine residuesontheopposite strand, a feature that appears to be unprecedented in antitumor platinum complexes. In the case of 2, the cleavage bypasses the first platinated gua- nine site and stops at one nucleotide prior to the second platinated site, confirming that very few 1,3-intrastrand cross-links are formed by 2. These results are supported by molecular-modeling studies of intra- and interstrand cross-links of duplex N1 with 1 and 2. The remarkable differences between 1 and 2 in DNA binding and cross-linking provide mechanistic insights into their different cytotoxicity against the tumor cell lines. these insights are useful for designing future antitumor agents..
KW - Antitumor agents
KW - DNA structures
KW - Mass spectrometry
KW - Molecular modeling
KW - Platinum
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U2 - 10.1002/chem.200900217
DO - 10.1002/chem.200900217
M3 - Article
C2 - 19350599
AN - SCOPUS:66249130986
SN - 0947-6539
VL - 15
SP - 5245
EP - 5253
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 21
ER -