15663-27-1 Usage
History of discovery
Cisplatin is currently one of the most commonly used drugs used in combination chemotherapy with its chemical full name being cis-dichlorodiamineplatinum. It belongs to inorganic metal complexes. After the dissociation of the chlorine atom, it can be cross-linked with the DNA of the cancer cell DNA, thereby destroying the DNA function. It can form intra-strand or inter-strand crosslink with the DNA and may also form a cross-link with DNA and protein, and can inhibit cell mitosis, belonging to cell cycle non-specific drugs. In addition to its anti-cancer effect, it is still capable of inhibiting lymphocyte transformation and having immunosuppression effect and thus can be used as the metal complex-class anti-cancer drugs.
In 1844, it had been first successfully developed by the French chemist Mario Rampini and has been ever called Rampini's salt. It appears as an orange crystal. It has a small solubility (being 0.252 g/ 100 g of water at 25 ℃) and can be produced through the reaction between tetrachloro platinum (II) solution of potassium and ammonia.
In 1891, the modern founder of coordination chemistry, Werner, starting from the study of this class of compounds, had successfully established a complex theory, and clarified the cis structure of the Rampini's salt.
It was not until 1965 that the anticancer activity of cisplatin was found by Rosenberg and his colleagues from University of Michigan USA. When studying the effect of the electric filed on the growth of E. coli, they found that when putting into the metallic platinum to the medium containing ammonium chloride and then sending through 2 ampere for two hours, the reproduction of E. coli was inhibited.
Further studies had showed that this is the effect of the cisplatin which is the product produced through the chemical reaction between the ammonia chloride and the platinum ion produced by electrolytic oxidation in the electrode. Rosenberg thought that given that cisplatin can prevent cell division, it should also have anticancer activity. Through the anti-cancer test, it has been proven that there is a good anti-cancer effect of cisplatin, drawing broad interest in metal complexes pharmacology. People had organized international cooperation research on chemistry, biology and medical field, finally enabling the successful applications of cisplatin in the treatment of cancer.
In December 1978, the US Food and Drug Administration had approved cisplatin for clinical application and make it as a commodity to supply the market. It has properties such as broad anti-tumor spectrum and being effective in treating hypoxic cells. However, it has toxicity to the kidneys, nervous system and pancreas. Modern pharmacology has classified this product as antineoplastic agents.
Pharmacological effects
Cisplatin is the most commonly used metal platinum complexes with the platinum atoms containing in the molecule being important for its anti tumor effect. However, it is also effective in the form of cis while being invalid in the Trans form. It can be cross-linked to DNA strand, showing cytotoxicity. After its dissolution inside the human body, it doesn’t need carrier transport in the body while being able to penetrate through the charged cell membrane. Owing to the low intracellular chloride concentration (4mmol /L), chloride ions are replaced by the water with the charge being positive which has a similar effect as bifunctional group of alkylating agent. It can combine with the nuclear DNA bases, forming three forms of cross-linking, resulting in DNA damage, further destroying DNA replication and transcription with the capability of inhibiting the synthesis of RNA and proteins at high concentrations as well. Cisplatin is characterized by broad anti-cancer spectrum, being effective in treating hypoxic cells and strong action. It has been widely used in the treatment of testicular cancer, ovarian cancer, uterine cancer, bladder cancer, cervical cancer, prostate cancer and brain cancer with significant efficacy. However, cisplatin has certain toxicity when being used in the treatment of cancer and thus being able to cause side effects. Therefore, it is necessary to continuously identify analogues of cisplatin with less toxicity and clinical effect being similar as cisplatin. So far scientists from various countries have been synthesized and tested thousands of cisplatin-related metal complexes and have developed the second-generation anti-cancer platinum complexes with carboplatin being the representative. The third generation anticancer metal complexes have also been identified with titanocene dichloride as the representative. These compounds have nothing to do with cisplatin from the chemical perspective but they have relative good efficacy in treating some kinds of cancer which can be hardly treated by cisplatin without doing harm to the kidney function. Now people in this area are continuing extensive research with the efforts majorly lining in exploring the anticancer mechanism of metal complexes at the molecular level. China has already started producing the goods of cisplatin and has carried out research in this area.
Cisplatin belongs to non-specific cell cycle drugs with cytotoxicity. Since the proliferation and synthesis rate of cancer cells is more rapid than normal cells, the cancer cell is more sensitive than normal cell to the toxic effects of this product. It can inhibit the DNA replication of cancer cell, and destroy the structure of the cell membrane. It has a strong broad-spectrum anti-cancer effect. It can be used for the treatment of ovarian cancer, prostate cancer, testicular cancer and other genitourinary malignancies with an excellent efficacy. When being used in combination with vincristine, cyclophosphamide and 5-fluorouracil, it has an excellent efficacy in the treatment of malignant lymphoma, breast cancer, carcinoma of head and neck squamous cell, thyroid cancer, and osteosarcoma, etc. Cisplatin, in combination with radiotherapy, can be used in the treatment for patients with advanced non-small cell lung cancer; nasopharyngeal cancer and esophageal cancer with prominent effect. It also has certain efficacy in the treatment of liver cancer and soft tissue sarcoma. Cisplatin, as a strong accumulative drug, is easy to produce renal toxicity with the gastrointestinal reactions being relatively common with neutropenia occurring in some patients but can be restored after the withdrawal of drugs for 7 to 14 days.
