41575-94-4 Usage
Description
Carboplatin, also known as Paraplatin, is a second-generation platinum compound analog used as a chemotherapy medication for the treatment of various types of cancers. It belongs to a class of alkylating agents and works through three major mechanisms: attaching alkyl groups to DNA bases, inducing cross-link formation to prevent DNA separation, and causing mispairing of nucleotides leading to mutations. Carboplatin is available in 50-, 150-, and 450-mg vials for intravenous administration and is characterized by its white crystalline form.
Uses
Used in Anthelmintic Applications:
Carboplatin is used as an anthelmintic agent for treating certain parasitic infections.
Used in Antitumor Applications:
Carboplatin is used as an antineoplastic agent for the treatment of a broad spectrum of solid tumors, including brain tumors, neuroblastoma, rhabdomyosarcoma, and germ cell tumors. It is particularly effective in treating advanced ovarian carcinoma of epithelial origin and small cell carcinoma of the lung.
Used in Pediatric Cancer Treatment:
Carboplatin is used as a chemotherapy agent for pediatric cancer, with approximately one-third of children with solid tumors estimated to receive carboplatin at some point during their treatment.
Used in Chemotherapy for Specific Cancers:
Carboplatin is used as a chemotherapy agent for the treatment of ovarian cancer, bladder cancer, germ cell tumors, head and neck cancers, small cell lung cancer, and non-small cell lung cancer (NSCLC). It is particularly effective in treating cancer of the ovary, embryonal carcinoma of the testis, microcellular carcinoma of the lung, neuroblastoma, and squamous cell carcinomas of the head and neck.
Used as an Analog of Cisplatin with Reduced Nephrotoxicity:
Carboplatin is used as an alternative to cisplatin due to its significantly reduced nephrotoxicity, making it a safer option for patients with kidney impairment or those requiring long-term chemotherapy treatment.
Mechanism of action
Once carboplatin penetrates the cell membrane, carboplatin is subjected to hydrolysis becoming positively charged. The hydrolyzed product is capable of reacting with any nucleophile, such as the sulfhydryl groups on proteins and nitrogen donor atoms on nucleic acids. Carboplatin connects to the N7 reactive center on purine bases, which elicits DNA injury that blocks replicative machinery and directs cancer cells towards apoptosis. The spectrum of chemical changes induced by carboplatin within DNA is wide, however, the most prominent is the formation of the 1,2-intrastrand [d(GpG)and d(ApG)] adducts of purines.
Mechanism of action
Carboplatin, another square planar Pt(II) complex, forms the same cytotoxic hydrated intermediate as cisplatin but does so at a slower rate, making it a less potent chemotherapeutic agent.
Originator
Johnson Matthey (United Kingdom)
Indications
Carboplatin (Paraplatin) is an analogue of cisplatin. Its
plasma half-life is 3 to 5 hours, and it has no significant
protein binding. Renal excretion is the major route of
drug elimination.
Despite its lower chemical reactivity, carboplatin
has antitumor activity that is similar to that of cisplatin
against ovarian carcinomas, small cell lung cancers,
and germ cell cancers of the testis. Most tumors that
are resistant to cisplatin are cross-resistant to carboplatin.
The major advantage of carboplatin over cisplatin is
a markedly reduced risk of toxicity to the kidneys, peripheral
nerves, and hearing; additionally, it produces
less nausea and vomiting. It is, however, more myelosuppressive
than cisplatin. Other adverse effects include
anemia, abnormal liver function tests, and occasional allergic
reactions.
Manufacturing Process
cis-Diammine platinum diiodide was reacted with silver sulfate to give cis-diaquodiammine platinum sulfate. This was reacted with the barium salt of
1,1-cyclobutanedicarboxylic acid to yield Carboplatin.
Therapeutic Function
Antitumor
Pharmaceutical Applications
Carboplatin, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), is a second-generation platinum drug.
Its structure is based on cisplatin with the difference that the chloride ligands are exchanged for a bidentate
chelating ligand. A consequence is that carboplatin is less reactive than cisplatin and therefore is less nephrotoxic
and orthotoxic than the parent compound. Unfortunately, it is more myelosuppressive than cisplatin,
which reduces the patients’ white blood cell count and makes them susceptible to infections. Carboplatin
was licensed by the FDA in 1989 under the brand name Paraplatin and has since then gained worldwide
recognition. Carboplatin on its own or in combination with other anticancer agents is used in the treatment
of a variety of cancer types including head and neck, ovarian, small-cell lung, testicular cancer and others.
Carboplatin is a pale-white solid showing good aqueous solubility. The synthesis starts with potassium
tetrachloroplatinate, which is reacted to the orange [PtI4]2- anion.
