DNA-intrastrand guanine, guanine cross-linking by cisplatin: comparison of three model compounds with head-head orientation of the nucleobases

Schoellhorn, H.; Raudaschl‐Sieber, Gabriele; Muêller, G.; Thewalt, Ulf; Lippert, Bernhard

doi:10.1021/ja00307a018

Cited by 78 publications

(67 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Almost all crystal structures of cDDP-guanine adducts published so far have an HT (head-to-tail) orientation, with a preferred Pt coordination at the N 7 position of the purine ligand. However, since an HT arrangement in native DNA is unfavoured due to steric effects, the presently obtained solid state structure was based on the reported X-ray data for the HH (head-to-head) analogous system with ethylguanine, 40 including eight water molecules and two sulphate ions in the unit cell (due to cisplatin's activation with Ag 2 SO 4 ). It is worth noticing that the two guanine ligands are not geometrically equivalent in this optimized geometry (I and II, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…56,57 PW calculations performed for the cDDP-G 2 adduct were accomplished using the crystal structure of cis-[Pt(NH 3 ) 2 EG 2 ]SO 4 Á4H 2 O (EG = ethylguanine). 40 Unit cell parameters were kept at their experimental values. The ethyl groups in the asymmetric unit were deleted and the spatial coordinates of hydrogen atoms were inferred empirically and inserted in the crystal structure using the XCrysden software.…”

Section: Theoretical Calculationsmentioning

confidence: 99%

See 1 more Smart Citation

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

Marques

Gianolio

Cibin

et al. 2015

Phys. Chem. Chem. Phys.

View full text Add to dashboard Cite

The interaction of the widely used anticancer drug cisplatin with DNA bases was studied by EXAFS and vibrational spectroscopy (FTIR, Raman and INS), coupled with DFT/plane-wave calculations. Detailed information was obtained on the local atomic structure around the Pt(II) centre, both in the cisplatinpurine (adenine and guanine) and cisplatin-glutathione adducts. Simultaneous neutron and Raman scattering experiments allowed us to obtain a reliable and definite picture of this cisplatin interplay with its main pharmacological target (DNA), at the molecular level. The vibrational experimental spectra were fully assigned in the light of the calculated pattern for the most favoured geometry of each drug-purine adduct, and cisplatin's preference for guanine (G) relative to adenine (A) within the DNA double helix was experimentally verified: a complete N by S substitution in the metal coordination sphere was only observed for [cDDP-A 2 ], reflecting a somewhat weaker Pt-A binding relative to Pt-G. The role of glutathione on the drug's pharmacokinetics, as well as on the stability of platinated DNA adducts, was evaluated as this is the basis for glutathione-mediated intracellular drug scavenging and in vivo resistance to Pt-based anticancer drugs. Spectroscopic evidence of the metal's preference for glutathione's sulfur over purine's nitrogen binding sites was gathered, at least two sulfur atoms being detected in platinum's first coordination sphere.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Theoretical Calculationsmentioning

confidence: 99%

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

Marques

Gianolio

Cibin

et al. 2015

Phys. Chem. Chem. Phys.

View full text Add to dashboard Cite

show abstract

“…Thus, the modification of the hydrogen-bonding pattern after chlorine substitution by NH 3 groups changes the ligand orientation to head to tail. 12 The head to head atropisomers in platinum complexes with heterocyclic ligands similar to the purine nucleobases are difficult to isolate and have been found to exist in only a few crystal structures of cis-[Pt(NH 3 ) 2 (9-EtGH) 2 ] 13 and cis-[Pt(NH 3 ) 2 (9-EtGH)(9-methyladenine)], 14 the normal feature being a head to tail 9b orientation. In DNA, the platinum compounds cross-link adjacent purine residues in a head to head conformation, these atropisomers being considered adequate for modeling platinum-DNA interactions.…”

