Cisplatin
Encyclopedia
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) (CDDP) (trade names Platinol and Platinol-AQ) is a chemotherapy
drug
. It is used to treat various types of cancers, including sarcoma
s, some carcinoma
s (e.g. small cell lung cancer
, and ovarian cancer
), lymphoma
s, and germ cell tumor
s. It was the first member of a class of platinum
-containing anti-cancer drugs, which now also includes carboplatin
and oxaliplatin
. These platinum complexes react in vivo, binding to and causing crosslinking of DNA
, which ultimately triggers apoptosis
(programmed cell death).
in 1893. In 1965, Barnett Rosenberg
, van Camp et al. of Michigan State University
discovered that electrolysis
of platinum electrodes generated a soluble platinum complex which inhibited binary fission in Escherichia coli
(E. coli) bacteria. Although bacterial cell growth continued, cell division was arrested, the bacteria growing as filaments up to 300 times their normal length. The octahedral Pt(IV) complex cis PtCl4(NH3)2, but not the trans isomer, was found to effective at forcing filamentous growth of E. coli cells. The square planar Pt(II) complex, cis PtCl2(NH3)2 turned out to be even more effective at forcing filamentous growth. This finding led to the finding that cis PtCl2(NH3)2 was indeed highly effective at regressing the mass of sarcoma
s in rat
s. Confirmation of this finding, and extension of testing to other tumour cell lines launched the medicinal applications of cisplatin. Cisplatin was approved for use in testicular and ovarian cancers by the U.S. Food and Drug Administration on December 19, 1978.
, guanine
is preferred. Subsequent to formation of [PtCl(guanine-DNA)(NH3)2]+, crosslinking can occur via displacement of the other chloride ligand, typically by another guanine. Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis
. The damaged DNA elicits DNA repair
mechanisms, which in turn activate apoptosis
when repair proves impossible. Recently it was shown that the apoptosis
induced by cisplatin on human colon cancer cells depends on the mitochondrial serine-protease Omi/Htra2. Since this was only demonstrated for colon carcinoma cells, it remains an open question if the Omi/Htra2 protein participates in the cisplatin-induced apoptosis in carcinomas from other tissues.
Most notable among the changes in DNA are the 1,2-intrastrand cross-links with purine
bases. These include 1,2-intrastrand d(G
pG) adducts which form nearly 90% of the adducts and the less common 1,2-intrastrand d(ApG) adducts. 1,3-intrastrand d(GpXpG) adducts occur but are readily excised by the nucleotide
excision repair (NER
). Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to cisplatin's activity. Interaction with cellular proteins, particularly HMG
domain proteins, has also been advanced as a mechanism of interfering with mitosis, although this is probably not its primary method of action.
Note that although cisplatin is frequently designated as an alkylating agent, it has no alkyl group and so cannot carry out alkylating reactions. It is correctly classified as alkylating-like.
and increased DNA repair
. Oxaliplatin
is active in highly cisplatin-resistant cancer cells in the laboratory; however, there is little evidence for its activity in the clinical treatment of patients with cisplatin-resistant cancer. The drug Paclitaxel
may be useful in the treatment of cisplatin-resistant cancer; the mechanism for this activity is unknown.
', thiourea
reacts with the sample to give derivatives which can easily be separated and detected by HPLC
.
Approved for clinical use by the United States Food and Drug Administration
(FDA) in 1978, it revolutionized the treatment of certain cancers. Detailed studies on its molecular mechanism of action
, using a variety of spectroscopic methods including X-ray, NMR spectroscopy, and other physico-chemical methods, revealed its ability to form irreversible crosslinks with bases in DNA.
The synthesis of cisplatin is a classic in inorganic chemistry
. Starting from potassium tetrachloroplatinate(II)
, K2[PtCl4], the first NH3 ligand is added to any of the four equivalent positions, but the second NH3 could be added cis or trans to the bound amine
ligand
. Because Cl− has a larger trans effect
than NH3, the second amine preferentially substitutes trans to a chloride ligand, and therefore cis to the original amine. The trans effect of the halides follows the order I->Br->Cl-, therefore the synthesis is conducted using [PtI4]2− to ensure high yield and purity of the cis isomer, followed by conversion of the PtI2(NH3)2 into PtCl2(NH3)2, as first described by Dhara.
