Phenanthriplatin

Last updated
Phenanthriplatin
Phenanthriplatin.svg
Phenanthriplatin 3D BS.png
Clinical data
ATC code
  • none
Identifiers
  • cis-[Pt(NH3)2-(phenanthridine)Cl]NO3
CAS Number
Chemical and physical data
Formula C13H15ClN4O3Pt
Molar mass 505.82 g·mol−1
3D model (JSmol)
  • Cl[Pt-2]([NH3+])([NH3+])[n+]0c1ccccc1c2ccccc2c0.[O-][N+]([O-])=O

Phenanthriplatin or cis-[Pt(NH3)2-(phenanthridine)Cl]NO3 is a new drug candidate. It belongs to a family of platinum(II)-based agents which includes cisplatin, oxaliplatin and carboplatin. [1] 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. [2]

Contents

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. [3]

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. [4]

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. [4] 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. [3] 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. [5] 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. [4] This allows the drug to remain intact, facilitating its entry into the cell’s nucleus to effectively exert its anticancer activity.

Related Research Articles

Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

<span class="mw-page-title-main">Carboplatin</span> Medication used to treat cancer

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 used by injection into a vein.

<span class="mw-page-title-main">Cisplatin</span> Chemical compound and pharmaceutical drug

Cisplatin is a chemical compound with formula cis-[Pt(NH3)2Cl2]. 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, cervical cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors and neuroblastoma. It is given by injection into a vein.

Triplatin tetranitrate 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.

<span class="mw-page-title-main">Crosslinking of DNA</span> Phenomenon in genetics

In genetics, crosslinking of DNA occurs when various exogenous or endogenous agents react with two nucleotides of DNA, forming a covalent linkage between them. This crosslink can occur within the same strand (intrastrand) or between opposite strands of double-stranded DNA (interstrand). These adducts interfere with cellular metabolism, such as DNA replication and transcription, triggering cell death. These crosslinks can, however, be repaired through excision or recombination pathways.

<span class="mw-page-title-main">Alkylating antineoplastic agent</span> Pharmaceutical drugs

An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group (CnH2n+1) to DNA.

<span class="mw-page-title-main">Satraplatin</span> Chemical compound

Satraplatin is a platinum-based antineoplastic agent that was under investigation as a treatment of patients with advanced prostate cancer who have failed previous chemotherapy. It has not yet received approval from the U.S. Food and Drug Administration. First mentioned in the medical literature in 1993, satraplatin is the first orally active platinum-based chemotherapeutic drug; other available platinum analogues—cisplatin, carboplatin, and oxaliplatin—must be given intravenously.

<span class="mw-page-title-main">Structure specific recognition protein 1</span> Protein-coding gene in the species Homo sapiens

FACT complex subunit SSRP1 also known as structure specific recognition protein 1 is a protein that in humans is encoded by the SSRP1 gene.

<span class="mw-page-title-main">Nedaplatin</span> Chemical compound

Nedaplatin is a platinum-based antineoplastic drug which is used for cancer chemotherapy. The complex consists of two ammine ligands and the dianion derived from glycolic acid.

<span class="mw-page-title-main">Stephen J. Lippard</span> American chemist

Stephen James Lippard is the Arthur Amos Noyes Emeritus Professor of Chemistry at the Massachusetts Institute of Technology. He is considered one of the founders of bioinorganic chemistry, studying the interactions of nonliving substances such as metals with biological systems. He is also considered a founder of metalloneurochemistry, the study of metal ions and their effects in the brain and nervous system. He has done pioneering work in understanding protein structure and synthesis, the enzymatic functions of methane monooxygenase (MMO), and the mechanisms of cisplatin anticancer drugs. His work has applications for the treatment of cancer, for bioremediation of the environment, and for the development of synthetic methanol-based fuels.

<span class="mw-page-title-main">Hydrophile</span> Molecular entity that is attracted to water

A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.

Platinum-based antineoplastic drugs are chemotherapeutic agents used to treat cancer. Their active moieties are coordination complexes of platinum. These drugs are used to treat almost half of people receiving chemotherapy for cancer. In this form of chemotherapy, commonly used drugs include cisplatin, oxaliplatin, and carboplatin, but several have been proposed or are under development. Addition of platinum-based chemotherapy drugs to chemoradiation in women with early cervical cancer seems to improve survival and reduce risk of recurrence.

Ruthenium anti-cancer drugs are coordination complexes of ruthenium complexes that have anticancer properties. They promise to provide alternatives to platinum-based drugs for anticancer therapy. No ruthenium anti-cancer drug has been commercialized.

Auger therapy is a form of radiation therapy for the treatment of cancer which relies on low-energy electrons to damage cancer cells, rather than the high-energy radiation used in traditional radiation therapy. Similar to other forms of radiation therapy, Auger therapy relies on radiation-induced damage to cancer cells to arrest cell division, stop tumor growth and metastasis and kill cancerous cells. It differs from other types of radiation therapy in that electrons emitted via the Auger effect are released with low kinetic energy. In contrast to traditional α- and β-particle emitters, Auger electron emitters exhibit low cellular toxicity during transit in blood or bone marrow.

Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.

Arabinopyranosyl-<i>N</i>-methyl-<i>N</i>-nitrosourea Chemical compound

Arabinopyranosyl-N-methyl-N-nitrosourea, also known as Aranose (Араноза) is a cytostatic anticancer chemotherapeutic drug of an alkylating type. Chemically it is a nitrosourea derivative. It was developed in the Soviet Union in the 1970s. It was claimed by its developers that its advantages over other nitrosoureas are a relatively low hematological toxicity and a wider therapeutic index, which allows for its outpatient administration.

<span class="mw-page-title-main">KP1019</span> Chemical compound

KP1019, or indazole trans-[tetrachlorobis(1H-indazole)ruthenate(III)], is one of four ruthenium anti-cancer drugs to enter into phase I clinical trials, the others being BOLD-100, NAMI-A and TLD-1433. Research into ruthenium-based drugs has provided novel alternatives for platinum-based chemotherapeutics such as Cisplatin and its derivatives. KP1019 is useful for metastatic tumors and cis-platin resistant tumors. It exhibits potent cytotoxicity against primary tumors, particularly in colorectal cancer.

RAPTA is a class of experimental cancer drugs. They consist of a central ruthenium(II) atom complexed to an arene group, chlorides, and 1,3,5-triaza-7-phosphaadamantane (PTA) forming an organoruthenium half-sandwich compound. Other related ruthenium anti-cancer drugs include NAMI-A, KP1019 and BOLD-100.

Deborah Beth Zamble was a Canadian chemist and Canada Research Chair in Biological Chemistry at the University of Toronto. Her research considered how bacteria processed metal nutrients.

<span class="mw-page-title-main">Lobaplatin</span> Chemical compound

Lobaplatin is a platinum-based antineoplastic metallodrug approved exclusively in China for the treatment of small cell lung cancer, inoperable metastatic breast cancer and chronic myelogenous leukaemia. The drug is a third-generation analogue of cisplatin, the first globally approved and widely used platinum-based anticancer drug.

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. 1 2 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. 1 2 3 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.