41575-94-4

Basic information

• Product Name: Carboplatin
• Synonyms: 1,1-cyclobutanedicarboxylatediammineplatinum(ii);1-cyclobutanedicarboxylato(2-)-o,o’)-diammine((sp-4-2)-platinu;1-cyclobutanedicarboxylato)diammine-(cis-platinum(ii;cbdca;cis-(1,1-cyclobutanedicarboxylato)diammineplatinum(ii);diammine-1,1-cyclobutanedicarboxylateplatinumi;nsc-241240;SP-4-2)-Diammine[1,1-cyclobutanedicar-boxylato-(2-)O,O’]platinum
• CAS NO: 41575-94-4
• Molecular Formula: C₆H₁₂N₂O₄Pt
• Molecular Weight: 371.25
• EINECS: 255-446-0
• Product Categories: Pharmaceutical material and intermeidates;Active Pharmaceutical Ingredients;Antitumors for Research and Experimental Use;Biochemistry;Classes of Metal Compounds;Cyclobutanes & Cyclobutenes;Pt (Platinum) Compounds;Simple 4-Membered Ring Compounds;Transition Metal Compounds;Intermediates & Fine Chemicals;Pharmaceuticals;anti-cancer;metal-ammine complexes;NEMAZINE;Anti cancer;Anti can;Inhibitors;API
• Mol File: 41575-94-4.mol

Chemical Properties

• Melting Point: 228-230°C
• Boiling Point: 366.4oCat 760 mmHg
• Flash Point: 189.6oC
• Appearance: white/crystal
• Storage Temp.: Store at RT
• Solubility: Sparingly soluble in water, very slightly soluble in acetone and in ethanol (96 per cent).
• Water Solubility: Soluble in water.
• Stability: Stable. Incompatible with strong oxidizing agents.
• Merck: 14,1822
• CAS DataBase Reference: Carboplatin(CAS DataBase Reference)
• NIST Chemistry Reference: Carboplatin(41575-94-4)
• EPA Substance Registry System: Carboplatin(41575-94-4)

Safety Data

• Hazard Codes: T
• Statements: 46-61-20/21/22-42/43-20/21
• Safety Statements: 53-22-26-36/37/39-45
• RIDADR: 2811
• WGK Germany: 3
• RTECS: TP2300000
• Hazardous Substances Data: 41575-94-4(Hazardous Substances Data)

Usage

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.

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

Synthetic route

cis-diaminediiodoplatinum(II) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → carboplatinum (41575-94-4)

Conditions	Yield
With barium dihydroxide; silver sulfate In water byproducts: AgI, BaSO4; addn. of Ag2SO4 to slight excess of Pt-complex, stirring (4 h), filtration off of AgI, concn., addn. of soln. of ligand (neutralized with Ba(OH)2); filtration off of BaSO4, concn. (crystn.), washing (EtOH, Et2O), drying(vac.); elem. anal.;	88%
Stage #1: cis-diaminediiodoplatinum(II) With silver sulfate In water for 4h; Stage #2: cyclobutane-1,1'-dicarboxylic acid With barium hydroxide octahydrate In water	85%
Stage #1: cis-diaminediiodoplatinum(II) With silver nitrate In water Darkness; Stage #2: cyclobutane-1,1'-dicarboxylic acid With potassium hydroxide for 3h; pH=5;	50.3%
With potassium hydroxide In water; N,N-dimethyl-formamide Pt-compd. dissolved in DMF with heating, addn. of the acid and aq. KOH, heated in an unstoppered flask at 60°C for 20 h; cooled, filtered, addn. of ether;	40%

cis-diamminediiodoplatinum (II) (13841-96-8, 15978-93-5, 15978-94-6) + Ag salt of cyclobutanedicarboxylic acid → carboplatinum (41575-94-4)

Conditions	Yield
In water at 20℃; for 48h; Darkness;	80%

cisplatin (15663-27-1) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → carboplatinum (41575-94-4)

Conditions	Yield
With potassium hydroxide In water; N,N-dimethyl-formamide Pt-compd. dissolved in DMF with heating, addn. of the acid and aq. KOH, heated in an unstoppered flask at 60°C for 20 h; cooled, filtered, addn. of ether;	70%
With potassium hydroxide In N,N-dimethyl acetamide; water Pt-compd. dissolved in DMA, addn. of the acid and aq. KOH, heated in an unstoppered flask at 60°C for 20 h; cooled, filtered, addn. of ether;	35%

diamine platinum sulfate (142159-62-4, 67063-11-0) + barium cyclobutane-1,1-dicarboxylate monohydrate → carboplatinum (41575-94-4)