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
. It is used to treat various types of cancers, including sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
s, some carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
s (e.g. small cell lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
, and ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
), lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
s, and germ cell tumor
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
s. It was the first member of a class of platinum
Platinum
Platinum is a chemical element with the chemical symbol Pt and an atomic number of 78. Its name is derived from the Spanish term platina del Pinto, which is literally translated into "little silver of the Pinto River." It is a dense, malleable, ductile, precious, gray-white transition metal...
-containing anti-cancer drugs, which now also includes carboplatin
Carboplatin
Carboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
and oxaliplatin
Oxaliplatin
Oxaliplatin is a coordination complex that is used in cancer chemotherapy. These platinum-based drugs are usually classified as alkylating agents, although they are not actually alkylating groups ....
. These platinum complexes react in vivo, binding to and causing crosslinking of DNA
Crosslinking of DNA
Crosslinks in DNA occur when various exogenous or endogenous agents react with two different positions in the DNA. This can either occur in the same strand or in the opposite strands of the DNA . Crosslinks also occur between DNA and protein...
, which ultimately triggers apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
(programmed cell death).
History
The compound cis-PtCl2(NH3)2 was first described by M. Peyrone in 1845, and known for a long time as Peyrone's salt. The structure was deduced by Alfred WernerAlfred Werner
Alfred Werner was a Swiss chemist who was a student at ETH Zurich and a professor at the University of Zurich. He won the Nobel Prize in Chemistry in 1913 for proposing the octahedral configuration of transition metal complexes. Werner developed the basis for modern coordination chemistry...
in 1893. In 1965, Barnett Rosenberg
Barnett Rosenberg
Barnett Rosenberg was an American chemist best known for the discovery of the anti-cancer drug cisplatin.Rosenberg graduated from Brooklyn College in 1948 and obtained his PhD in Physics at New York University in 1956...
, van Camp et al. of Michigan State University
Michigan State University
Michigan State University is a public research university in East Lansing, Michigan, USA. Founded in 1855, it was the pioneer land-grant institution and served as a model for future land-grant colleges in the United States under the 1862 Morrill Act.MSU pioneered the studies of packaging,...
discovered that electrolysis
Electrolysis
In chemistry and manufacturing, electrolysis is a method of using a direct electric current to drive an otherwise non-spontaneous chemical reaction...
of platinum electrodes generated a soluble platinum complex which inhibited binary fission in Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
(E. coli) bacteria. Although bacterial cell growth continued, cell division was arrested, the bacteria growing as filaments up to 300 times their normal length. The octahedral Pt(IV) complex cis PtCl4(NH3)2, but not the trans isomer, was found to effective at forcing filamentous growth of E. coli cells. The square planar Pt(II) complex, cis PtCl2(NH3)2 turned out to be even more effective at forcing filamentous growth. This finding led to the finding that cis PtCl2(NH3)2 was indeed highly effective at regressing the mass of sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
s in rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s. Confirmation of this finding, and extension of testing to other tumour cell lines launched the medicinal applications of cisplatin. Cisplatin was approved for use in testicular and ovarian cancers by the U.S. Food and Drug Administration on December 19, 1978.
Pharmacology
Following administration, one of the chloride ligands is slowly displaced by water (an aqua ligand), in a process termed aquation. The aqua ligand in the resulting [PtCl(H2O)(NH3)2]+ is itself easily displaced, allowing the platinum atom to bind to bases. Of the bases on DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
is preferred. Subsequent to formation of [PtCl(guanine-DNA)(NH3)2]+, crosslinking can occur via displacement of the other chloride ligand, typically by another guanine. Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
. The damaged DNA elicits DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
mechanisms, which in turn activate apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
when repair proves impossible. Recently it was shown that the apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
induced by cisplatin on human colon cancer cells depends on the mitochondrial serine-protease Omi/Htra2. Since this was only demonstrated for colon carcinoma cells, it remains an open question if the Omi/Htra2 protein participates in the cisplatin-induced apoptosis in carcinomas from other tissues.