In addition, the DNA damage effect of this product can also possibly change the antigenicity in the nucleus or the cell surface so that the original hidden surface antigen is exposed, stimulating the immune suppression of antibodies and exert their cytotoxic effects. This information is edited by Xiongfeng Dai from lookchem.
Adverse reactions and side effects
Upon being subject to one-time injection of cisplatin for 50mg/m2, 25% to 30% of patients can get azotemia. Upon a larger dose and continuous medication, it can have serious and long-lasting kidney toxicity, manifested as tubular swelling, degenerative disease, elevated level of serum urea nitrogen, decreased creatinine clearance, hematuria, proteinuria, and even uremia.
It may have mild to moderate bone marrow toxicity whose degree depends on the amount of cisplatin. Anemia is common and may be accompanied with hemolysis. The patients can get severe nausea and vomiting which often appears at the beginning of treatment within 1h, lasting 8~12 h. The patients can administrate dexamethasone, ondansetron and diazepam to reduce the reaction.
It can cause malignant renal toxicity and is prone to occur at patients free from hydration and patients of diuretic therapy.
Combination with renal toxic antibiotics may increase the risk of enhancing acute renal failure.
It can commonly cause high-frequency hearing loss, and occasionally significant hearing loss. Tinnitus can occur at rare cases.
There may be significant symptoms of hyponatremia, hypomagnesemia, hypocalcemia, and hypokalemia which may occur in a few days after treatment.
After several times of administration can cause allergic reaction which can occur within minutes after administration, being manifested as facial edema, wheezing, tachycardia, etc. The patients should be quickly subject to anti-allergy measures such as antihistamine and adrenocorticotropic hormone.
There may be peripheral nerve toxicity. Hyperuricemia occurs rarely. There are occasional symptoms of orthostatic hypotension.
Chemical Properties
Different sources of media describe the Chemical Properties of 15663-27-1 differently. You can refer to the following data:
1. It appears as orange or yellow crystalline powder with the Mp being 268-272°C (decomposition). It is slightly soluble in water and easily soluble in dimethylformamide. In aqueous solution, it can be gradually transformed into trans-and hydrolysis.
2. Cisplatin is a white powder or yellow crystalline solid; freezing/melting point = 270°C (decomposes). Soluble in water
Description
Different sources of media describe the Description of 15663-27-1 differently. You can refer to the following data:
1. Cisplastin is an non-organic platinum-containing drug with alkylating properties. It causes
cross-linking of DNA and RNA chains. In particular, it has been shown, that cisplastin, like
other alkylating agents, bind primarily at N7 of two neighboring deoxyguanylates to DNA,
which inhibits its replication. It is only used intravenously. It is highly reactive with carcinomas of the testicles, ovaries, heat, neck, spleen, lungs, and so on.
2. Cisplatin is a platinum-containing compound that acts as a DNA-crosslinking agent and interferes with replication and transcription, culminating in apoptosis. It forms intra- and interstrand crosslinks with DNA with intrastrand guanine-to-guanine or guanine-to-alanine links accounting for the majority of DNA binding. Cisplatin halts the cell cycle at the G2/M phase in vitro and is active against murine tumors transplanted into mice and in mouse xenograft models, including a reduction in tumor growth in a model of squamous cell carcinoma of the head and neck when administered at doses ranging from 7.5 to 12.5 mg/kg. Cisplatin also inhibits the RecA recombinase of M. tuberculosis (IC50 = 2 μM), blocking protein splicing and cell growth. Formulations containing cisplatin have been used, alone and in combination therapy, in the treatment of a variety of cancers.
Originator
Blastolem,Lemery,Mexico
Uses
Different sources of media describe the Uses of 15663-27-1 differently. You can refer to the following data:
1. Used as an antineoplastic
2. Cisplatin is a cytostatic agent and it is used to treat various
cancer types, including cancer of ovary, testis, lung, head,
neck, bladder, neuroblastoma, and nephroblastoma, and
Hodgkin’s disease and non-Hodgkin lymphoma.
3. muscle relaxant (skeletal)
4. antitumor agent
Definition
Different sources of media describe the Definition of 15663-27-1 differently. You can refer to the following data:
1. ChEBI: A diamminedichloroplatinum compound in which the two ammine ligands and two chloro ligands are oriented in a cis planar configuration around the central platinum ion. An anticancer drug that interacts with, and forms cross-links between, D
A and proteins, it is used as a neoplasm inhibitor to treat solid tumours, primarily of the testis and ovary.