Conditions	Yield
In water heating Pt-complex and Ba-compd. in water at 60°C for 10 h; filtn., evapn. to dryness, dissolution of residue in DMF, hot filtn., concn., pptn. with ethanol, elem. anal.;	70%

cisplatin (15663-27-1) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) + lithium hydroxide (1310-65-2) → carboplatinum (41575-94-4)

Conditions	Yield
In water; N,N-dimethyl-formamide Pt-compd. dissolved in DMF with heating, addn. of the acid and aq. LiOH, heated in an unstoppered flask at 60°C for 20 h; cooled, filtered, addn. of ether;	65%

cis-diaminediiodoplatinum(II) + 1,1-cyclobutanedicarboxylic acid disilver salt → carboplatinum (41575-94-4)

Conditions	Yield
In ethanol; water at 20℃; for 48h; Darkness;	48%
In water byproducts: AgI; Pt- and Ag-complex mixed together in water, stirred in dark for 2-3 d; ppt. filtered, filtrate evapd. to dryness;
In water for 2 - 3h;

cis-diaminediiodoplatinum(II) + Ba(2+)*C6H6O4(2-)=Ba(C6H6O4) + water (7732-18-5) + silver sulfate → carboplatinum (41575-94-4)

Conditions	Yield
In water byproducts: AgI, BaSO4; addn. of cis-Pt(NH3)2I2 (1 mmol) to aq. soln. of Ag2SO4 (0.98 mmol), stirring for 4 h in dark, removal of ppt. (AgI), slowly addn. of BaC6H6O4 to filtrate (cis-(Pt(NH3)2(H2O)2)(SO4)), stirring for 20 min; filtration, evapn. of filtrate to dryness, addn. of MeOH, filtration, washing with Et2O, drying in vac.;

cis-diaminediiodoplatinum(II) + water (7732-18-5) + 1,1-cyclobutanedicarboxylic acid disodium salt (100476-94-6) + silver nitrate → carboplatinum (41575-94-4)

Conditions

Yield

In water; acetone byproducts: AgI, NaNO3; dissolving of cis-Pt(NH3)2I2 (1 mmol) in C3H6O, addn. of AgNO3 (2.2 mmol), stirring for 10-20 min, removal of ppt.(AgI), evapn. of filtrate, crystn. of Pt(NH3)2(ONO2)2 in Et2O, drying in vac., dissolving in H2O, addn. of Na2C6H6O4, stirring for 4-5 days; filtration, evapn. of filtrate to dryness, addn. of MeOH, filtration, washing with Et2O, drying in vac.;

cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → carboplatinum (41575-94-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaOH / water 2: water View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / water 2: water / 2 - 3 h View Scheme

cis-diaminediiodoplatinum(II) + Ba(2+)*C6H6O4(2-)=Ba(C6H6O4) → carboplatinum (41575-94-4)

Conditions	Yield
Stage #1: cis-diaminediiodoplatinum(II) With silver sulfate In water at 50℃; for 24h; Stage #2: Ba(2+)*C6H6O4(2-)=Ba(C6H6O4) In water at 40℃;

cis-diaminediiodoplatinum(II) + 1,1-cyclobutanedicarboxylic acid disodium salt (100476-94-6) → carboplatinum (41575-94-4)

Conditions	Yield
Stage #1: cis-diaminediiodoplatinum(II) With silver nitrate Stage #2: 1,1-cyclobutanedicarboxylic acid disodium salt In water

(OC-6-33)-diamminebis(3-carboxypropanoato)(cyclobutane-1,1-dicarboxylato)platinum(IV) (1415566-00-5) → carboplatinum (41575-94-4)

Conditions	Yield
With β-nicotinamide adenine dinucleotide, disodium salt, reduced form; flavin-adenin dinucleotide, disodium salt In aq. phosphate buffer at 25℃; pH=7; Catalytic behavior; Reagent/catalyst; pH-value; Irradiation; chemoselective reaction;

C22H29BF2N4O8Pt → carboplatinum (41575-94-4) + 3-[4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-yl]propionic acid

Conditions	Yield
In d7-N,N-dimethylformamide for 9h; Irradiation;

carboplatinum (41575-94-4) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → 2C6H12N2O4Pt*3C6H8O4

Conditions	Yield
In water at 20℃; for 5h;	99.6%

carboplatinum (41575-94-4) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → C6H12N2O4Pt*3C6H8O4

Conditions	Yield
In water at 20℃; for 5h;	99.6%

carboplatinum (41575-94-4) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → C6H12N2O4Pt*5C6H8O4