Section: Introductionmentioning

confidence: 99%

cis-[PtCl₂(4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine)₂]: A Sterically Restrictive New Cisplatin Analogue. Reaction Kinetics with Model Nucleobases, DNA Interaction Studies, Antitumor Activity, and Structure−Activity Relationships

et al. 1998

View full text Add to dashboard Cite

The formation and isolation of the antitumor drug cisplatin analogue cis- The reactivity of the complex to model nucleobases 9-ethylguanine (9-EtGH) and 1-methylcytosine (1-MeC) has been investigated by 1 H NMR spectroscopy at 45°C in aqueous media. The results show that 1 reacts slowly with 9-EtGH (t 1/2 ≈ 5 days) by displacement of Cl -, producing cis- ) 2 (9-EtGH-N 7 ) 2 ], which is similar to the major cross-link adduct of cisplatin with DNA. However, 1 gives no reaction with 1-MeC. This appears to be due to the lesser reactivity of 1-MeC and to competition between the cross-link reaction and dimerization of 1 to [Pt 2 (µ-mtpo-N 3 ,N 4 ) 4 ]. Circular dichroism studies of DNA in the presence of 1 show that the platinum complex reacts efficiently after 48 h at a optimum ratio of 0.25 Pt atom/mol of DNA nucleotide. These results and those obtained from reaction of 1 with 9-EtGH suggest that the platinum compound binds the N7 atoms of two guanines of the same strand, forming intrastrand cross-linked adducts. Chelation of DNA bases by 1 causes important conformational changes, bringing the guanines close together. The anticancer activity of complex 1 has been tested against the human cancer cell lines MCF-7 breast carcinoma and A121 ovarian carcinoma. Results indicate a moderate antitumor activity against breast carcinoma and a marked and selective cytotoxic effect against ovarian carcinoma.

show abstract

“…The mechanism of anticancer activity involves formation of platinum-DNA adducts that are capable of inhibiting DNA and RNA synthesis (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) and inducing programmed cell death (17,18). Cisplatin binds preferentially to the N7 position of purine residues.…”

mentioning

confidence: 99%

“…The monofunctional adduct subsequently closes to a bifunctional adduct by linking a second purine that can be either of the same strand or of the opposite strand (19). There is general consensus that the antitumor efficacy of cisplatin is associated with the formation of DNA 1,2-intrastrand d(GpG) or d(ApG) cross-links (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). The 1,2-intrastrand crosslinks locally unwind and bend doublestranded DNA toward the major groove (14,20,21), and the disturbance of DNA secondary structure seems to be the ultimate reason for inhibition of DNA replication and/or transcription and for triggering apoptotic cell death (22,23).…”

mentioning

confidence: 99%

Chiral discrimination in platinum anticancer drugs.

Benedetti

Malina

Kašpárková

et al. 2002

Environ Health Perspect

View full text Add to dashboard Cite

In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated.

show abstract

DNA-intrastrand guanine, guanine cross-linking by cisplatin: comparison of three model compounds with head-head orientation of the nucleobases

Cited by 78 publications

References 1 publication

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

cis-[PtCl₂(4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine)₂]: A Sterically Restrictive New Cisplatin Analogue. Reaction Kinetics with Model Nucleobases, DNA Interaction Studies, Antitumor Activity, and Structure−Activity Relationships

Chiral discrimination in platinum anticancer drugs.

Contact Info

Product

Resources

About

DNA-intrastrand guanine, guanine cross-linking by cisplatin: comparison of three model compounds with head-head orientation of the nucleobases

Cited by 78 publications

References 1 publication

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

cis-[PtCl2(4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine)2]: A Sterically Restrictive New Cisplatin Analogue. Reaction Kinetics with Model Nucleobases, DNA Interaction Studies, Antitumor Activity, and Structure−Activity Relationships

Chiral discrimination in platinum anticancer drugs.

Contact Info

Product

Resources

About

cis-[PtCl₂(4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine)₂]: A Sterically Restrictive New Cisplatin Analogue. Reaction Kinetics with Model Nucleobases, DNA Interaction Studies, Antitumor Activity, and Structure−Activity Relationships