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{{Short description|Chemical compound}}
{{Drugbox {{Drugbox
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| Watchedfields = changed
⚫ | verifiedrevid = 245690629
| IUPAC_name = | IUPAC_name =
| image = Triplatin tetranitrate.svg | image = Triplatin tetranitrate.svg
| width = 300 | width = 300

<!--Clinical data--> <!--Clinical data-->
| tradename = | tradename =
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| legal_status = | legal_status =
| routes_of_administration = | routes_of_administration =

<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = | bioavailability =
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| elimination_half-life = | elimination_half-life =
| excretion = | excretion =

<!--Identifiers--> <!--Identifiers-->
| CASNo_Ref = {{cascite}} | CAS_number_Ref = {{cascite|changed|CAS}}
| CAS_number = <!--172903-00-3, provided in ''WHO Drug Information''--> | CAS_number = 172903-00-3<!--172903-00-3, provided in ''WHO Drug Information'' and chebi, and unii-->
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| UNII = HAJ1000ARC
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 85611
| ATC_prefix = none | ATC_prefix = none
| ATC_suffix = | ATC_suffix =
| ATC_supplemental = | ATC_supplemental =
| PubChem = | PubChem = 91825660
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| DrugBank = | DrugBank =
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<!--Chemical data--> <!--Chemical data-->
| C=12 | H=54 | Cl=2 | N=14 | O=12 | Pt=3 | C=12 | H=50 | Cl=2 | N=14 | O=12 | Pt=3
⚫ | synonyms =
| molecular_weight = 1242.8018 g/mol
| StdInChI=1S/2C6H16N2.2ClH.4NO3.6H3N.3Pt/c2*7-5-3-1-2-4-6-8;;;4*2-1(3)4;;;;;;;;;/h2*1-8H2;2*1H;;;;;6*1H3;;;/q;;;;4*-1;;;;;;;3*+2/p-2
⚫ | synonyms =
| StdInChIKey = RMFNGLHOFHJMHN-UHFFFAOYSA-L
| SMILES = ()=O.()=O.Cl()()CCCCCC()()CCCCCC()()Cl.()=O.()=O
}} }}


'''Triplatin tetranitrate''' (]; also known as '''BBR3464''') is a ]-based ] ] that underwent ]s for the treatment of human ].<ref>{{cite journal |title=The status of platinum anticancer drugs in the clinic and in clinical trials |journal=Dalton Transactions |volume=39 |pages=8113–27 |year=2010 |doi=10.1039/C0DT00292E |last1=Wheate |first1=Nial J. |last2=Walker |first2=Shonagh |last3=Craig |first3=Gemma E. |last4=Oun |first4=Rabbab |issue=35 |pmid=20593091 }}</ref> The drug acts by forming ]s with cellular ], preventing ] and ], thereby inducing ]. Other platinum-containing anticancer drugs include ], ], and ]. '''Triplatin tetranitrate''' (]; also known as '''BBR3464''') is a ] that underwent ]s for the treatment of human ].<ref>{{cite journal | vauthors = Wheate NJ, Walker S, Craig GE, Oun R | title = The status of platinum anticancer drugs in the clinic and in clinical trials | journal = Dalton Transactions | volume = 39 | issue = 35 | pages = 8113–27 | date = September 2010 | pmid = 20593091 | doi = 10.1039/C0DT00292E | url = https://ses.library.usyd.edu.au/bitstream/2123/9269/2/41%20Dalton%20perspective.pdf | hdl = 2123/14271 | authorlink1 = Nial J. Wheate | hdl-access = free }}</ref> The drug acts by forming ]s with cellular ], preventing ] and ], thereby inducing ]. Other platinum-containing anticancer drugs include ], ], and ].<ref>{{cite journal | vauthors = Farrell NP | title = Multi-platinum anti-cancer agents. Substitution-inert compounds for tumor selectivity and new targets | journal = Chemical Society Reviews | volume = 44 | issue = 24 | pages = 8773–85 | date = December 2015 | pmid = 25951946 | doi = 10.1039/c5cs00201j | s2cid = 5171072 }}</ref>