2. cisplatin: A platinum complex, cis-[PtCl2(NH3)2], used in cancer treatmentto inhibit the growth oftumours. It acts by binding betweenstrands of DNA.
Indications
Cisplatin (Platinol) is an inorganic coordination complex
with a broad range of antitumor activity. It is especially
useful in the treatment of testicular and ovarian
cancer. It binds to DNA at nucleophilic sites, such as the
N7 and O6 of guanine, producing alterations in DNA
structure and inhibition of DNA synthesis. Adjacent
guanine residues on the same DNA strand are preferentially
cross-linked. This platinating activity is analogous
to the mode of action of alkylating agents. Cisplatin also
binds extensively to proteins. It does not appear to be
phase specific in the cell cycle.
Production Methods
Cisplatin is obtained by the method described by Kauffman
and Cowan, in which potassium(II) tetrachloroplatinate
is treated with buffered aqueous ammonia solution.
Pure cisplatin is obtained by recrystallization from dilute
hydrochloric acid.
Manufacturing Process
The synthesis proceeds dy reduction of potassium hexachlorplatinate with
hydrazine to give potassium tetrachloroplatinate. This is converted to
potassium tetraiodoplatinate by treatment with potassium iodide and then
reacted with 6 M ammonium hydroxide to give crystals of cisplatin
Therapeutic Function
Antitumor
General Description
Different sources of media describe the General Description of 15663-27-1 differently. You can refer to the following data:
1. administrationin the treatment of a wide variety of cancers includingnon-Hodgkin’s lymphoma, bladder cancer, ovarian cancer,testicular cancer, and cancers of the head and neck. A liposomalform is also available as well as an injectable collagenmatrix gel containing cisplatin. Compared with other platins,cisplatin is the most reactive and therefore the most effectivein platinating DNA. After IV administration, the agent iswidely distributed, highly protein bound (90%), and concentratesin the liver and kidney. After infusion, covalent attachmentto plasma proteins occurs such that after 4 hours, 90%of drug is protein bound. The elimination of platinum fromthe blood is a slow process with a terminal elimination halflifeof 5 to 10 days. Metabolism involves aquation, which occursto a greater extent once distribution out of the plasmahas occurred. Additional metabolites have been seen resultingfrom reaction with glutathione and cysteine. The greaterreactivity of cisplatin gives rise to significant toxicitiescompared with other platins. These include dose-limitingnephrotoxicity, which normally presents as elevated bloodurea nitrogen (BUN) and creatinine. This effect is cumulativeupon repeated dosing and may progress further to necrosis,altered epithelial cells, cast formation, and thickening ofthe tubular basement membranes but is generally reversibleupon discontinuation of drug treatment. Sodium thiosulfatemay be given to reduce the nephrotoxicity. Neurotoxicitymay also be dose limiting, normally presenting initially asnumbness but may progress to seizure. Other adverse effectsinclude myelosuppression, nausea, vomiting, alopecia,ototoxicity, ocular toxicity, azoospermia, impotence, myocardialinfarction, thrombotic events, and inappropriatesecretion of antidiuretic hormone.
2. An anticancer drug. Orange-yellow to deep yellow solid or powder.
Air & Water Reactions
Insoluble in water.
Reactivity Profile
Cisplatin is incompatible with oxidizing agents. Cisplatin is also incompatible with aluminum. Cisplatin may react with sodium bisulfite and other antioxidants.
Fire Hazard
Flash point data for Cisplatin are not available; however, Cisplatin is probably combustible.
Pharmaceutical Applications
CDDP, also referred to as cisplatinum or cisplatin, is a yellow powder and has found widespread use a
chemotherapeutic agent.
Biological Activity
Potent anticancer agent that blocks DNA synthesis. Induces apoptosis via p53-dependent and -independent mechanisms. Inhibits X-linked inhibitor of apoptosis protein (XIAP) expression and activates caspase-3. In certain glioma cell lines, sensitizes cells to TNF- α -induced apoptosis.
Biochem/physiol Actions
Potent platinum-based antineoplastic agent. Forms cytotoxic adducts with the DNA dinucleotide d(pGpG), inducing intrastrand cross-links.
Mechanism of action
Cisplatin shows biphasic plasma decay with a distribution
phase half-life of 25 to 49 minutes and an elimination
half-life of 2 to 4 days. More than 90% of the
drug is bound to plasma proteins, and binding may approach
100% during prolonged infusion. Cisplatin does
not cross the blood-brain barrier. Excretion is predominantly
renal and is incomplete.
Clinical Use
Cisplatin, combined with bleomycin and vinblastine
or etoposide, produces cures in most patients with
metastatic testicular cancer or germ cell cancer of the
ovary. Cisplatin also shows some activity against carcinomas
of the head and neck, bladder, cervix, prostate,
and lung.
Side effects
Renal toxicity is the major potential toxicity of
cisplatin. Severe nausea and vomiting that often accompany
cisplatin administration may necessitate hospitalization.
