Phenanthridine

Structurally, the molecule is flat but otherwise unremarkable.{{cite journal |doi=10.1107/S0108270193005062 |title=Redetermination of the Structure of Phenanthridine |date=1993 |last1=Brett |first1=W. A. |last2=Rademacher |first2=P. |last3=Boese |first3=R. |journal=Acta Crystallographica Section C Crystal Structure Communications |volume=49 |issue=9 |pages=1564–1566 |bibcode=1993AcCrC..49.1564B }}

Phenanthridine is typically extracted from coal tar, an abundant resource where it is found at a level of about 0.1%.{{cite book |doi=10.1002/14356007.a26_091.pub2 |chapter=Tar and Pitch |title=Ullmann's Encyclopedia of Industrial Chemistry |date=2011 |last1=Blümer |first1=Gerd-Peter |last2=Collin |first2=Gerd |last3=Höke |first3=Hartmut |isbn=978-3-527-30673-2 }}

Phenanthridine was prepared by Pictet and Ankersmit by pyrolysis of the condensation product of benzaldehyde and aniline.{{cite journal | doi = 10.1002/jlac.18912660107 | title = Ueber das Phenanthridin | date = 1891 | last1 = Pictet | first1 = Amé | last2 = Ankersmit | first2 = H. J. | journal = Justus Liebigs Annalen der Chemie | volume = 266 | issue = 1–2 | pages = 138–153 }} 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.{{cite journal | doi = 10.1002/cber.18960290206| title = Ueber eine neue Synthese der Phenanthridinbasen| date = 1896| last1 = Pictet| first1 = Amé| last2 = Hubert| first2 = A.| journal = Berichte der Deutschen Chemischen Gesellschaft| volume = 29| issue = 2| pages = 1182–1189}} 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.{{cite journal | doi = 10.1039/JR9310002447| title = CCCXXXV.—Researches in the phenanthridine series. Part I. A new synthesis of phenanthridine homologues and derivatives| date = 1931| last1 = Morgan| first1 = Gilbert T.| last2 = Walls| first2 = Leslie Percy| journal = J. Chem. Soc.| pages = 2447–2456}} For this reason, the reaction is also called the Morgan–Walls reaction.{{cite book | editor = Jie Jack Li | date = 2004 | title = Name Reactions in Heterocyclic Chemistry | publisher = Wiley }}

:File:Pictet-Hubert reaction V1.svg

The reaction is similar to the Bischler–Napieralski reaction and the Pictet–Spengler reaction.

In terms of reactivity, phenanthridine resembles its more common isomer acridine. It is a weak base. It forms a methiodide. It resists common oxidants.{{cite journal |doi=10.1021/cr60143a004 |title=The Chemistry of Phenanthridine and its Derivatives |date=1950 |last1=Theobald |first1=R. S. |last2=Schofield |first2=K. |journal=Chemical Reviews |volume=46 |pages=170–189 }} It forms adducts with metal ions.{{Cite journal |last1=Park |first1=Ga Young |last2=Wilson |first2=Justin J. |last3=Song |first3=Ying |last4=Lippard |first4=Stephen J. |date=2012-07-24 |title=Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile |journal=Proceedings of the National Academy of Sciences |volume=109 |issue=30 |pages=11987–11992 |doi=10.1073/pnas.1207670109 |doi-access=free |pmc=3409760 |pmid=22773807|bibcode=2012PNAS..10911987P }}

Phenanthridine undergoes metabolic transformation primarily through oxidative pathways in both microbial and vertebrate systems.{{Cite journal |last1=Ghosh |first1=Prasenjit |last2=Mukherji |first2=Suparna |date=September 2023 |title=Fate, detection technologies and toxicity of heterocyclic PAHs in the aquatic and soil environments |url=https://linkinghub.elsevier.com/retrieve/pii/S0048969723031200 |journal=Science of the Total Environment |language=en |volume=892 |pages=164499 |doi=10.1016/j.scitotenv.2023.164499|pmid=37301389 |bibcode=2023ScTEn.89264499G |url-access=subscription }} The major metabolite is the amide phenanthridone.,{{Cite journal |last1=Bleeker |first1=E.A.J. |last2=Noor |first2=L. |last3=Kraak |first3=M.H.S. |last4=de Voogt |first4=P. |last5=Admiraal |first5=W. |date=2001 |title=Comparative metabolism of phenanthridine by carp (Cyprinus carpio) and midge larvae (Chironomus riparius) |url=https://linkinghub.elsevier.com/retrieve/pii/S026974910000107X |journal=Environmental Pollution |language=en |volume=112 |issue=1 |pages=11–17 |doi=10.1016/S0269-7491(00)00107-X|pmid=11202649 |url-access=subscription }} 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.{{Cite journal |last1=Benson |first1=Janet M. |last2=Royer |first2=Robert E. |last3=Galvin |first3=Jennifer B. |last4=Shimizu |first4=Robert W. |date=March 1983 |title=Metabolism of phenanthridine to phenanthridone by rat lung and liver microsomes after induction with benzo[a]pyrene and aroclor |url=https://linkinghub.elsevier.com/retrieve/pii/0041008X83903526 |journal=Toxicology and Applied Pharmacology |language=en |volume=68 |issue=1 |pages=36–42 |doi=10.1016/0041-008X(83)90352-6|pmid=6302951 |bibcode=1983ToxAP..68...36B |url-access=subscription }}{{Cite journal |last1=Kobetičová |first1=Klára |last2=Šimek |first2=Zdeněk |last3=Brezovský |first3=Jan |last4=Hofman |first4=Jakub |date=September 2011 |title=Toxic effects of nine polycyclic aromatic compounds on Enchytraeus crypticus in artificial soil in relation to their properties |url=https://linkinghub.elsevier.com/retrieve/pii/S0147651311000972 |journal=Ecotoxicology and Environmental Safety |language=en |volume=74 |issue=6 |pages=1727–1733 |doi=10.1016/j.ecoenv.2011.04.013|pmid=21531022 |bibcode=2011EcoES..74.1727K |url-access=subscription }}

