Phenanthridine
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Names | |
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Preferred IUPAC name
Phenanthridine[1] | |
Other names
Benzo[c]quinoline
6-Phenanthridine 3,4-Benzoquinoline 9-Azaphenanthrene 3,4-Benzoisioquinoline 5-Azaphenanthrene CCRIS 1234 | |
Identifiers | |
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3D model (JSmol)
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ChEBI |
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ChemSpider |
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ECHA InfoCard | 100.005.396 Edit this at Wikidata |
EC Number |
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PubChem CID
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UNII |
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CompTox Dashboard (EPA)
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Properties | |
C13H9N | |
Molar mass | 179.222 g·mol−1 |
Appearance | colorless solid |
Density | 1.341 g/cm3 |
Melting point | 104–107 °C |
Boiling point | 349 °C at 1.025 hPa |
almost insoluble (7.7 μg/mL at pH 7.4) | |
Vapor pressure | 0.0000208 mmHg |
Acidity (pKa) | 4.61[2] |
Hazards | |
GHS labelling:[1] | |
GHS05: Corrosive GHS06: Toxic GHS07: Exclamation mark | |
Danger | |
H301, H315, H318, H335 | |
P261, P264, P264+P265, P270, P271, P280, P301+P316, P302+P352, P304+P340, P305+P354+P338, P317, P319, P321, P330, P332+P317, P362+P364, P403+P233, P405, P501 | |
Flash point | 100 °C (closed cup) |
Lethal dose or concentration (LD, LC): | |
LD50 (median dose)
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oral, rat: 100 mg/kg (acute toxic) |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Phenanthridine is a nitrogen heterocyclic compound with the formula C13H9N. 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 ethidium bromide and propidium iodide. Phenanthridine was discovered by Amé Pictet and H. J. Ankersmit in 1891.
Structure
[edit ]Structurally, the molecule is flat but otherwise unremarkable.[3]
Preparation
[edit ]Phenanthridine is typically extracted from coal tar, an abundant resource where it is found at a level of about 0.1%.[4]
Phenanthridine was prepared by Pictet and Ankersmit by pyrolysis of the condensation product of benzaldehyde and aniline.[5] In the Pictet–Hubert reaction (1899) the compound is formed in a reaction of the 2-aminobiphenyl – formaldehyde adduct (an N-acyl-o-xenylamine) with zinc 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 heating 2-aminobiphenyl with formic acid to give o-formamidobiphenyl. The intermediate is then treated with phosphorus 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 by phosphorus oxychloride and using nitrobenzene as a reaction solvent.[7] For this reason, the reaction is also called the Morgan–Walls reaction.[8]
The reaction is similar to the Bischler–Napieralski reaction and the Pictet–Spengler reaction.
Reactions
[edit ]In terms of reactivity, phenanthridine resembles its more common isomer acridine. It is a weak base. It forms a methiodide. It resists common oxidants.[9] It forms adducts with metal ions.[10]
Metabolism
[edit ]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 the cytochrome 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]
Research
[edit ]Phenanthridine derivatives have attracted attention from medicinal chemists.[18] The two main mechanisms of action are: topoisomerase inhibition[19] and DNA intercalation.[20] [21] When functionalized, phenanthridine derivatives can exhibit strong DNA-binding affinity, enzyme inhibition and cytotoxic effects.[22] [23] s[24]
Phenanthridine derivatives basis for DNA-binding fluorescent dyes, such as ethidium bromide and propidium 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.[25]
Medicinal chemistry
[edit ]Phenanthridine exhibits some mutagenic properties following activation with rat liver enzymes (S-9 fraction), which simulates mammalian metabolism, making it a suspected human carcinogen.[26] In addition it has been found that phenanthridine was genotoxic [27] and phototoxic [28] 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]
Hydropthenanthridines
[edit ]Many hydrophenanthridines have been identified in nature. These compounds, all of which are chiral, feature one or two partially hydrogenated rings. Some examples are hamayne, norpluviine, and the crinines.[29]
References
[edit ]- ^ International Union of Pure and Applied Chemistry (2014). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. p. 212. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4.