Cisplatin has mild bone marrow toxicity, yielding
both leukopenia and thrombocytopenia. Anemia is
common and may require transfusions of red blood
cells. Anaphylactic allergic reactions have been described.
Hearing loss in the high frequencies (4000 Hz)
may occur in 10 to 30% of patients. Other reported toxicities
include peripheral neuropathies with paresthesias,
leg weakness, and tremors. Excessive urinary excretion
of magnesium also may occur.
Safety Profile
Confirmed carcinogen
with experimental carcinogenic and
tumorigenic data. Poison by ingestion,
intramuscular, submtaneous, intravenous,
and intraperitoneal routes. Human systemic
effects: change in audttory acuity, change in
kidney tubules, changes in bone marrow,
corrosive to skin, depressed renal function
tests, hallucinations, nausea or vomiting.
Experimental teratogenic and reproductive
effects. Human mutation data reported.
When heated to decomposition it emits very
toxic fumes of Cland NOx. See also
PLATINUM COMPOUNDS.
Synthesis
Cisplatin, cis-diaminodichloroplatinum (30.2.5.1), is made by reducing potassium hexachloroplatinate by hydrazine to potassium tetrachloroplatinate, which reacts
with ammonia to give cisplatin (30.2.5.1) .
Potential Exposure
A potential danger to those involved in the manufacture, formulation and administration of this anticancer chemotherapy agent. Contact with water causes decomposition.
Veterinary Drugs and Treatments
In veterinary medicine, the systemic use of cisplatin is presently
limited to use in dogs. The drug has been, or may be, useful in a
variety of neoplastic diseases including squamous cell carcinomas,
transitional cell carcinomas, ovarian carcinomas, mediastinal carcinomas,
osteosarcomas, pleural adenocarcinomas, nasal carcinomas,
and thyroid adenocarcinomas.
Cisplatin may be useful for the palliative control of neoplastic
pulmonary effusions after intracavitary
administration.
In horses, cisplatin has been used for intralesional injection for
skin tumors.
Drug interactions
Potentially hazardous interactions with other drugs
Aldesleukin: avoid concomitant use.
Antibacterials: increased risk of nephrotoxicity
and possibly ototoxicity with aminoglycosides,
capreomycin, polymyxins or vancomycin.
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Cytotoxics: increased risk of ototoxicity with
ifosfamide; increased pulmonary toxicity with
bleomycin and methotrexate.
Carcinogenicity
Cisplatin is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
Metabolism
It is rapidly hydrated, resulting in a short plasma half-life of less than 30 minutes. It is eliminated predominantly via the kidney, but approximately 10% of a given dose undergoes biliary excretion. It is highly nephrotoxic and can cause significant damage to the renal tubules, especially in patients with preexisting kidney disease or one kidney or who are concurrently receiving other nephrotoxic drugs (e.g., cyclophosphamide or ifosfamide). Dosages should be reduced in any of the above situations. Clearance decreases with chronic therapy, and toxicities can manifest at a late date. To proactively protect patients against kidney damage, patients should be hydrated with chloride-containing solutions. Saline or mannitol diuretics can be administered to promote continuous excretion of the drug and its hydrated analogues. Sodium thiosulfate, which accumulates in the renal tubules, also has been used to neutralize active drug in the kidneys in an effort to avoid nephrotoxicity.
Shipping
UN2928 Toxic solids, corrosive, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, 8-Corrosive material, Technical Name Required. UN3290 Toxic solid, corrosive, inorganic, n.o.s., Hazard class: 6.1; Labels: 6.1-Poisonous materials, 8-Corrosive material. UN3288 Toxic solids, inorganic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials
Purification Methods
Recrystallise it from dimethylformamide and check the purity by IR and UV-VIS spectroscopy. [Raudaschl et al. Inorg Chim Acta 78 143 1983.] HIGHLY TOXIC, SUSPECTED CARCINOGEN.
Incompatibilities
Aluminum reacts with cisplatin and decreases the drug’s effectiveness. Do not use any aluminum equipment to prepare or administer cisplatin.
Waste Disposal
Disposal of unused product must be undertaken by qualified personnel who are knowledgeable in all applicable regulations and follow all pertinent safety precautions including the use of appropriate protective equipment. For proper handling and disposal, always comply with federal, state, and local regulations
References
1) Van Waardenburg et al. (2004), Platinated DNA adducts enhance poisoning of DNA topoisomerase I by camptothecin; J. Biol. Chem,, 279 54502
2) Siddik et al. (2003), Cisplatin: mode of cytotoxic action and molecular basis of resistance; Oncogene, 22 7265
3) Seki et al. (2000), Cisplatin (CDDP) specifically induces apoptosis via sequential activation of caspase-8, -3 and -6 in osteosarcoma; Cancer Chemother. Pharmacol., 45 199
4) Nomura et al. (2004), Cisplatin inhibits the expression of X-linked inhibitor of apoptosis protein in human LNCaP cells; Urol. Oncol., 22 453
5) Raghavan et al. (2015), Dimethylsulfoxide inactivates the anticancer effect of cisplatin against myelogenous leukemia cell lines in in vitro assays.; Indian J. Phamracol., 47 322
Check Digit Verification of cas no
The CAS Registry Mumber 15663-27-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,5,6,6 and 3 respectively; the second part has 2 digits, 2 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 15663-27:
(7*1)+(6*5)+(5*6)+(4*6)+(3*3)+(2*2)+(1*7)=111
111 % 10 = 1
So 15663-27-1 is a valid CAS Registry Number.
