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Phenanthriplatin

Clinical data
ATC code	none
Identifiers
IUPAC name cis-NO3
CAS Number	1416900-51-0
Chemical and physical data
Formula	C13H15ClN4O3Pt
Molar mass	505.82 g·mol
3D model (JSmol)	Interactive image
SMILES Cl()()0c1ccccc1c2ccccc2c0.()=O

Phenanthriplatin or cis-NO₃ is a new drug candidate. It belongs to a family of platinum(II)-based agents which includes cisplatin, oxaliplatin and carboplatin. Phenanthriplatin was discovered by Professor Stephen J. Lippard at Massachusetts Institute of Technology 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 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 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-based anticancer agents, residing primarily in the cell's nucleus. The ultimate target of the drug is nuclear DNA.

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.

A study examining the effects of monofunctional adducts on bacterial growth reported a significant decrease in Escherichia coli (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

1. Apps MG, Choi EH, Wheate NJ (August 2015). "The state-of-play and future of platinum drugs". Endocrine-Related Cancer. 22 (4): R219–R233. doi:10.1530/ERC-15-0237. hdl:2123/24426. PMID 26113607.
2. "Blend Therapeutics".
3. ^ Kellinger MW, Park GY, Chong J, Lippard SJ, Wang D (September 2013). "Effect of a monofunctional phenanthriplatin-DNA adduct on RNA polymerase II transcriptional fidelity and translesion synthesis". Journal of the American Chemical Society. 135 (35): 13054–13061. doi:10.1021/ja405475y. PMC 3791135. PMID 23927577.
4. ^ Park GY, Wilson JJ, Song Y, Lippard SJ (July 2012). "Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile". Proceedings of the National Academy of Sciences of the United States of America. 109 (30): 11987–11992. Bibcode:2012PNAS..10911987P. doi:10.1073/pnas.1207670109. PMC 3409760. PMID 22773807.
5. Johnstone TC, Alexander SM, Lin W, Lippard SJ (January 2014). "Effects of monofunctional platinum agents on bacterial growth: a retrospective study". Journal of the American Chemical Society. 136 (1): 116–118. doi:10.1021/ja411742c. PMC 3920743. PMID 24364388.

• Drugs not assigned an ATC code
• Alkylating antineoplastic agents
• IARC Group 2A carcinogens
• Coordination complexes
• Platinum(II) compounds
• Ammine complexes
• Chloro complexes