Most notable among the changes in DNA are the 1,2-intrastrand cross-links with purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
bases. These include 1,2-intrastrand d(G
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
pG) adducts which form nearly 90% of the adducts and the less common 1,2-intrastrand d(ApG) adducts. 1,3-intrastrand d(GpXpG) adducts occur but are readily excised by the nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
excision repair (NER
Nucleotide excision repair
Nucleotide excision repair is a DNA repair mechanism. DNA constantly requires repair due to damage that can occur to bases from a vast variety of sources including chemicals, radiation and other mutagens...
). Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to cisplatin's activity. Interaction with cellular proteins, particularly HMG
High mobility group
High-Mobility Group or HMG is a group of chromosomal proteins that help withtranscription, replication, recombination, and DNA repair.-Families:The HMG proteins are subdivided into 3 superfamilies each containing a characteristic functional domain:...
domain proteins, has also been advanced as a mechanism of interfering with mitosis, although this is probably not its primary method of action.
Note that although cisplatin is frequently designated as an alkylating agent, it has no alkyl group and so cannot carry out alkylating reactions. It is correctly classified as alkylating-like.
Usage
Cisplatin is administered intravenously as short-term infusion in physiological saline for treatment of solid malignancies.Cisplatin resistance
Cisplatin combination chemotherapy is the cornerstone of treatment of many cancers. Initial platinum responsiveness is high but the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Many mechanisms of cisplatin resistance have been proposed including changes in cellular uptake and efflux of the drug, increased detoxification of the drug, inhibition of apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and increased DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
. Oxaliplatin
Oxaliplatin
Oxaliplatin is a coordination complex that is used in cancer chemotherapy. These platinum-based drugs are usually classified as alkylating agents, although they are not actually alkylating groups ....
is active in highly cisplatin-resistant cancer cells in the laboratory; however, there is little evidence for its activity in the clinical treatment of patients with cisplatin-resistant cancer. The drug Paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
may be useful in the treatment of cisplatin-resistant cancer; the mechanism for this activity is unknown.
Transplatin
Transplatin, the trans stereoisomer of cisplatin, has formula trans-[PtCl2(NH3)2] and does not exhibit a comparably useful pharmacological effect. Its low activity is generally thought to be due to rapid deactivation of the drug before it can arrive at the DNA. It is toxic, and it is desirable to test batches of cis-platin for the absence of the trans isomer. In a procedure by Woollins et al., which is based on the classic 'Kurnakov testKurnakov test
Soviet chemist Nikolai Semenovich Kurnakov utilised the phenomonon of trans-effect in distinguishing the pairs of cis- and trans-isomers of square complexes of [PtA2X2] type by treating them with thiourea. This is as know the famous kurnakov reaction.-Uses:Kurnakov test is used to distinguish...
', thiourea
Thiourea
Thiourea is an organosulfur compound of with the formula SC2 . It is structurally similar to urea, except that the oxygen atom is replaced by a sulfur atom, but the properties of urea and thiourea differ significantly. Thiourea is a reagent in organic synthesis. "Thioureas" refers to a broad...
reacts with the sample to give derivatives which can easily be separated and detected by HPLC
High-performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...
.
Side effects
Cisplatin has a number of side-effects that can limit its use:- NephrotoxicityNephrotoxicityNephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
(kidney damage) is a major concern. The dose is reduced when the patient's creatinine clearance (a measure of renal functionRenal functionRenal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
) is reduced. Adequate hydration and diuresisDiureticA diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
is used to prevent renal damage. The nephrotoxicity of platinum-class drugs seems to be related to reactive oxygen speciesReactive oxygen speciesReactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
and in animal models can be ameliorated by free radical scavenging agents (e.g., amifostineAmifostineAmifostine is a cytoprotective adjuvant used in cancer chemotherapy and radiotherapy involving DNA-binding chemotherapeutic agents. It is marketed by MedImmune under the trade name Ethyol.-Indications:...