==Drug development== ==Drug development==
Triplatin tetranitrate contains three platinum centres linked by amine ligands. Other ligands attached to this ], include ]. Its invention arose from earlier work showing that diplatinum analogues of cisplatin were cytotoxic. BBR3464 was patented in the mid-1990s and was originally licensed to the pharmaceutical company ]. In preclinical trials, it demonstrated cytotoxic activity in cancer cell lines that had either intrinsic or acquired resistance to cisplatin. On this basis it entered Phase I (Toxicity) clinical trials under the auspices of Novuspharma before the rights were transferred to Cell Therapeutics. It is currently undergoing Phase II (Efficacy) trials with mixed results. So far trials of the drug with patients suffering from ovarian cancer, small cell lung cancer and gastric or gastro-oesophageal adenocarcinomas have been reported in the literature. Triplatin belongs to the anticancer class of polynuclear platinum complexes (PPCs), developed in the laboratory of Professor Nicholas Farrell, where one or more platinum centers are linked by amine ligands. BBR3464 was patented in the mid-1990s and clinical development and licensing was performed initially by Boehringer Mannheim Italia and eventually by the pharmaceutical company Roche, when clinical development was led by Novuspharma. In preclinical trials it demonstrated cytotoxic activity in cancer cell lines that had either intrinsic or acquired resistance to cisplatin. Triplatin remains the only “non-classical” platinum drug (not based on the cisplatin structure) to have entered human clinical trials. Phase I and Phase II clinical results have been summarized.<ref>{{cite journal |last1=Farrell |first1=Nicholas P. | name-list-style = vanc |title=Progress in Platinum-Derived Drug Development. |journal=Drugs of the Future |date=2012 |volume=37 |issue=11 |pages=795–806 |doi=10.1358/dof.2012.037.011.1830167|s2cid=75603138 }}</ref>


== Mode of action == == Mode of action ==
The main target of triplatin is cellular DNA, similar to cisplatin. The drug forms novel adducts with DNA, structurally distinct from those formed by cisplatin. More recently, cellular accumulation mediated by heparan sulfate proteoglycans and high-affinity ] (GAG) binding indicates that cationic PPCs are intrinsically dual-function agents, acting by mechanisms discrete from the neutral, mononuclear agents.<ref>{{cite journal | vauthors = Tsotsoros SD, Lutz PB, Daniel AG, Peterson EJ, de Paiva RE, Rivera E, Qu Y, Bayse CA, Farrell NP | display-authors = 6 | title = 2+ for HIVNCp7 targeting | journal = Chemical Science | volume = 8 | issue = 2 | pages = 1269–1281 | date = February 2017 | pmid = 28451269 | pmc = 5355868 | doi = 10.1039/c6sc02515c }}</ref>
The main target of triplatin is cellular DNA, similar to cisplatin. Outside of the cell, the concentration of chloride (approx. 100 millimolar) prevents the drugs from hydrolysing, but once inside the cell, where the concentration of chloride drops to between 4 and 20 millimolar, the chloride ligands of BBR3464 come off and the drug is capable of forming coordinate covalent bonds with purine bases on DNA. The novel adducts BBR3464 forms with DNA are though to be the mechanism by which this drug acts; the adducts are able to prevent DNA transcription and replication, thus inducing cell apoptosis.


== Side effects == == Side effects ==
In phase I studies, when given once every 28 days, the main dose-limiting toxicities (DLT) of Triplatin (BBR 3464) were neutropenia and diarrhea encountered at a dose level of 1.1&nbsp;mg/m2. Diarrhea was treatable with loperamide.<ref>{{cite journal | vauthors = Gourley C, Cassidy J, Edwards C, Samuel L, Bisset D, Camboni G, Young A, Boyle D, Jodrell D | display-authors = 6 | title = A phase I study of the trinuclear platinum compound, BBR 3464, in combination with protracted venous infusional 5-fluorouracil in patients with advanced cancer | journal = Cancer Chemotherapy and Pharmacology | volume = 53 | issue = 2 | pages = 95–101 | date = February 2004 | pmid = 14605864 | doi = 10.1007/s00280-003-0721-x | s2cid = 19707262 }}</ref> Lack of nephrotoxicity and low urinary excretion supported use of drug without hydration.<ref>{{cite journal | vauthors = Sessa C, Capri G, Gianni L, Peccatori F, Grasselli G, Bauer J, Zucchetti M, Viganò L, Gatti A, Minoia C, Liati P, Van den Bosch S, Bernareggi A, Camboni G, Marsoni S | display-authors = 6 | title = Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex | journal = Annals of Oncology | volume = 11 | issue = 8 | pages = 977–83 | date = August 2000 | pmid = 11038034 | doi = 10.1023/a:1008302309734 | doi-access = free }}</ref>
All platinum based drugs, and particularly BBR3464, cause large dose limiting side-effects. For BBR3464 these are largely diarrhea, cramps and vomiting, but are so severe that the maximum tolerated dose (MTD) in humans is between 0.9 to 1.1 milligrams per square metre. This is considerably lower than the MTD for all the platinum based drugs currently used in the clinic, like cisplatin (60–120 mg) and carboplatin (approx. 800 mg).