InChI:InChI=1/2ClH.2H3N.Pt/h2*1H;2*1H3;/q;;;;+2/p-2
15663-27-1Relevant articles and documents
Copper-free click-chemistry platform to functionalize cisplatin prodrugs
Pathak, Rakesh K.,McNitt, Christopher D.,Popik, Vladimir V.,Dhar, Shanta
, p. 6861 - 6865 (2014)
The ability to rationally design and construct a platform technology to develop new platinum(IV) [PtIV] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin by using well-defined chemistry is critical for discovering new platinum-based therapeutics. With limited numbers of possibilities considering the sensitivity of PtIV centers, we used a strain-promoted azide-alkyne cycloaddition approach to provide a platform, in which new functionalities can easily be installed on cisplatin prodrugs from a single PtIV precursor. The ability of this platform to be incorporated in nanodelivery vehicle and conjugation to fluorescent reporters were also investigated.
Glassy carbon electrodes deliver unpredictable reduction potentials for platinum(IV) antitumor prodrugs
McCormick, Meghan C.,Schultz, Franklin A.,Baik, Mu-Hyun
, p. 28 - 34 (2016)
Reductive activation of six-coordinate Pt(IV) complexes to afford square-planar Pt(II) complexes has exhibited surprisingly divergent and unpredictable cathodic peak potentials during cyclic voltammetry (CV) measurements under widely employed experimental conditions. A systematic, detailed investigation reveals that glassy carbon (GC) electrodes are responsible for this erratic behavior. More reproducible CVs are obtained with platinum metal electrodes, which display cathodic responses at much more positive potentials. The unreliable and negatively shifted peak potentials observed at GC are attributed to a non-uniform oxide layer that is formed on the electrode surface causing slow electron transfer. A simple procedure of repetitive scanning to reducing potentials is found to be effective for cleaning and activating the GC surface, such that it exhibits the more consistent and accurate peak potential responses seen with a Pt electrode.
Kinetic characterization of the interactions of trans-dichloro-platinum(IV) anticancer prodrugs and a model compound with thiosulfate
Dong, Jingran,Huo, Shuying,Song, Changying,Shen, Shigang,Ren, Yanli,Shi, Tiesheng
, p. 127 - 133 (2014)
Sodium thiosulfate has been utilized as a rescuing agent for relief of the toxic effects of cisplatin and carboplatin. In this work, we characterized the kinetics of reactions of the trans-dichloro-platinum(IV) complexes cis-[Pt(NH3)2Cl4], ormaplatin [Pt(dach)Cl 4] and trans-[PtCl2(CN)4]2- (anticancer prodrugs and a model compound) with thiosulfate at biologically important pH. An overall second-order rate law was established for the reduction of trans-[PtCl2(CN)4]2- by thiosulfate, and varying the pH from 4.45 to 7.90 had virtually no influence on the reaction rate. In the reactions of thiosulfate with cis-[Pt(NH3) 2Cl4] and with [Pt(dach)Cl4], the kinetic traces displayed a fast reduction step followed by a slow substitution involving the intermediate Pt(II) complexes. The reduction step also followed second-order kinetics. Reductions of cis-[Pt(NH3)2Cl 4] and [Pt(dach)Cl4] by thiosulfate proceeded with similar rates, presumably due to their similar configurations, whereas the reduction of trans-[PtCl2(CN)4]2- was about 1,000 times faster. A common reduction mechanism is suggested, and the transition state for the rate-determining step has been delineated. The activation parameters are consistent with transfer of Cl+ from the platinum(IV) center to the attacking thiosulfate in the rate-determining step.
Synthesis of pyrophosphatotetraamminediplatinum(II) complex and its transformations in hydrochloric acid solutions
Starkov,Patrushev
, p. 312 - 312 (2007)
A new method for the synthesis of [Pt2(NH3) 4P2O7] is proposed. Its transformations in a hydrochloric acid medium are described. Nauka/Interperiodica 2007.