Biological Activity
Antitumor agent that forms platinum-DNA adducts. Causes intra- and interstrand DNA crosslinks blocking DNA replication and transcription. Enhances radiation-induced single-strand DNA breakage and displays lower nephrotoxicity than analog cisplatin (cis-Diaminodichloroplatinum ).
Biochem/physiol Actions
Carboplatin is a platinum-based antineoplastic drug that damages DNA by forming intrastrand cross-links with neighboring guanine residues. Tumors acquire resistance to these drugs through the loss of DNA-mismatch repair (MMR) activity and the resultant decrease in the induction of programmed cell death.
Clinical Use
This drug induces fewer nonhematological toxicities (e.g., emesis, nephrotoxicity, and ototoxicity) compared to cisplatin, and it is approved for use only in the treatment of ovarian cancer. Unlabeled uses include combination therapy in lung, testicular, and head and neck cancers.
Side effects
The ultimate damage done to cells as a result of carboplatin use, however, approaches that of cisplatin. The plasma half-life of carboplatin is 3 hours, and the drug is less extensively bound to serum proteins. Excretion is predominantly renal, and doses must be reduced in patients with kidney disease. Suppression of platelets and white blood cells is the most significant toxic reaction of carboplatin use.
Synthesis
Carboplatin, cis-diamino-(1,1-cyclobutandicarboxylate)platinum(II), is
made from cisplatin by reacting it with a solution of silver nitrate, and then with cyclobutan-1,1-dicarboxylic acid to form the desired carboplatin (30.2.5.2).
Veterinary Drugs and Treatments
Like cisplatin, carboplatin may be useful in a variety of veterinary
neoplastic diseases
including squamous cell carcinomas, ovarian
carcinomas, mediastinal carcinomas, pleural adenocarcinomas,
nasal carcinomas and thyroid adenocarcinomas. Carboplatin’s primary
use currently in small animal medicine is in the adjunctive
treatment (post amputation) of osteogenic sarcomas. Its effectiveness
in treating transitional cell carcinoma of the bladder has been
disappointing; however, carboplatin may have more efficacy against
melanomas than does cisplatin.
Carboplatin, unlike cisplatin, appears to be relatively safe to use
in cats.
Carboplatin may be considered for intralesional use in conditions
such as equine sarcoids or in treating adenocarcinoma in
birds.
Whether carboplatin is more efficacious than cisplatin for certain
cancers does not appear to be decided
at this point, but the
drug does appear to have fewer adverse effects (less renal toxicity
and reduced
vomiting) in dogs.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: increased risk of nephrotoxicity
and possibly ototoxicity with aminoglycosides,
capreomycin, polymyxins or vancomycin.
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Metabolism
There is little, if any, true metabolism of carboplatin.
Excretion is primarily by glomerular filtration in the
urine, with 70% of the drug excreted within 24 hours,
most of it in the first 6 hours. Approximately 32% of the
dose is excreted unchanged.
Platinum from carboplatin slowly becomes protein
bound, and is subsequently excreted with a terminal halflife of 5 days or more.
references
[1]. banerji u, sain n, sharp sy, et al. an in vitro and in vivo study of the combination of the heat shock protein inhibitor 17-allylamino-17-demethoxygeldanamycin and carboplatin in human ovarian cancer models. cancer chemother pharmacol, 2008, 62(5): 769-778. [2]. fiebiger w, olszewski u, ulsperger e, et al. in vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines. clin transl oncol, 2011, 13(1): 43-49. [3]. smith ie, evans bd. carboplatin (jm8) as a single agent and in combination in the treatment of small cell lung cancer. cancer treat rev, 1985, 12 suppl a: 73-75.
Check Digit Verification of cas no
The CAS Registry Mumber 41575-94-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 4,1,5,7 and 5 respectively; the second part has 2 digits, 9 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 41575-94:
(7*4)+(6*1)+(5*5)+(4*7)+(3*5)+(2*9)+(1*4)=124
124 % 10 = 4
So 41575-94-4 is a valid CAS Registry Number.