==References== == References ==
{{reflist}} {{reflist}}


{{Chemotherapeutic agents}} {{Chemotherapeutic agents}}
{{Platinum compounds}}


] ]
] ]
] ]
] ]
]

Latest revision as of 22:38, 24 September 2024

Chemical compound Pharmaceutical compound
Triplatin tetranitrate
Clinical data
ATC code
  • none
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
Chemical and physical data
FormulaC12H50Cl2N14O12Pt3
Molar mass1238.77 g·mol
3D model (JSmol)
SMILES
  • ()=O.()=O.Cl()()CCCCCC()()CCCCCC()()Cl.()=O.()=O
InChI
  • InChI=1S/2C6H16N2.2ClH.4NO3.6H3N.3Pt/c2*7-5-3-1-2-4-6-8;;;4*2-1(3)4;;;;;;;;;/h2*1-8H2;2*1H;;;;;6*1H3;;;/q;;;;4*-1;;;;;;;3*+2/p-2
  • Key:RMFNGLHOFHJMHN-UHFFFAOYSA-L
  (verify)

Triplatin tetranitrate (rINN; also known as BBR3464) is a platinum-based cytotoxic drug that underwent clinical trials for the treatment of human cancer. The drug acts by forming adducts with cellular DNA, preventing DNA transcription and replication, thereby inducing apoptosis. Other platinum-containing anticancer drugs include cisplatin, carboplatin, and oxaliplatin.

Drug development

Triplatin belongs to the anticancer class of polynuclear platinum complexes (PPCs), developed in the laboratory of Professor Nicholas Farrell, where one or more platinum centers are linked by amine ligands. BBR3464 was patented in the mid-1990s and clinical development and licensing was performed initially by Boehringer Mannheim Italia and eventually by the pharmaceutical company Roche, when clinical development was led by Novuspharma. In preclinical trials it demonstrated cytotoxic activity in cancer cell lines that had either intrinsic or acquired resistance to cisplatin. Triplatin remains the only “non-classical” platinum drug (not based on the cisplatin structure) to have entered human clinical trials. Phase I and Phase II clinical results have been summarized.

Mode of action

The main target of triplatin is cellular DNA, similar to cisplatin. The drug forms novel adducts with DNA, structurally distinct from those formed by cisplatin. More recently, cellular accumulation mediated by heparan sulfate proteoglycans and high-affinity glycosaminoglycan (GAG) binding indicates that cationic PPCs are intrinsically dual-function agents, acting by mechanisms discrete from the neutral, mononuclear agents.

Side effects

In phase I studies, when given once every 28 days, the main dose-limiting toxicities (DLT) of Triplatin (BBR 3464) were neutropenia and diarrhea encountered at a dose level of 1.1 mg/m2. Diarrhea was treatable with loperamide. Lack of nephrotoxicity and low urinary excretion supported use of drug without hydration.

References

  1. Wheate NJ, Walker S, Craig GE, Oun R (September 2010). "The status of platinum anticancer drugs in the clinic and in clinical trials" (PDF). Dalton Transactions. 39 (35): 8113–27. doi:10.1039/C0DT00292E. hdl:2123/14271. PMID 20593091.
  2. Farrell NP (December 2015). "Multi-platinum anti-cancer agents. Substitution-inert compounds for tumor selectivity and new targets". Chemical Society Reviews. 44 (24): 8773–85. doi:10.1039/c5cs00201j. PMID 25951946. S2CID 5171072.
  3. Farrell NP (2012). "Progress in Platinum-Derived Drug Development". Drugs of the Future. 37 (11): 795–806. doi:10.1358/dof.2012.037.011.1830167. S2CID 75603138.
  4. Tsotsoros SD, Lutz PB, Daniel AG, Peterson EJ, de Paiva RE, Rivera E, et al. (February 2017). "2+ for HIVNCp7 targeting". Chemical Science. 8 (2): 1269–1281. doi:10.1039/c6sc02515c. PMC 5355868. PMID 28451269.
  5. Gourley C, Cassidy J, Edwards C, Samuel L, Bisset D, Camboni G, et al. (February 2004). "A phase I study of the trinuclear platinum compound, BBR 3464, in combination with protracted venous infusional 5-fluorouracil in patients with advanced cancer". Cancer Chemotherapy and Pharmacology. 53 (2): 95–101. doi:10.1007/s00280-003-0721-x. PMID 14605864. S2CID 19707262.
  6. Sessa C, Capri G, Gianni L, Peccatori F, Grasselli G, Bauer J, et al. (August 2000). "Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex". Annals of Oncology. 11 (8): 977–83. doi:10.1023/a:1008302309734. PMID 11038034.
Intracellular chemotherapeutic agents / antineoplastic agents (L01)
SPs/MIs
(M phase)
Block microtubule assembly
Block microtubule disassembly
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DNA precursors/
antimetabolites
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  • PtCl2(Cod)
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