Synthesis and Cytotoxic Study of a Platinum(IV) Anticancer Prodrug with Selectivity toward Luteinizing Hormone-Releasing Hormone (LHRH) Receptor-Positive Cancer Cells
Yao, Houzong,Xu, Zoufeng,Li, Cai,Tse, Man-Kit,Tong, Zixuan,Zhu, Guangyu
, p. 11076 - 11084 (2019)
Platinum drugs including cisplatin are widely used in clinics to treat various types of cancer. However, the lack of cancer-cell selectivity is one of the major problems that lead to side effects in normal tissues. Luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in many types of cancer cells but rarely presented in normal cells, making LHRH receptor a good candidate for cancer targeting. In this study, we report the synthesis and cytotoxic study of a novel platinum(IV) anticancer prodrug functionalized with LHRH peptide. This LHRH-platinum(IV) conjugate is highly soluble in water and quite stable in a PBS buffer. Cytotoxic study reveals that the prodrug selectively targets LHRH receptor-positive cancer cell lines with the cytotoxicities 5-8 times higher than those in LHRH receptor-negative cell lines. In addition, the introduction of LHRH peptide enhances the cellular accumulation in a manner of receptor-mediated endocytosis. Moreover, the LHRH-platinum(IV) prodrug is proved to kill cancer cells by binding to the genomic DNA, inducing apoptosis, and arresting the cell cycle at the G2/M phase. In summary, we report a novel LHRH-platinum(IV) anticancer prodrug having largely improved selectivity toward LHRH receptor-positive cancer cells, relative to cisplatin.
Microwave-assisted synthesis of the anticancer drug cisplatin, cis-[Pt(NH3)2Cl2]
Petruzzella, Emanuele,Chirosca, Cristian V.,Heidenga, Cameron S.,Hoeschele, James D.
, p. 3384 - 3392 (2015)
A microwave-assisted synthesis of cisplatin, cis-[Pt(NH3)2Cl2], has been developed and optimized on both a 0.2 and 0.05 millimolar scale. The optimized synthetic procedure was modeled after the Lebedinskii-Golovnya method and is suitable for incorporating the radionuclide, 195mPt, into cisplatin for biological studies. Highest yields (47%) and purity are obtained using a K2PtCl4:NH4OAc:KCl molar ratio of 1:4:2 at a temperature of 100 °C. The entire synthesis and purification procedure requires approximately 80 min. At a reaction temperature of 150 °C, the trans isomer is the exclusive product, suggesting that complexes of the general form, trans-[Pt(RNH2)2Cl2], can be synthesized directly from K2PtCl4 using [RNH3]OAc (R = alkyl or aryl moieties) via a microwave process. Two novel separation procedures have been developed which efficiently remove the major impurity (1:1 Magnus-type salt) from the crude reaction product, yielding a product of purity comparable to that obtained by the Dhara method and suitable for biological studies. These procedures are applicable to both the micro- and macro-scale of synthesis. The question of whether this microwave-assisted synthesis of cisplatin will be a preferred method for incorporating 195mPt into cisplatin is yet to be determined. This journal is
A 1,2-d(GpG) cisplatin intrastrand cross-link influences the rotational and translational setting of DNA in nucleosomes
Ober, Matthias,Lippard, Stephen J.
, p. 2851 - 2861 (2008)
The mechanism of action of platinum-based anticancer drugs such as cis-diamminedichloro-platinum(II), or cisplatin, involves three early steps: cell entry, drug activation, and target binding. A major target in the cell, responsible for the anticancer activity, is nuclear DNA, which is packaged in nucleosomes that comprise chromatin. It is important to understand the nature of platinum-DNA interactions at the level of the nucleosome. The cis-{Pt(NH 3)2}2+ 1,2-d(GpG) intrastrand cross-link is the DNA lesion most commonly encountered following cisplatin treatment. We therefore assembled two site-specifically platinated nucleosomes using synthetic DNA containing defined cis-{Pt(NH3)2}2+ 1,2-d(GpG) cross-links and core histones from HeLa-S3 cancer cells. The structures of these complexes were investigated by hydroxyl radical footprinting and exonuclease III mapping. Our experiments demonstrate that the 1,2-d(GpG) cross-link alters the rotational setting of the DNA on the histone octamer core such that the lesion faces inward, with disposition angles of the major groove relative to the core of ξ ≈ -20° and ξ ≈ 40°. We observe increased solvent accessibility of the platinated DNA strand, which may be caused by a structural perturbation in proximity of the 1,2-d(GpG) cisplatin lesion. The effect of the 1,2-d(GpG) cisplatin adduct on the translational setting of the nucleosomal DNA depends strongly on the position of the adduct within the sequence. If the cross-link is located at a site that is in phase with the preferred rotational setting of the unplatinated nucleosomal DNA, the effect on the translational position is negligible. Minor exonuclease III digestion products in this substrate indicate that the cisplatin adduct permits only those translational settings that differ from one another by integral numbers of DNA helical turns. If the lesion is located out of phase with the preferred rotational setting, the translational position of the main conformation was shifted by 5 bp. Additionally, a fraction of platinated nucleosomes with widely distributed translational positions was observed, suggesting increased nucleosome sliding relative to platinated nucleosomes containing the 1,3-intrastrand d(GpTpG) cross-link investigated previously (Ober, M.; Lippard, S. J. J. Am. Chem. Soc. 2007, 129, 6278-6286).