- ^ Lide, David R. (1998), Handbook of Chemistry and Physics (87 ed.), Boca Raton, FL: CRC Press, pp. 3–460, ISBN 0-8493-0594-2
- ^ 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.
- ^ Blümer, Gerd-Peter; Collin, Gerd; Höke, Hartmut (2011). "Tar and Pitch". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a26_091.pub2. ISBN 978-3-527-30673-2.
- ^ 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.
- ^ Park, Ga Young; Wilson, Justin J.; Song, Ying; Lippard, Stephen J. (2012年07月24日). "Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile". Proceedings of the National Academy of Sciences. 109 (30): 11987–11992. Bibcode:2012PNAS..10911987P. doi:10.1073/pnas.1207670109 . PMC 3409760 . PMID 22773807.
- ^ Ghosh, Prasenjit; Mukherji, Suparna (September 2023). "Fate, detection technologies and toxicity of heterocyclic PAHs in the aquatic and soil environments". Science of the Total Environment. 892: 164499. Bibcode:2023ScTEn.89264499G. doi:10.1016/j.scitotenv.2023.164499. PMID 37301389.
- ^ Bleeker, E.A.J.; Noor, L.; Kraak, M.H.S.; de Voogt, P.; Admiraal, W. (2001). "Comparative metabolism of phenanthridine by carp (Cyprinus carpio) and midge larvae (Chironomus riparius)". Environmental Pollution. 112 (1): 11–17. doi:10.1016/S0269-7491(00)00107-X. PMID 11202649.
- ^ a b Benson, Janet M.; Royer, Robert E.; Galvin, Jennifer B.; Shimizu, Robert W. (March 1983). "Metabolism of phenanthridine to phenanthridone by rat lung and liver microsomes after induction with benzo[a]pyrene and aroclor". Toxicology and Applied Pharmacology. 68 (1): 36–42. Bibcode:1983ToxAP..68...36B. doi:10.1016/0041-008X(83)90352-6. PMID 6302951.
- ^ Kobetičová, Klára; Šimek, Zdeněk; Brezovský, Jan; Hofman, Jakub (September 2011). "Toxic effects of nine polycyclic aromatic compounds on Enchytraeus crypticus in artificial soil in relation to their properties". Ecotoxicology and Environmental Safety. 74 (6): 1727–1733. Bibcode:2011EcoES..74.1727K. doi:10.1016/j.ecoenv.2011年04月01日3. PMID 21531022.
- ^ Rangarajan, Subhashree; Friedman, Simon H. (2007年04月15日). "Design, synthesis, and evaluation of phenanthridine derivatives targeting the telomerase RNA/DNA heteroduplex". Bioorganic & Medicinal Chemistry Letters. 17 (8): 2267–2273. doi:10.1016/j.bmcl.2007年01月07日0. ISSN 0960-894X. PMID 17317174.
- ^ Guo, Lei; Liu, Xiaojun; Nishikawa, Kiyohiro; Plunkett, William (2007年05月18日). "Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials". Molecular Cancer Therapeutics. 6 (5): 1501–1508. doi:10.1158/1535-7163.MCT-06-0780. ISSN 1535-7163. PMID 17513599.
- ^ Vadivel, Marichandran; Aravinda, T.; Swamynathan, K.; Kumar, B. Vinay; Kumar, Sandeep (2021年06月15日). "DNA binding activity of novel discotic phenathridine derivative". Journal of Molecular Liquids. 332: 115798. doi:10.1016/j.molliq.2021.115798. ISSN 0167-7322.
- ^ Rangarajan, Subhashree; Friedman, Simon H. (2007年04月15日). "Design, synthesis, and evaluation of phenanthridine derivatives targeting the telomerase RNA/DNA heteroduplex". Bioorganic & Medicinal Chemistry Letters. 17 (8): 2267–2273. doi:10.1016/j.bmcl.2007年01月07日0. ISSN 0960-894X. PMID 17317174.
- ^ Guo, Lei; Liu, Xiaojun; Nishikawa, Kiyohiro; Plunkett, William (2007年05月18日). "Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials". Molecular Cancer Therapeutics. 6 (5): 1501–1508. doi:10.1158/1535-7163.MCT-06-0780. ISSN 1535-7163. PMID 17513599.
