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Phenanthriplatin or ''cis''- t(NH3)2-(phenanthridine)ClO3 is a new drug candidate. It belongs to a family of platinum(II)-based agents which includes
cisplatin Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...
,
oxaliplatin Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication (platinum-based antineoplastic class) used to treat colorectal cancer. It is given by intravenous, infusion into a vein. Common side effects include paresth ...
and
carboplatin Carboplatin, sold under the brand name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is a ...
. Phenanthriplatin was discovered by Professor Stephen J. Lippard at
Massachusetts Institute of Technology The Massachusetts Institute of Technology (MIT) is a Private university, private research university in Cambridge, Massachusetts, United States. Established in 1861, MIT has played a significant role in the development of many areas of moder ...
and is currently being developed by Blend Therapeutics for its potential use in human cancer therapy.


Structure and synthesis

Structurally, phenanthriplatin is similar to cisplatin, differing only in the presence of a
phenanthridine Phenanthridine is a nitrogen heterocyclic compound with the formula . It is a colorless solid, although impure samples can be brownish. It is a precursor to DNA-binding fluorescent dyes through intercalation. Examples of such dyes are ethidiu ...
ligand instead of a chloride in its structure. To synthesise phenanthriplatin, one equivalent of silver nitrate is added to a solution of cisplatin in dimethylformamide. The mixture is stirred at 55 °C away from light and the resulting silver chloride precipitate is filtered out. Next, phenanthridine is added to the supernatant and this is also mixed at 55 °C for 16 hours. The reaction mixture is then rotary evaporated to dryness and the residue is dissolved in methanol. Undissolved cisplatin is filtered out and
diethyl ether Diethyl ether, or simply ether, is an organic compound with the chemical formula , sometimes abbreviated as . It is a colourless, highly Volatility (chemistry), volatile, sweet-smelling ("ethereal odour"), extremely flammable liquid. It belongs ...
is added to the filtrate to precipitate out phenanthriplatin crystals. Phenanthriplatin is then collected by filtration, washed twice with diethyl ether before dissolving it in methanol. The drug is precipitated by adding it dropwise to a vigorously stirred solution of diethyl ether. The pure drug is then collected by vacuum filtration and dried in vacuo.


Mechanism of action

Phenanthriplatin is thought to penetrate cell membranes in its ionised form by either passive diffusion or carrier-mediated active transport. The hydrophobic phenanthridine ligand of the drug is thought to maximise its cellular uptake, rendering it more effective and cytotoxic compared with cisplatin. Once it has entered the cell, phenanthriplatin is distributed in a similar manner to other
platinum Platinum is a chemical element; it has Symbol (chemistry), symbol Pt and atomic number 78. It is a density, dense, malleable, ductility, ductile, highly unreactive, precious metal, precious, silverish-white transition metal. Its name origina ...
-based anticancer agents, residing primarily in the cell's nucleus. The ultimate target of the drug is nuclear
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
. Phenanthriplatin forms monofunctional adducts with guanosine residues in the DNA. The large and hydrophobic nature of the phenanthridine ligand introduces steric hindrance within the major groove of the DNA, which impedes RNA polymerase II, a major protein used by the cell to transcribe DNA. Since transcription is essential for DNA synthesis and gene expression, phenanthriplatin inhibits both these processes in cancerous cells, ultimately inducing cellular
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
. A study examining the effects of monofunctional adducts on bacterial growth reported a significant decrease in ''
Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...
'' (E. coli) cell growth when inoculated with phenanthriplatin. It also demonstrated that phenanthriplatin, like cisplatin, was able to dissolve lysogens as well as alter the morphology of ''E. coli'' into longer, filamentous cells. These results confirm that the drug’s anticancer activity is exerted through interacting with cells’ DNA. Phenanthriplatin has been reported to have increased selectivity to cancerous cells compared to healthy cells, thereby reducing toxic side effects usually associated with current anticancer drugs and further supporting its potential use in chemotherapy. It has also been shown to have a lower tendency to react with other molecules in the body. Studies have reported that phenanthriplatin bound N-acetyl methionine, a sulphur-containing molecule, at a much lower rate compared to other monofunctional platinum adducts. This allows the drug to remain intact, facilitating its entry into the cell’s nucleus to effectively exert its anticancer activity.


References

{{Platinum compounds Alkylating antineoplastic agents IARC Group 2A carcinogens Coordination complexes Platinum(II) compounds Ammine complexes Chloro complexes