Oxidation of 3,6-dioxa-1,8-octanedithiol by platinum(IV) anticancer prodrug and model complex: Kinetic and mechanistic studies
Huo, Shuying,Shen, Shigang,Liu, Dongzhi,Shi, Tiesheng
, p. 6522 - 6528 (2012)
Thioredoxins are small redox proteins and have the active sites of Cys-Xaa-Yaa-Cys; they are overexpressed by many different cancer cells. Cisplatin and Pt(II) analogues could bind to the active sites and inhibit the activities of the proteins, as demonstrated by other researchers. Platinum(IV) anticancer drugs are often regarded as prodrugs, but their interactions with thioredoxins have not been studied. In this work, 3,6-dioxa-1,8-octanedithiol (dithiol) was chosen as a model compound for the active sites of thioredoxins, and its reactions with cis-[Pt(NH3)2Cl4] and trans-[PtCl2(CN)4]2- (cisplatin prodrug and a model complex) were studied. The pKa values for the dithiol were characterized to be 8.7 ± 0.2 and 9.6 ± 0.2 at 25.0 °C and an ionic strength of 1.0 M. The reaction kinetics was followed by a stopped-flow spectrophotometer over a wide pH range. An overall second-order rate law was established, -d[Pt(IV)]/dt = k′[Pt(IV)][dithiol], where k′ stands for the observed second-order rate constants. Values of k′ increased several orders of magnitude when the solution pH was increased from 3 to 9. A stoichiometry of Δ[Pt(IV)]/Δ[dithiol] = 1:1 derived for the reduction process and product analysis by mass spectrometry indicated that the dithiol was oxidized to form an intramolecular disulfide, coinciding with the nature of thioredoxin proteins. All of the reaction features are rationalized in terms of a reaction mechanism, involving three parallel rate-determining steps depending on the pH of the reaction medium. Rate constants for the rate-determining steps were evaluated. It can be concluded that Pt(IV) anticancer prodrugs can oxidize the reduced thioredoxins, and the oxidation mechanism is similar to those of the oxidations of biologically important reductants by some reactive oxygen species (ROS) such as hypochlorous acid/hypochlorite and chloramines.
Biological activity of a series of cisplatin-based aliphatic bis(carboxylato) Pt(IV) prodrugs: How long the organic chain should be?
Zanellato, Ilaria,Bonarrigo, Ilaria,Colangelo, Donato,Gabano, Elisabetta,Ravera, Mauro,Alessio, Manuela,Osella, Domenico
, p. 219 - 227 (2014)
The biological properties of a series of cisplatin-based Pt(IV) prodrug candidates, namely trans,cis,cis-[Pt(carboxylato)2Cl 2(NH3)2], where carboxylato = CH 3(CH2)nCOO- [(1), n = 0; (2), n = 2; (3), n = 4; (4), n = 6] having a large interval of lipophilicity are discussed. The stability of the complexes was tested in different pH conditions (i.e. from 1.0 to 9.0) to simulate the hypothetical conditions for an oral route of administration, showing a high stability (> 90%). The transformation into their active Pt(II) metabolites was demonstrated in the presence of ascorbic acid, with a pseudo-first order kinetics, the half-time of which smoothly decreases as the chain length of carboxylic acid increases. Their antiproliferative activity has been evaluated in vitro on a large panel of human cancer cell lines. As expected, the potency increases with the chain length: 3 and 4 resulted by far more active than cisplatin on all cell lines of about one or two orders of magnitude, respectively. Both complexes retained their activity also on cisplatin-resistant cell line, and exhibited a progressive increase of the selectivity compared with non-tumor cells. These results were confirmed with more prolonged treatment (up to 14 days) studied on multicellular tumor spheroids (MCTSs). In this case the Pt(IV) complexes exert a protracted antiproliferative action, even if the drug is removed from the culture medium. Finally, in a time-course experiment of the total platinum evaluation in mice blood (after a single oral administration of the title complexes), 2 gave the best results, representing a good compromise between lipophilicity and water solubility, that increase and decrease respectively on passing from 1 to 4.
Reduction of the anti-cancer drug analogue cis,trans,cis-[PtCl2(OCOCH3)2(NH 3)2] by L-cysteine and L-methionine and its crystal structure
Chen, Lie,Lee, Peng Foo,Ranford, John D.,Vittal, Jagadese J.,Wong, Siew Ying
, p. 1209 - 1212 (1999)
The complex cis,trans,cis-[PtCl2(OCOCH3)2(NH 3)2] 1 has been synthesized as a simplified and more soluble model of the anticancer drug cis,trans,cis-[PtCl2(OCOCH3)2(NH 3)(C6H11NH2)] (JM216). The crystal structure of 1 shows an octahedral co-ordination sphere around the PtIV with strong intramolecular and weak intermolecular hydrogen bonding. The kinetics of reduction of 1 by the divalent sulfur amino acids L-cysteine and L-methionine has been determined over a range of pH values by multinuclear NMR. The reduction is strongly pH dependent, being related to the protonation state of the amino acid and the basicity of the sulfur. Reduction rates are dramatically slower than for previous models of platinum(IV) drug systems.