). Nephrotoxicity is a dose-limiting. - NeurotoxicityNeurotoxicityNeurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
(nerve damage) can be anticipated by performing nerve conduction studies before and after treatment. - NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
: cisplatin is one of the most emetogenic chemotherapy agents, but this symptom is managed with prophylactic antiemetics (ondansetronOndansetronOndansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
, granisetronGranisetronGranisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect...
, etc.) in combination with corticosteroids. AprepitantAprepitantAprepitant is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists . It mediates its effect by blocking the neurokinin 1 receptor.Aprepitant is manufactured by Merck & Co...
combined with ondansetronOndansetronOndansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
and dexamethasoneDexamethasoneDexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
has been shown to be better for highly emetogenic chemotherapy than just ondansetronOndansetronOndansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
and dexamethasoneDexamethasoneDexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
. - OtotoxicityOtotoxicityOtotoxicity is damage to the ear , specifically the cochlea or auditory nerve and sometimes the vestibular system, by a toxin. It is commonly medication-induced; ototoxic drugs include antibiotics such as the aminoglycoside gentamicin, loop diuretics such as furosemide, and platinum-based...
(hearing loss): unfortunately there is at present no effective treatment to prevent this side effect, which may be severe. Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs (such as the aminoglycoside antibiotic class) may also cause ototoxicity, and the administration of this class of antibiotics in patients receiving cisplatin is generally avoided. The ototoxicity of both the aminoglycosides and cisplatin may be related to their ability to bind to melaninMelaninMelanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
in the stria vascularisStria vascularisThe upper portion of the spiral ligament contains numerous capillary loops and small blood vessels, and is termed the stria vascularis. It produces endolymph for the scala media, one of the three fluid-filled compartments of the cochlea...
of the inner ear or the generation of reactive oxygen speciesReactive oxygen speciesReactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
. - Electrolyte disturbanceElectrolyte disturbanceElectrolytes play a vital role in maintaining homeostasis within the body. They help to regulate myocardial and neurological function, fluid balance, oxygen delivery, acid-base balance and much more. Electrolyte imbalances can develop by the following mechanisms: excessive ingestion; diminished...
: Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to cisplatin, so it is not primarily due to the Cisplatin.
Approved for clinical use by the United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in 1978, it revolutionized the treatment of certain cancers. Detailed studies on its molecular mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
, using a variety of spectroscopic methods including X-ray, NMR spectroscopy, and other physico-chemical methods, revealed its ability to form irreversible crosslinks with bases in DNA.
Synthesis
Hearing lossThe synthesis of cisplatin is a classic in inorganic chemistry
Inorganic chemistry
Inorganic chemistry is the branch of chemistry concerned with the properties and behavior of inorganic compounds. This field covers all chemical compounds except the myriad organic compounds , which are the subjects of organic chemistry...
. Starting from potassium tetrachloroplatinate(II)
Potassium tetrachloroplatinate
Potassium tetrachloroplatinate is the chemical compound with the formula K2PtCl4. This reddish orange salt is an important reagent for the preparation of other coordination complexes of platinum. It consists of potassium cations and the square planar dianion PtCl42-...
, K2[PtCl4], the first NH3 ligand is added to any of the four equivalent positions, but the second NH3 could be added cis or trans to the bound amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
. Because Cl− has a larger trans effect
Trans effect
In inorganic chemistry, the trans effect is the labilization of ligands that are trans to certain other ligands, which can thus be regarded as trans-directing ligands...
than NH3, the second amine preferentially substitutes trans to a chloride ligand, and therefore cis to the original amine. The trans effect of the halides follows the order I->Br->Cl-, therefore the synthesis is conducted using [PtI4]2− to ensure high yield and purity of the cis isomer, followed by conversion of the PtI2(NH3)2 into PtCl2(NH3)2, as first described by Dhara.
External links
- Cisplatin: The Invention of an Anticancer Drug by Andri Smith
- Anti-cancer Agents: A treatment of Cisplatin and their analogues by Sia M. Liu (excellent detailed overview)
- MedlinePlus page on cisplatin
- IARC Monograph: "Cisplatin"
- http://ucl.ac.uk/histmed/publications/wellcome_witnesses_c20th_med/vol_30