- ^ Vadivel, Marichandran; Aravinda, T.; Swamynathan, K.; Kumar, B. Vinay; Kumar, Sandeep (2021年06月15日). "DNA binding activity of novel discotic phenathridine derivative". Journal of Molecular Liquids. 332: 115798. doi:10.1016/j.molliq.2021.115798. ISSN 0167-7322.
- ^ Lasák, Pavel; Motyka, Kamil; Kryštof, Vladimír; Stýskala, Jakub (September 2018). "Synthesis, Bacteriostatic and Anticancer Activity of Novel Phenanthridines Structurally Similar to Benzo[c]phenanthridine Alkaloids". Molecules. 23 (9): 2155. doi:10.3390/molecules23092155 . ISSN 1420-3049. PMC 6225299 . PMID 30150591.
- ^ Tumir, Lidija-Marija; Stojković, Marijana Radić; Piantanida, Ivo (2014年12月10日). "Come-back of phenanthridine and phenanthridinium derivatives in the 21st century". Beilstein Journal of Organic Chemistry. 10 (1): 2930–2954. doi:10.3762/bjoc.10.312. ISSN 1860-5397. PMC 4273281 . PMID 25550761.
- ^ Bernardo, Paul H.; Wan, Kah-Fei; Sivaraman, Thirunavukkarasu; Xu, Jin; Moore, Felicity K.; Hung, Alvin W.; Mok, Henry Y. K.; Yu, Victor C.; Chai, Christina L. L. (2008年11月13日). "Structure−Activity Relationship Studies of Phenanthridine-Based Bcl-X L Inhibitors". Journal of Medicinal Chemistry. 51 (21): 6699–6710. doi:10.1021/jm8005433. ISSN 0022-2623. PMID 18925736.
- ^ Azad, Iqbal; Ahmad, Rumana; Khan, Tahmeena; Saquib, Mohammad; Hassan, Firoj; Akhter, Yusuf; Khan, Abdul R; Nasibullah, Malik (2020年04月01日). "Phenanthridine Derivatives as Promising New Anticancer Agents: synthesis, Biological Evaluation and Binding Studies". Future Medicinal Chemistry. 12 (8): 709–739. doi:10.4155/fmc-2019-0016. ISSN 1756-8919. PMID 32208986.
- ^ Karcher, SUSAN J. (1995年01月01日), Karcher, SUSAN J. (ed.), "2 - RECOMBINANT DNA CLONING", Molecular Biology, San Diego: Academic Press, pp. 45–134, ISBN 978-0-12-397720-5 , retrieved 2025年03月13日
- ^ Lauby-Secretan, Beatrice; Baan, Robert; Grosse, Yann; Ghissassi, Fatiha El; Bouvard, Véronique; Benbrahim-Tallaa, Lamia; Guha, Neela; Galichet, Laurent; Straif, Kurt (2011年12月01日). "Bitumens and bitumen emissions, and some heterocyclic polycyclic aromatic hydrocarbons". The Lancet Oncology. 12 (13): 1190–1191. doi:10.1016/S1470-2045(11)70359-X. ISSN 1470-2045. PMID 22232803.
- ^ Bartoš, T.; Letzsch, S.; Škarek, M.; Flegrová, Z.; Čupr, P.; Holoubek, I. (2006). "GFP assay as a sensitive eukaryotic screening model to detect toxic and genotoxic activity of azaarenes". Environmental Toxicology. 21 (4): 343–348. Bibcode:2006EnTox..21..343B. doi:10.1002/tox.20190. ISSN 1522-7278. PMID 16841313.
- ^ Sedlačková, Eva; Bábelová, Andrea; Kozics, Katarína; Šelc, Michal; Srančíková, Annamária; Frecer, Vladimír; Gábelová, Alena (2015). "Ultraviolet A radiation potentiates the cytotoxic and genotoxic effects of 7 -dibenzo[c,g]carbazole and its methyl derivatives". Environmental and Molecular Mutagenesis. 56 (4): 388–403. Bibcode:2015EnvMM..56..388S. doi:10.1002/em.21927. ISSN 1098-2280. PMID 25421724.
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