{{Cite journal |last1=Rangarajan |first1=Subhashree |last2=Friedman |first2=Simon H. |date=2007-04-15 |title=Design, synthesis, and evaluation of phenanthridine derivatives targeting the telomerase RNA/DNA heteroduplex |url=https://www.sciencedirect.com/science/article/abs/pii/S0960894X07001205 |journal=Bioorganic & Medicinal Chemistry Letters |volume=17 |issue=8 |pages=2267–2273 |doi=10.1016/j.bmcl.2007.01.070 |pmid=17317174 |issn=0960-894X|url-access=subscription }} The two main mechanisms of action are: topoisomerase inhibition{{Cite journal |last1=Guo |first1=Lei |last2=Liu |first2=Xiaojun |last3=Nishikawa |first3=Kiyohiro |last4=Plunkett |first4=William |date=2007-05-18 |title=Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials |url=https://aacrjournals.org/mct/article/6/5/1501/235135/Inhibition-of-topoisomerase-II-and-G2-cell-cycle |journal=Molecular Cancer Therapeutics |volume=6 |issue=5 |pages=1501–1508 |doi=10.1158/1535-7163.MCT-06-0780 |pmid=17513599 |issn=1535-7163|url-access=subscription }} and DNA intercalation.{{Cite journal |last1=Vadivel |first1=Marichandran |last2=Aravinda |first2=T. |last3=Swamynathan |first3=K. |last4=Kumar |first4=B. Vinay |last5=Kumar |first5=Sandeep |date=2021-06-15 |title=DNA binding activity of novel discotic phenathridine derivative |url=https://www.sciencedirect.com/science/article/abs/pii/S0167732221005237 |journal=Journal of Molecular Liquids |volume=332 |pages=115798 |doi=10.1016/j.molliq.2021.115798 |issn=0167-7322|url-access=subscription }}  

Phenanthridine derivatives have attracted attention from medicinal chemists. The two main mechanisms of action are: topoisomerase inhibition and DNA intercalation.  {{Cite journal |last1=Lasák |first1=Pavel |last2=Motyka |first2=Kamil |last3=Kryštof |first3=Vladimír |last4=Stýskala |first4=Jakub |date=September 2018 |title=Synthesis, Bacteriostatic and Anticancer Activity of Novel Phenanthridines Structurally Similar to Benzo[c]phenanthridine Alkaloids |journal=Molecules |language=en |volume=23 |issue=9 |pages=2155 |doi=10.3390/molecules23092155 |doi-access=free |issn=1420-3049 |pmc=6225299 |pmid=30150591}} When functionalized, phenanthridine derivatives can exhibit strong DNA-binding affinity, enzyme inhibition and cytotoxic effects.{{Cite journal |last1=Tumir |first1=Lidija-Marija |last2=Stojković |first2=Marijana Radić |last3=Piantanida |first3=Ivo |date=2014-12-10 |title=Come-back of phenanthridine and phenanthridinium derivatives in the 21st century |url=https://www.beilstein-journals.org/bjoc/articles/1860-5397-10-312 |journal=Beilstein Journal of Organic Chemistry |language=en |volume=10 |issue=1 |pages=2930–2954 |doi=10.3762/bjoc.10.312 |pmid=25550761 |pmc=4273281 |issn=1860-5397}}{{Cite journal |last1=Bernardo |first1=Paul H. |last2=Wan |first2=Kah-Fei |last3=Sivaraman |first3=Thirunavukkarasu |last4=Xu |first4=Jin |last5=Moore |first5=Felicity K. |last6=Hung |first6=Alvin W. |last7=Mok |first7=Henry Y. K. |last8=Yu |first8=Victor C. |last9=Chai |first9=Christina L. L. |date=2008-11-13 |title=Structure−Activity Relationship Studies of Phenanthridine-Based Bcl-X L Inhibitors |url=https://pubs.acs.org/doi/10.1021/jm8005433 |journal=Journal of Medicinal Chemistry |language=en |volume=51 |issue=21 |pages=6699–6710 |doi=10.1021/jm8005433 |pmid=18925736 |issn=0022-2623|url-access=subscription }} s{{Cite journal |last1=Azad |first1=Iqbal |last2=Ahmad |first2=Rumana |last3=Khan |first3=Tahmeena |last4=Saquib |first4=Mohammad |last5=Hassan |first5=Firoj |last6=Akhter |first6=Yusuf |last7=Khan |first7=Abdul R |last8=Nasibullah |first8=Malik |date=2020-04-01 |title=Phenanthridine Derivatives as Promising New Anticancer Agents: synthesis, Biological Evaluation and Binding Studies |url=https://www.tandfonline.com/doi/full/10.4155/fmc-2019-0016 |journal=Future Medicinal Chemistry |volume=12 |issue=8 |pages=709–739 |doi=10.4155/fmc-2019-0016 |issn=1756-8919 |pmid=32208986|url-access=subscription }}