Preparation of cisplatin using microwave heating and continuous-flow processing as tools
Pedrick, Elizabeth A.,Leadbeater, Nicholas E.
, p. 481 - 483 (2011)
Microwave heating has been used for the small-scale preparation of cisplatin, [cis-PtCl2(NH3)2], in isomerically pure form without concomitant formation of Magnus' salt, [Pt(NH 3)4][PtCl4].
Stability, Reduction, and Cytotoxicity of Platinum(IV) Anticancer Prodrugs Bearing Carbamate Axial Ligands: Comparison with Their Carboxylate Analogues
Chen, Shu,Gunawan, Yuliana F.,Tse, Man-Kit,Yao, Houzong,Zhou, Qiyuan,Zhu, Guangyu
, (2020)
Platinum(IV) complexes containing carboxylate and carbamate ligands at the axial position have been reported previously. A better understanding of the similarity and difference between the two types of ligands will provide us with new insights and more choices to design novel Pt(IV) complexes. In this study, we systematically investigated and compared the properties of Pt(IV) complexes bearing the two types of ligands. Ten pairs of unsymmetric Pt(IV) complexes bearing axial carbamate or carboxylate ligands were synthesized and characterized. The stability of these Pt(IV) complexes in a PBS buffer with or without a reducing agent was investigated, and most of these complexes exhibited good stability. Besides, most Pt(IV) prodrugs with carbamate axial ligands were reduced faster than the corresponding ones with carboxylate ligands. Furthermore, the aqueous solubilities and lipophilicities of these Pt(IV) complexes were tested. All the carbamate complexes showed better aqueous solubility and decreased lipophilicity as compared to those of the corresponding carboxylate complexes, due to the increased polarity of carbamate ligands. Biological properties of these complexes were also evaluated. Many carbamate complexes showed cytotoxicity similar to that of the carboxylate complexes, which may derive from the lower cellular accumulation but faster reduction of the former. Our research highlights the differences between the Pt(IV) prodrugs containing carbamate and carboxylate axial ligands and may contribute to the future rational design of Pt-based anticancer prodrugs.
Fighting against Drug-Resistant Tumors using a Dual-Responsive Pt(IV)/Ru(II) Bimetallic Polymer
Butt, Hans-Jürgen,Han, Jianxiong,Liang, Xing-Jie,Sun, Wen,Wang, Yufei,Wu, Si,Zeng, Xiaolong
, (2020)
Drug resistance is a major problem in cancer treatment. Herein, the design of a dual-responsive Pt(IV)/Ru(II) bimetallic polymer (PolyPt/Ru) to treat cisplatin-resistant tumors in a patient-derived xenograft (PDX) model is reported. PolyPt/Ru is an amphiphilic ABA-type triblock copolymer. The hydrophilic A blocks consist of biocompatible poly(ethylene glycol) (PEG). The hydrophobic B block contains reduction-responsive Pt(IV) and red-light-responsive Ru(II) moieties. PolyPt/Ru self-assembles into nanoparticles that are efficiently taken up by cisplatin-resistant cancer cells. Irradiation of cancer cells containing PolyPt/Ru nanoparticles with red light generates 1O2, induces polymer degradation, and triggers the release of the Ru(II) anticancer agent. Meanwhile, the anticancer drug, cisplatin, is released in the intracellular environment via reduction of the Pt(IV) moieties. The released Ru(II) anticancer agent, cisplatin, and the generated 1O2 have different anticancer mechanisms; their synergistic effects inhibit the growth of drug-resistant cancer cells. Furthermore, PolyPt/Ru nanoparticles inhibit tumor growth in a PDX mouse model because they circulate in the bloodstream, accumulate at tumor sites, exhibit good biocompatibility, and do not cause side effects. The results demonstrate that the development of stimuli-responsive multi-metallic polymers provides a new strategy to overcome drug resistance.
INORGANIC-ORGANIC HYBRID COMPOUNDS INCLUDING ORGANIC PLATINUM-CONTAINING ANIONS, FOR USE IN MEDICINE
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Paragraph 0080; 0088, (2021/09/26)
The present invention relates to inorganic-organic hybrid compounds for use in medicine or for use as medication, consisting of an inorganic metal cation and an organic platinum-containing cytostatic anion, in particular also a cisplatin derivative.
Solid-Phase Reaction of Tetraammineplatinum(II) Chloride with Ammonium Heptamolybdate
Buslaeva, T. M.,Fesik, E. V.,Melnikova, T. I.,Tarasova, L. S.
, p. 1020 - 1024 (2020/07/27)
Abstract: The solid-phase reaction of [Pt(NH3)4]Cl2 and (NH4)6Mo7O24 under argon in the temperature range from 50 to 500°C was studied by thermal analysis and mass spectrometry.