Conditions	Yield
In water at 20℃; for 5h;	99.4%

carboplatinum (41575-94-4) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → 2C6H12N2O4Pt*C6H8O4

Conditions	Yield
In water at 20℃; for 5h;	99.3%

carboplatinum (41575-94-4) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → 2C6H12N2O4Pt*2C6H8O4

Conditions	Yield
In water at 20℃; for 5h;	99.2%

carboplatinum (41575-94-4) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → C6H12N2O4Pt*4C6H8O4

Conditions	Yield
In water at 20℃; for 5h;	99.2%

carboplatinum (41575-94-4) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → C6H12N2O4Pt*2C6H8O4

Conditions	Yield
In water at 20℃; for 5h;	99.1%

carboplatinum (41575-94-4) + cyclobutane-1,1'-dicarboxylic acid (5445-51-2) → dicycloplatin

Conditions	Yield
In water at 5℃; for 20h; Temperature; Time;	93.2%
In water at 30℃; for 0.15h; Temperature; Microwave irradiation;	90%
In water at 20℃;

carboplatinum (41575-94-4) + dihydrogen peroxide (7722-84-1) → (OC-6-33)-diammine(cyclobutane-1,1-dicarboxylato)dihydroxidoplatinum(IV) (113287-15-3)

Conditions	Yield
In water at 20℃;	93%

carboplatinum (41575-94-4) + acetic acid (64-19-7) → (OC-6-44)-acetatodiamminecyclobutane-1,1-dicarboxylatohydroxidoplatinum(IV)

Conditions	Yield
With dihydrogen peroxide for 48h; Darkness;	93%

carboplatinum (41575-94-4) + dihydrogen peroxide (7722-84-1) → diammine(cyclobutane-1,1-dicarboxylato)dihydroxidoplatinum(IV)

Conditions	Yield
In water at 20℃; for 24h; Darkness;	90%
at 20℃; Darkness;

carboplatinum (41575-94-4) + N-Bromosuccinimide (128-08-5) + water (7732-18-5) → cis,trans-[Pt(1,1-cyclobutanedicarboxylate)(NH3)2(OH)Br]

Conditions	Yield
at 20℃; for 12h;	87%

carboplatinum (41575-94-4) + water (7732-18-5) + dihydrogen peroxide (7722-84-1) → (OC-6-33)-diammine(cyclobutane-1,1-dicarboxylato)dihydroxidoplatinum(IV) (113287-15-3)

Conditions	Yield
at 20 - 50℃; for 1.5h;	86.5%

carboplatinum (41575-94-4) + 1,2-Dichloro-3-iodobenzene (2401-21-0) → cis,trans-[Pt(1,1-cyclobutane-dicarboxylate)(NH3)2Cl2]*2DMF

Conditions	Yield
In N,N-dimethyl-formamide at 75℃; for 0.5h; Darkness;	85%

carboplatinum (41575-94-4) + bromine (7726-95-6) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → cis,trans-[Pt(1,1-cyclobutane-dicarboxylate)(NH3)2Br2]

Conditions	Yield
at 20 - 50℃; for 0.666667h; Darkness;	84%

carboplatinum (41575-94-4) + dihydrogen peroxide (7722-84-1) + acetic acid (64-19-7) → C8H16N2O7Pt

Conditions	Yield
at 20℃; for 0.5h;	84%

carboplatinum (41575-94-4) + water (7732-18-5) + dihydrogen peroxide (7722-84-1) → diammine(cyclobutane-1,1-dicarboxylato)dihydroxidoplatinum(IV)

Conditions	Yield
at 60℃; for 4h;	83%

carboplatinum (41575-94-4) + N-Bromosuccinimide (128-08-5) → cis,trans-[Pt(1,1-cyclobutanedicarboxylate)(NH3)2Br2]

Conditions	Yield
In ethanol at 20℃; for 12h;	80%

carboplatinum (41575-94-4) + water (7732-18-5) → diammine(cyclobutane-1,1-dicarboxylato)dihydroxidoplatinum(IV)

Conditions	Yield
With dihydrogen peroxide at 70℃; for 5h; Darkness;	80%

carboplatinum (41575-94-4) + N-chloro-succinimide (128-09-6) + water (7732-18-5) → C6H13ClN2O5Pt(2+)

Conditions	Yield
Darkness;	79%

carboplatinum (41575-94-4) → (OC-6-33)-diammine(cyclobutane-1,1-dicarboxylato)dihydroxidoplatinum(IV) (113287-15-3)