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.{{Citation |last=Karcher |first=SUSAN J. |title=2 - RECOMBINANT DNA CLONING |date=1995-01-01 |work=Molecular Biology |pages=45–134 |editor-last=Karcher |editor-first=SUSAN J. |url=https://www.sciencedirect.com/science/article/abs/pii/B9780123977205500360 |access-date=2025-03-13 |place=San Diego |publisher=Academic Press |isbn=978-0-12-397720-5}}

Phenanthridine exhibits some mutagenic properties following activation with rat liver enzymes (S-9 fraction), which simulates mammalian metabolism, making it a suspected human carcinogen.{{Cite journal |last1=Lauby-Secretan |first1=Beatrice |last2=Baan |first2=Robert |last3=Grosse |first3=Yann |last4=Ghissassi |first4=Fatiha El |last5=Bouvard |first5=Véronique |last6=Benbrahim-Tallaa |first6=Lamia |last7=Guha |first7=Neela |last8=Galichet |first8=Laurent |last9=Straif |first9=Kurt |date=2011-12-01 |title=Bitumens and bitumen emissions, and some heterocyclic polycyclic aromatic hydrocarbons |url=https://linkinghub.elsevier.com/retrieve/pii/S147020451170359X |journal=The Lancet Oncology |language=English |volume=12 |issue=13 |pages=1190–1191 |doi=10.1016/S1470-2045(11)70359-X |issn=1470-2045 |pmid=22232803|url-access=subscription }} In addition it has been found that phenanthridine was genotoxic{{Cite journal |last1=Bartoš |first1=T. |last2=Letzsch |first2=S. |last3=Škarek |first3=M. |last4=Flegrová |first4=Z. |last5=Čupr |first5=P. |last6=Holoubek |first6=I. |date=2006 |title=GFP assay as a sensitive eukaryotic screening model to detect toxic and genotoxic activity of azaarenes |url=https://onlinelibrary.wiley.com/doi/10.1002/tox.20190 |journal=Environmental Toxicology |language=en |volume=21 |issue=4 |pages=343–348 |doi=10.1002/tox.20190 |pmid=16841313 |bibcode=2006EnTox..21..343B |issn=1522-7278}} and phototoxic{{Cite journal |last1=Sedlačková |first1=Eva |last2=Bábelová |first2=Andrea |last3=Kozics |first3=Katarína |last4=Šelc |first4=Michal |last5=Srančíková |first5=Annamária |last6=Frecer |first6=Vladimír |last7=Gábelová |first7=Alena |date=2015 |title=Ultraviolet A radiation potentiates the cytotoxic and genotoxic effects of 7 -dibenzo[c,g]carbazole and its methyl derivatives |url=https://onlinelibrary.wiley.com/doi/10.1002/em.21927 |journal=Environmental and Molecular Mutagenesis |language=en |volume=56 |issue=4 |pages=388–403 |doi=10.1002/em.21927 |pmid=25421724 |bibcode=2015EnvMM..56..388S |issn=1098-2280|url-access=subscription }} 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.

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| header = Hydrophenanthridines of the crinine-type alkaloids

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| caption3 = Augustisine

| image4 = Amaryllisine.svg

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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.{{cite book |doi=10.1002/14356007.a01_353.pub2 |chapter=Alkaloids |title=Ullmann's Encyclopedia of Industrial Chemistry |date=2010 |last1=Mascavage |first1=Linda M. |last2=Jasmin |first2=Serge |last3=Sonnet |first3=Philip E. |last4=Wilson |first4=Michael |last5=Dalton |first5=David R. |isbn=978-3-527-30385-4 }}

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Category:DNA-binding substances