Does cisplatin bind to DNA?
Cisplatin is believed to kill cancer cells by binding to DNA and interfering with its repair mechanism, eventually leading to cell death. The first step in the process (after the cisplatin molecule penetrates the cell membrane intact) is for a molecule of water to replace one of the chloride ions.
What DNA base does cisplatin bind to?
Cisplatin has been demonstrated to bind to the purine-N(7) of guanine and adenine residues on DNA, mainly forming 1,2-intrastrand crosslinks between adjacent two guanines (1,2-d(GpG), ~65%) or neighboring adenine and guanine (1,2-d(ApG), ~25%), as well as interstrand crosslinks and mono-functional adduct [7,8,9,10].
How does cisplatin bind to guanine?
The primary target of cisplatin is genomic DNA, specifically the N7 position of guanine bases. This point of attack first generates monofunctional adducts, which subsequently closes by coordination to the N7 position of an adjacent purine to afford an intrastrand cross-link.
How does cisplatin work chemistry?
The Pt(II) complex cisplatin is used as an anticancer drug. Cisplatin prevents DNA replication in cancer cells by a ligand replacement reaction with DNA in which a bond is formed between platinum and a nitrogen atom on guanine.
Does cisplatin bind to RNA?
Note that cisplatin binding is observed in idiosyncratic RNA folds, in which N7-atoms of purine residues normally coordinate magnesium ions (in the untreated ribosome) and are located adjacent to the RNA phosphates capable of stabilizing the cisplatin moiety by electrostatic interactions.
How does cisplatin affect the cell cycle?
Broadly, cisplatin is known to bind DNA and form DNA adducts, which is aimed to subsequently inhibit cell cycle progression and induce apoptosis.
Why does cisplatin prefer guanine over adenine?
When adenine binds, only a weak hydrogen bond forms between the chloride ligand of cisplatin and the H(2)N-C6 group of adenine. Second, a significantly stronger molecular orbital interaction is identified for guanine compared to adenine.
How does cisplatin enter the cell?
This supports the hypothesis that cisplatin can enter cells via passive permeation through the lipid phase of the membrane, but becomes trapped within the cytoplasm because dissociation of chloride ligands yields a membrane-impermeant positively-charged aqua derivative.
How many ligands are in cisplatin?
Structure/Function: Cisplatin has a square planar platinum center that coordinates four ligands, two chloride and two ammonium. The cis formation of this compound is responsible for the anticancer activity exhibited in tumor cells.
Why does cisplatin work but not transplatin?
As you saw previously, transplatin is not active. The distance between the two chlorine leaving groups is longer than in cisplatin (Figure 24), resulting in transplatin being unable to form 1,2-intrastrand DNA adducts similar to cisplatin.
What is cisplatin resistance?
One of the most prominent characteristics of cellular resistance to cisplatin is the reduced accumulation of the compound. As a consequence of reduced uptake or retention, the formation of platinum-DNA adducts is correspondingly decreased, reducing cytotoxicity, resulting in more resistance to the platinum compound.
Is cisplatin cell cycle specific?
As such, cisplatin is not cell cycle specific, although cells appear to be maximally sensitive to cisplatin in G1, just prior to the onset of DNA synthesis, and minimally sensitive in peak DNA synthesis, with entry into S-phase resulting in a 2-fold decrease in sensitivity (Ref.
How does cisplatin cross the cell membrane?
What type of ligand is cisplatin?
It has two chloride ion ligands situated adjacent to one another, and two remaining ammonia ligands likewise, in a square (tetragonal) planar structure.
What is the structure of cisplatin?
[Pt(NH3)2Cl2]Cisplatin / Formula
What is the difference between cisplatin and transplatin?
The key difference between cisplatin and transplatin is that cisplatin produces much more DNA abduct than transplatin. Cisplatin and transplatin are structural isomers of each other. Cisplatin is the cis isomer of Dichlorodiammineplatinum(II) while transplatin is the trans isomer of the same compound.
Is cisplatin and transplatin more stable?
Although transplatin molecule is more stable than cisplatin by 0.52 eV, we found cisplatin to be more favorable for reaction due to the following reasons: 1) the energy cost to remove a Cl atom is less from cisplatin than transplatin.
Why is cisplatin vulnerable to cytoplasmic inactivation?
The active mono-aquated form of cisplatin is a highly reactive species which can be recognized by several endogenous nucleophiles, thus making the drug potentially vulnerable and leading to premature cytoplasmic inactivation.