Triplatin tetranitrate: Difference between revisions

{{Short description|Chemical compound}}

| verifiedrevid = 447613838

| CAS_number_Ref = {{cascite|correct|CAS}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = HAJ1000ARC

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 85611

| C=12 | H=50 | Cl=2 | N=14 | O=12 | Pt=3

| synonyms =

| SMILES = [O-][N+]([O-])=O.[O-][N+]([O-])=O.Cl[Pt-2]([NH3+])([NH3+])[NH2+]CCCCCC[NH2+][Pt-2]([NH3+])([NH3+])[NH2+]CCCCCC[NH2+][Pt-2]([NH3+])([NH3+])Cl.[O-][N+]([O-])=O.[O-][N+]([O-])=O

'''Triplatin tetranitrate''' ([[International Nonproprietary Name|rINN]]; also known as '''BBR3464''') is a [[platinum-based cytotoxic drug]] that underwent [[clinical trial]]s for the treatment of human [[cancer]].<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 [[adduct]]s with cellular [[DNA]], preventing [[DNA transcription]] and [[DNA replication|replication]], thereby inducing [[apoptosis]]. Other platinum-containing anticancer drugs include [[cisplatin]], [[carboplatin]], and [[oxaliplatin]].<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>

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>

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.<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>

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>

== References ==

{{Platinum compounds}}

[[Category:Coordination complexes]]

[[Category:Platinum(II) compounds]]

[[Category:Ammine complexes]]