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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
Interactions with DNA Models of the Oxaliplatin Analog (cis-1,3-DACH)PtCl2
Alessandra Barbanente1, Paride Papadia2, Anna Maria Di Cosola1
1Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy.
Abstract:
It is generally accepted that adjacent guanine residues in DNA are the primary target for platinum antitumor drugs and that differences in the conformations of the Pt-DNA adducts can play a role in their antitumor activity. In this study, we investigated the effect of the carrier ligand cis-1,3-diaminocyclohexane (cis-1,3-DACH) upon formation, stability, and stereochemistry of the (cis-1,3-DACH)PtG2 and (cis-1,3-DACH)Pt(d(GpG)) adducts (G = 9-EthlyGuanine, guanosine, 5'- and 3'-guanosine monophosphate; d(GpG) = deoxyguanosil(3'-5')deoxyguanosine). A peculiar feature of the cis-1,3-DACH carrier ligand is the steric bulk of the diamine, which is asymmetric with respect to the Pt-coordination plane. The (cis-1,3-DACH)Pt(5'GMP)2 and (cis-1,3-DACH)Pt(3'GMP)2 adducts show preference for the ΛHT and ∆HT conformations, respectively (HT stands for Head-to-Tail). Moreover, the increased intensity of the circular dichroism signals in the cis-1,3-DACH derivatives with respect to the analogous cis-(NH3)2 species could be a consequence of the greater bite angle of the cis-1,3-DACH carrier ligand with respect to cis-(NH3)2. Finally, the (cis-1,3-DACH)Pt(d(GpG)) adduct is present in two isomeric forms, each one giving a pair of H8 resonances linked by a NOE cross peak. The two isomers were formed in comparable amounts and had a dominance of the HH conformer but with some contribution of the ΔHT conformer which is related to the HH conformer by having the 3'-G base flipped with respect to the 5'-G residue.
Insights
The study reveals how the bulky cis-1,3-diaminocyclohexane ligand influences platinum-DNA adduct formation and stereochemistry. This carrier ligand
Area of Science:
- Medicinal Chemistry
- Bioinorganic Chemistry
- DNA Damage and Repair
Background:
- Platinum-based chemotherapy agents target DNA, with guanine residues being primary targets.
- The conformation of platinum-DNA adducts influences their antitumor activity.
- Carrier ligands play a crucial role in modulating the properties of platinum-DNA adducts.
Purpose of the Study:
- To investigate the impact of the cis-1,3-diaminocyclohexane (cis-1,3-DACH) ligand on the formation, stability, and stereochemistry of platinum-guanine DNA adducts.
- To compare the effects of the cis-1,3-DACH ligand with the cis-diammine ligand.
Main Methods:
- Synthesis and characterization of (cis-1,3-DACH)PtG2 and (cis-1,3-DACH)Pt(d(GpG)) adducts.
- Spectroscopic analysis, including circular dichroism (CD) and Nuclear Overhauser Effect (NOE).
- Conformational analysis of platinum-DNA adducts.
Main Results:
- The cis-1,3-DACH ligand induces specific conformations (ΛHT and ∆HT) in (cis-1,3-DACH)Pt(5'GMP)2 and (cis-1,3-DACH)Pt(3'GMP)2 adducts, respectively.
- Increased CD signal intensity suggests a larger bite angle for cis-1,3-DACH compared to cis-(NH3)2.
- The (cis-1,3-DACH)Pt(d(GpG)) adduct exists as two isomers, predominantly in the HH conformer with some ΔHT contribution.
Conclusions:
- The steric bulk and asymmetry of the cis-1,3-DACH ligand significantly influence platinum-DNA adduct stereochemistry.
- The cis-1,3-DACH ligand offers a distinct conformational control over platinum-guanine adducts compared to cis-(NH3)2.
- Understanding these conformational preferences is vital for designing novel platinum-based anticancer drugs.
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