Conditions	Yield
With dihydrogen peroxide In water at 20℃;	73%

carboplatinum (41575-94-4) + N-chloro-succinimide (128-09-6) + ethylene glycol (107-21-1) → (OC-6-34)-diamminechlorido(cyclobutane-1,1′-dicarboxylate)(2-hydroxyethanolato)platinum(IV)

Conditions	Yield
at 20℃; for 3h; Darkness;	71%

succinic acid anhydride (108-30-5) + carboplatinum (41575-94-4) + N-Bromosuccinimide (128-08-5) → cis,trans,cis-[Pt(cyclobutane-1,1-dicarboxylato)(succinato)(Br)(NH3)2]

Conditions	Yield
With water In acetone at 20℃; Darkness;	69.8%

carboplatinum (41575-94-4) + dihydrogen peroxide (7722-84-1) → C6H14N2O6Pt(2+)

Conditions	Yield
In water at 60℃; for 4h;	62%

carboplatinum (41575-94-4) + N-chloro-succinimide (128-09-6) + water (7732-18-5) → C6H13ClN2O5Pt

Conditions	Yield
at 20℃;	55%

Upstream product

• 15663-27-1 cisplatin 
• 5445-51-2 cyclobutane-1,1'-dicarboxylic acid 
• 1415566-00-5 (OC-6-33)-diamminebis(3-carboxypropanoato)(cyclobutane-1,1-dicarboxylato)platinum(IV) 
• 13841-96-8 cis-diamminediiodoplatinum (II) 
• 100476-94-6 1,1-cyclobutanedicarboxylic acid disodium salt 
• 142159-62-4 diamine platinum sulfate 
• 1310-65-2 lithium hydroxide 
• 7732-18-5 water 

Downstream Products

• 15663-27-1 cisplatin 
• 113287-15-3 (OC-6-33)-diammine(cyclobutane-1,1-dicarboxylato)dihydroxidoplatinum(IV) 
• 287402-09-9 dicycloplatin 
• 15730-38-8 bis(N,N-diethyldithiocarbamate)platinum(II) 

Relevant articles and documents

Nanoscale Coordination Polymers Codeliver Carboplatin and Gemcitabine for Highly Effective Treatment of Platinum-Resistant Ovarian Cancer

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

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.

An intramolecular photoswitch can significantly promote photoactivation of Pt(iv) prodrugs

Selective activation of prodrugs at diseased tissue through bioorthogonal catalysis represents an attractive strategy for precision cancer treatment. Achieving efficient prodrug photoactivation in cancer cells, however, remains challenging. Herein, we report two Pt(iv) complexes, designated as rhodaplatins {rhodaplatin 1, [Pt(CBDCA-O,O′)(NH3)2(RhB)OH]; rhodaplatin 2, [Pt(DACH)ox(RhB)(OH)], where CBDCA is cyclobutane-1,1-dicarboxylate, RhB is rhodamine B, DACH is (1R,2R)-1,2-diaminocyclohexane, and ox is oxalate}, that bear an internal photoswitch to realize efficient accumulation, significant co-localization, and subsequent effective photoactivation in cancer cells. Compared with the conventional platform of external photocatalyst plus substrate , rhodaplatins presented up to 4.8 × 104-fold increased photoconversion efficiency in converting inert Pt(iv) prodrugs to active Pt(ii) species under physiological conditions, due to the increased proximity and covalent bond between the photoswitch and Pt(iv) substrate. As a result, rhodaplatins displayed increased photocytotoxicity compared with a mixture of RhB and conventional Pt(iv) compound in cancer cells including Pt-resistant ones. Intriguingly, rhodaplatin 2 efficiently accumulated in the mitochondria and induced apoptosis without causing genomic DNA damage to overcome drug resistance. This work presents a new approach to develop highly effective prodrugs containing intramolecular photoswitches for potential medical applications. This journal is

BODI-Pt, a Green-Light-Activatable and Carboplatin-Based Platinum(IV) Anticancer Prodrug with Enhanced Activation and Cytotoxicity

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.

