Phenanthridine is a nitrogenheterocyclic compound with the formulaC13H9N. It is a colorless solid, although impure samples can be brownish. It is a precursor to DNA-bindingfluorescent dyes throughintercalation. Examples of such dyes areethidium bromide andpropidium iodide. Phenanthridine was discovered byAmé Pictet and H. J. Ankersmit in 1891.
Phenanthridine is typically extracted fromcoal tar, an abundant resource where it is found at a level of about 0.1%.[4]
Phenanthridine was prepared by Pictet and Ankersmit bypyrolysis of the condensation product ofbenzaldehyde andaniline.[5] In thePictet–Hubert reaction (1899) the compound is formed in a reaction of the2-aminobiphenyl – formaldehyde adduct (anN-acyl-o-xenylamine) withzinc chloride at elevated temperatures.[6] This traditional method proceeds in low yield and gives various side products (approximately 30-50%). The pyrolysis method involves passing benzylideneaniline through a pumice-filled tube heated to 600–800 °C, where rearrangement and decomposition occur. The resulting pyrolysis products are collected and purified through fractional distillation to remove side products such as benzene, benzonitrile, aniline, and biphenyl. The remaining crude phenanthridine can be crystallized as a mercurochloride salt for further isolation.
The second method is the Morgan–Walls reaction that gives a 42% yield of phenanthridine after purification. It involves a cyclodehydration process. This route starts with heating2-aminobiphenyl with formic acid to give o-formamidobiphenyl. The intermediate is then treated withphosphorus oxychloride to promote cyclization.Nitrobenzene as a high-boiling solvent can improve the yield by allowing higher reaction temperatures.
Morgan and Walls in 1931 improved the Pictet–Hubert reaction by replacing the metal byphosphorus oxychloride and usingnitrobenzene as a reaction solvent.[7] For this reason, the reaction is also called theMorgan–Walls reaction.[8]
In terms of reactivity, phenanthridine resembles its more common isomeracridine. It is a weak base. It forms amethiodide. It resists common oxidants.[9] It forms adducts with metal ions.[10]
Phenanthridine undergoes metabolic transformation primarily through oxidative pathways in both microbial and vertebrate systems.[11] The major metabolite is the amide phenanthridone.,[12] which is primarily done by thecytochrome P450 enzymes. The phenanthridone metabolite is more mutagenic than the parent compound.
A study that tested the metabolism of phenanthridine to phenanthridone by rat lung and liver microsomes suggests that further hydroxylation or epoxidation could enhance phenanthridone's mutagenic effects.[13][14]
[15] The two main mechanisms of action are: topoisomerase inhibition[16] and DNA intercalation.[17]
Phenanthridine derivatives have attracted attention from medicinal chemists.[15] The two main mechanisms of action are: topoisomerase inhibition[16] and DNA intercalation.[17][18] When functionalized, phenanthridine derivatives can exhibit strong DNA-binding affinity, enzyme inhibition and cytotoxic effects.[19][20] s[21]
Phenanthridine derivatives basis for DNA-binding fluorescent dyes, such asethidium bromide andpropidium iodide, which intercalate between nucleic acid base pairs.
Looking at a derivative mentioned in the mechanism of action, the efficacy of ethidium bromide is clarified by being mentioned as a potent mutagen. In addition, the intercalating properties of ethidium bromide with DNA is used in laboratory applications for visualizing nucleic acids during gel electrophoresis, where careful considerations of ethidium bromide concentration and the electrophoresis conditions is essential for obtaining accurate results.[22]
Phenanthridine exhibits some mutagenic properties following activation with rat liver enzymes (S-9 fraction), which simulates mammalian metabolism, making it a suspected humancarcinogen.[23] In addition it has been found that phenanthridine wasgenotoxic[24] andphototoxic[25] as well. Furthermore, phenanthridine can be metabolized to phenanthridone, which has been identified as directly mutagenic in Salmonella strain TA-98. Research suggests that phenanthridone can interact with DNA and induce mutations without requiring enzymatic activation.[13]
Many hydrophenanthridines have been identified in nature. These compounds, all of which arechiral, feature one or two partially hydrogenated rings. Some examples arehamayne, norpluviine, and thecrinines.[26]
^Lide, David R. (1998),Handbook of Chemistry and Physics (87 ed.), Boca Raton, FL: CRC Press, pp. 3–460,ISBN0-8493-0594-2
^Brett, W. A.; Rademacher, P.; Boese, R. (1993). "Redetermination of the Structure of Phenanthridine".Acta Crystallographica Section C Crystal Structure Communications.49 (9):1564–1566.Bibcode:1993AcCrC..49.1564B.doi:10.1107/S0108270193005062.
^Pictet, Amé; Ankersmit, H. J. (1891). "Ueber das Phenanthridin".Justus Liebigs Annalen der Chemie.266 (1–2):138–153.doi:10.1002/jlac.18912660107.
^Pictet, Amé; Hubert, A. (1896). "Ueber eine neue Synthese der Phenanthridinbasen".Berichte der Deutschen Chemischen Gesellschaft.29 (2):1182–1189.doi:10.1002/cber.18960290206.
^Morgan, Gilbert T.; Walls, Leslie Percy (1931). "CCCXXXV.—Researches in the phenanthridine series. Part I. A new synthesis of phenanthridine homologues and derivatives".J. Chem. Soc.:2447–2456.doi:10.1039/JR9310002447.
^Jie Jack Li, ed. (2004).Name Reactions in Heterocyclic Chemistry. Wiley.
^Theobald, R. S.; Schofield, K. (1950). "The Chemistry of Phenanthridine and its Derivatives".Chemical Reviews.46:170–189.doi:10.1021/cr60143a004.