InChI:InChI=1/C6H8O4.2H2N.Pt/c7-4(8)6(5(9)10)2-1-3-6;;;/h1-3H2,(H,7,8)(H,9,10);2*1H2;/q;2*-1;+4/p-2/rC6H10N2O4Pt/c7-13(8)11-4(9)6(2-1-3-6)5(10)12-13/h1-3,7-8H2
41575-94-4Relevant articles and documents
Nanoscale Coordination Polymers Codeliver Carboplatin and Gemcitabine for Highly Effective Treatment of Platinum-Resistant Ovarian Cancer
Poon, Christopher,Duan, Xiaopin,Chan, Christina,Han, Wenbo,Lin, Wenbin
, p. 3665 - 3675 (2016)
Due to the ability of ovarian cancer (OCa) to acquire drug resistance, it has been difficult to develop efficient and safe chemotherapy for OCa. Here, we examined the therapeutic use of a new self-assembled core-shell nanoscale coordination polymer nanoparticle (NCP-Carbo/GMP) that delivers high loadings of carboplatin (28.0 ± 2.6 wt %) and gemcitabine monophosphate (8.6 ± 1.5 wt %). A strong synergistic effect was observed between carboplatin and gemcitabine against platinum-resistant OCa cells, SKOV-3 and A2780/CDPP, in vitro. The coadministration of carboplatin and gemcitabine in the NCP led to prolonged blood circulation half-life (11.8 ± 4.8 h) and improved tumor uptake of the drugs (10.2 ± 4.4% ID/g at 24 h), resulting in 71% regression and 80% growth inhibition of SKOV-3 and A2780/CDDP tumors, respectively. Our findings demonstrate that NCP particles provide great potential for the codelivery of multiple chemotherapeutics for treating drug-resistant cancer.
Synthesis of monofunctional platinum(iv) carboxylate precursors for use in Pt(iv)-peptide bioconjugates
?mi?owicz, Dariusz,Metzler-Nolte, Nils
, p. 15465 - 15476 (2018)
Herein we present platinum(iv) bioconjugates with polyarginine peptides as prospective prodrug delivery systems. Asymmetrical platinum(iv) complexes 3 were obtained via oxidation of parent platinum(ii) complexes 2 with N-bromosuccinimide (NBS) in the presence of succinic anhydride. The combination of these two oxidation reagents furnishes the platinum(iv) environment with two different axial ligands, one of which bears a free carboxylic acid. All platinum(ii) and (iv) compounds were characterized by FT-IR, ESI-MS, HPLC, 1H-, 13C- and 195Pt-NMR. Standard solid-phase peptide chemistry was used for the synthesis of polyarginine (R9) peptides. Coupling of the platinum complexes with peptides N-terminally afforded peptide monoconjugates, which were purified by semi-preparative HPLC and characterized by analytical HPLC and ESI-MS. Platinum(iv)-peptide bioconjugates as well as platinum(ii) and platinum(iv) complexes were tested as cytotoxic agents against two different human cancer cell lines (MCF-7, HepG2) and normal human fibroblasts cell lines (GM5657T). Preliminary in vitro data showed that all platinum(iv) complexes exhibit lower activity than their platinum(ii) precursors towards most cell lines. Interestingly, in the case of HepG2 cells, the Pt(iv)-(R)9-G-A-L bioconjugate (4a) showed even higher activity compared to the non-targeting platinum(iv) parent compound.
BODI-Pt, a Green-Light-Activatable and Carboplatin-Based Platinum(IV) Anticancer Prodrug with Enhanced Activation and Cytotoxicity
Chen, Shu,Deng, Zhiqin,Matsuda, Yudai,Tse, Man-Kit,Yao, Houzong,Zhu, Guangyu
supporting information, (2020/09/02)
Platinum drugs are widely used in clinics to treat various types of cancer. However, a number of severe side effects induced by the nonspecific binding of platinum drugs to normal tissues limit their clinical use. The conversion of platinum(II) drugs into more inert platinum(IV) derivatives is a promising strategy to solve this problem. Some platinum(IV) prodrugs, such as carboplatin-based tetracarboxylatoplatinum(IV) prodrugs, are not easily reduced to active platinum(II) species, leading to low cytotoxicity in vitro. In this study, we report the design and synthesis of a carboplatin-based platinum(IV) prodrug functionalized with a boron dipyrromethene (bodipy) ligand at the axial position, and the ligand acts as a photoabsorber to photoactivate the platinum(IV) prodrug. This compound, designated as BODI-Pt, is highly stable in the dark but quickly activated under irradiation to release carboplatin and the axial ligands. A cytotoxic study reveals that BODI-Pt is effective under irradiation, with cytotoxicity 11 times higher than that in the dark and 39 times higher than that of carboplatin in MCF-7 cells. Moreover, BODI-Pt has been proven to kill cancer cells by binding to the genomic DNA, arresting the cell cycle at the G2/M phase, inducing oncosis, and generating ROS upon irradiation. In summary, we report a green-light-activatable and carboplatin-based Pt(IV) prodrug with improved cytotoxicity against cancer cells, and our strategy can be used as a promising way to effectively activate carboplatin-based platinum(IV) prodrugs.
Bioorthogonal Catalytic Activation of Platinum and Ruthenium Anticancer Complexes by FAD and Flavoproteins
Alonso-de Castro, Silvia,Cortajarena, Aitziber L.,López-Gallego, Fernando,Salassa, Luca
supporting information, p. 3143 - 3147 (2018/03/13)
Recent advances in bioorthogonal catalysis promise to deliver new chemical tools for performing chemoselective transformations in complex biological environments. Herein, we report how FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), and fo