Anti-tumor platinum (IV) complexes bearing the anti-inflammatory drug naproxen in the axial position

The role of inflammation in cancer generation is gaining importance in the field of cancer research. The chemo-anti-inflammatory strategy that involves using non-steroidal anti-inflammatory drug compounds as effective anti-tumor agents is being acceded globally. In the present study, seven new Pt (IV) complexes based on cisplatin, carboplatin and oxaliplatin scaffold bearing the anti-inflammatory drug naproxen in the axial position were synthesized and characterized by elemental analysis, ESI-MS, Fourier transform-infrared, 1H- and 195Pt-NMR spectroscopy. The reduction behavior in the presence of ascorbic acid was studied using high-performance liquid chromatography. The cytotoxicity against two human breast cell lines and the anti-inflammatory properties were evaluated. All the complexes are able to promote a comparable activity, with average three- and 13-fold more cytotoxic than cisplatin against MCF7 and MDA-MB-231 cell lines, respectively. The complexes show remarkable anti-inflammatory effects, which indicated their potential in treating cancer associated with inflammation and reducing side-effects of chemotherapy.

Bioorthogonal Catalytic Activation of Platinum and Ruthenium Anticancer Complexes by FAD and Flavoproteins

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

MONOMALEIMIDE-FUNCTIONALIZED PLATINUM COMPOUNDS FOR CANCER THERAPY

The present invention relates to novel monomaleimide-functionalized platinum compounds of formula (I), including in particular novel monomaleimide-functionalized oxaliplatin and carboplatin derivatives, as well as their use as medicaments, particularly for the treatment or prevention of cancer.

DNA binding studies of a series of cis-[Pt(Am)2X2] complexes (Am = inert amine, X = labile carboxylato ligand)

A series of platinum(II) complexes of formulae cis-[Pt(Am) 2X2] (where Am represents an inert amine and X a labile (carboxylato) ligand) have been prepared and characterized by elemental analysis, ESI-MS, IR and 1H NMR spectroscopy. The single-crystal molecular structures were determined for cis-[Pt(opea)(cbdca-2H)], cis-[Pt(hmpy)(cbdca-2H)], cis-[Pt(NH3)2(bzmal-2H)] and cis-[Pt(hmpy)(μ-dcch-2H)2] (where opea is picolylamine, hmpy represents 4-hydroxymethylpyridine, cbdca-2H, is 1,1-cyclobutanedicarboxylate anion, bzmal-2H stands for benzylmalonate anion and dcch-2H is trans-1,2-cyclohexanedicarboxylate anion). The interaction of all compounds with DNA was investigated with different techniques: viscosity measurements and emission fluorescence spectroscopy were used to investigate the changes induced by the binding of the platinum compounds to calf-thymus DNA, while atomic force microscopy and electrophoretic mobility allowed evaluating the potential alterations of pBR322 plasmid DNA. The cytotoxic behavior of the platinum compounds on human leukemia HL-60 tumor cell lines was also examined.

Molecular interaction fields vs. quantum-mechanical-based descriptors in the modelling of lipophilicity of platinum(iv) complexes

We report QSAR calculations using VolSurf descriptors to model the lipophilicity of 53 Pt(iv) complexes with a diverse range of axial and equatorial ligands. Lipophilicity is measured using an efficient HPLC method. Previous models based on a subset of these data are shown to be inadequate, due to incompatibility of whole molecule descriptors between carboxylato and hydroxido ligands. Instead, the interaction surfaces of complexes with various probes are used as independent descriptors. Partial least squares modelling using three latent variables results in an accurate (R2 = 0.92) and robust model (Q2 = 0.87) of lipophilicity, that moreover highlights the importance of size and hydrophobicity terms and the modest relevance of hydrogen bonding.

Novel tetracarboxylatoplatinum(iv) complexes as carboplatin prodrugs

It is widely accepted that platinum(iv) complexes act as prodrugs and have to be activated by reduction to the respective platinum(ii) analogs. Recently it could be shown that introduction of lipophilic carboxylato ligands in the axial position leads to diaminedichloridoplatinum(iv) compounds with exceptionally high cytotoxicity. With the aim of improving the antiproliferative properties of carboplatin, a series of twenty-one novel Pt(iv) complexes, featuring the equatorial ligand sphere of carboplatin as well as lipophilic axial carboxylato ligands, was synthesized. In depth characterization is based on elemental analysis, ESI-MS, ATR-IR, and multinuclear (1H, 13C, 15N, and 195Pt) NMR spectroscopy. Their cytotoxic activity in four cell lines (CH1, SK-OV-3, SW480, and A549), lipophilicity, electrochemistry and additionally the rate of reduction in the presence of ascorbic acid were investigated. In contrast to analogous diaminedicarboxylatodichloridoplatinum(iv) compounds, the cytotoxicity of novel diaminetetracarboxylato counterparts could not substantially be increased by simply enhancing their lipophilic character. It seems that not only the reduction potential, but also the rate of reduction has a tremendous influence on the cytotoxic properties. This has to be taken into account for the development of novel anticancer platinum(iv) agents.