Luotonin A. A Naturally Occurring Human DNA Topoisomerase I Poison

Çağır, Ali; Jones, Shannon H.; Gao, Rong; Eisenhauer, Brian M.; Hecht, Sidney M.

doi:10.1021/ja0368857

Cited by 261 publications

(159 citation statements)

References 37 publications

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“…The luotonins are used in traditional Chinese medicine and are reported to exhibit activity against a range of ailments including rheumatism, inflammation, influenza, hepatitis and leukemia. 43 Luotonin A has been reported to show activity as an antitumour compound and is an inhibitor for human DNA topoisomerase I. 43 The compounds were isolated some ten years ago 4 and luotonin A has been a popular synthetic target.…”

Section: Heteroaryl Radical Cyclisationmentioning

confidence: 99%

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

et al. 2007

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Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone 2, mackinazolinone 3, tryptanthrin 4, luotonin A 5 and rutaecarpine 8 were synthesised by radical cyclisation onto 3H-quinazolin-4-one.The 3H-quinazolin-4-one ring system is important to the biological activity of both naturally occurring alkaloids, biosynthesised from anthranilic acid, and pharmaceuticals. The alkaloids include vasicinone 1 and deoxyvasicinone 2, 1 mackinazolinone 3, 2 tryptanthrin 4, 3 luotonins A 5, B 6 and E 7 4 and rutaecarpine 8. 5 3H-Quinazolin-4-one alkaloids have been recently reviewed. 6 All the 3H-quinazolin-4-one natural products have interesting biological activity and have therefore been extensively investigated for useful pharmaceutical activity. The 3H-quinazolin-4-one ring is regarded as a 'privileged structure' in combinatorial synthesis. 7 These are structures which represent molecules that are capable of binding at multiple sites with high affinity and facilitate more rapid discovery of useful medicinally active compounds. 7Our study involved the development of protocols involving radical cyclisation for the synthesis of polycyclic 3H-quinazolin-3-ones (Scheme 1). The protocols have also been used for the synthesis of novel polycyclic quinazolinones including the natural Department of Chemistry, Loughborough University, Loughborough, Leics, UK LE11 3TU. E-mail: g.w.weaver@lboro.ac.uk; Fax: 44(0) 1509 223925; Tel: 44(0) All of the above cyclisations are 'oxidative' i.e. the intermediate p-radicals are not reduced by triorganometal hydrides [e.g. tributyltin hydyride (Bu 3 SnH)] as normally observed for these reagents. The cyclisations proceed by aromatic homolytic substitution with abstraction of hydrogen in a rearomatisation process. Aromatic homolytic substitution has been recently reviewed 27 and the mechanism of Bu 3 SnH mediated 'oxidative' cyclisation elaborated. 28 The pyrimidin-4-one ring of the quinazolin-4-ones has some aromaticity and therefore aromatic homolytic substitution could be predicted, and was observed in our studies, as shown in Scheme 1 (9 to 11 via the p-radical 10). However, the lower aromaticity could favour reductive cyclisation in which the intermediate p-radical 10 is intercepted by reagents such as Bu 3 SnH. Our prediction that radical cyclisation onto the quinazolin-4-one ring would be 'oxidative' was supported by the 'oxidative' radical cyclisation onto related ring systems, e.g. pyrimidine-2,4-diones, 23,24This journal is

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Section: Heteroaryl Radical Cyclisationmentioning

confidence: 99%

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

et al. 2007

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“…[20] Luotonin A exhibits cytotoxicity toward the murine leukemia P388 cell line [18] by stabilizing the topoisomerase I/DNA complex. [21] This has established luotonin A as an attractive pyrroloquinazoline target for total synthesis, which we achieved by a tin-free radical cascade cyclization Abstract: AmideÀiminyl radicals are versatile and efficient intermediates in cascade radical cyclizations of N-acylcyanamides. They are easily trapped by alkenes or (hetero-)aromatic rings and cyclize into a series of new heterocyclic compounds which bear a pyrroloquinazoline moiety.…”

Section: Introductionmentioning

confidence: 99%

Unprecedented Aromatic Homolytic Substitutions and Cyclization of AmideIminyl Radicals: Experimental and Theoretical Study

Beaume

Courillon

Derat

et al. 2008

Chemistry A European J

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Amide-iminyl radicals are versatile and efficient intermediates in cascade radical cyclizations of N-acylcyanamides. They are easily trapped by alkenes or (hetero-)aromatic rings and cyclize into a series of new heterocyclic compounds which bear a pyrroloquinazoline moiety. As an illustration of the synthetic importance of these compounds, the total synthesis of the natural antitumor compound luotonin A was achieved through a tin-free radical cascade cyclization process. Not only do amide-iminyl radicals lead to new tetracyclic heterocycles but these nitrogen-centered radical species also react in aromatic homolytic substitutions. Indeed, the amide-iminyl radical moiety unprecedentedly displaces methyl, methoxy, and fluorine radicals from an aromatic carbon atom. This seminal reaction in the field of radical chemistry has been developed experimentally and its mechanism has additionally been investigated by a theoretical study.

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“…The N-4/5 atom of 1, 13, 155 (n = 1), 32, and 33 and their derivatives formed salts with mineral acids. Reactions with Br 2 in glacial AcOH, CHCl 3 , MeOH, and other solvents transformed them into tribromides (181) at the Py N atom that reacted with ketones (acetone, acetophenone) to give the corresponding hydrobromides (182). Treatment of their solutions with NaHCO 3 gave the bromides of deoxyvasicinone, deoxyvasicinethione, deoxypeganine, and their derivatives (183).…”

Section: Electrophilic Substitution In the Aromatic Ring Of Tricyclicmentioning

confidence: 99%

“…The alkaloids luotonin A and B (29 and 30) exhibit cytotoxic activity against the P-388 murine leukemia cell line (IC 50 = 1.8 Pg/mL) [8] and stabilizing activity for human DNA topoisomerase 1 [180][181][182][183].…”

Section: Electrophilic Substitution In the Aromatic Ring Of Tricyclicmentioning

confidence: 99%

Tricyclic Quinazoline Alkaloids: Isolation, Synthesis, Chemical Modification, and Biological Activity

Shakhidoyatov

Элмурадов

2014

Chem Nat Compd

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Luotonin A. A Naturally Occurring Human DNA Topoisomerase I Poison

Cited by 261 publications

References 37 publications

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

Unprecedented Aromatic Homolytic Substitutions and Cyclization of AmideIminyl Radicals: Experimental and Theoretical Study

Tricyclic Quinazoline Alkaloids: Isolation, Synthesis, Chemical Modification, and Biological Activity

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