Synthesis and topoisomerase poisoning activity of A-ring and E-ring substituted luotonin A derivatives

Nacro, Kassoum; Zha, Conxiang Charles; Guzzo, Peter R.; Herr, R. J.; Peace, Denise; Friedrich, Thomas

doi:10.1016/j.bmc.2007.03.067

Cited by 41 publications

(24 citation statements)

References 70 publications

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“…1) [4]. There is a considerable interest in the synthesis of new analogs of luotonin A and the study of their biological properties [5][6][7] because of its lower toxicity and higher chemical stability compared with camptothecin. The antiproliferative activity of new A-ring-and E-ring-modified derivatives has been assayed in different cancer cell lines showing an equivalent activity to the parent luotonin A [5].…”

Section: Introductionmentioning

confidence: 99%

Liquid chromatographic analysis of the anticancer alkaloid luotonin A and some new derivatives in human serum samples

González‐Ruiz

Mussardo

Corda

et al. 2010

J of Separation Science

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The quantitation of the natural cytotoxic and anti-inflammatory alkaloid luotonin A and five recently synthesized derivatives is described, constituting the first report of a HPLC method for the analysis of these compounds in human serum samples. The conditions for the chromatographic separation were optimized and the method was validated for the analysis of these compounds in biological samples according to international guidelines. An RP-HPLC method with fluorimetric detection and a C(18) stationary phase was applied. Different ACN/water mobile phases were assayed, including 0-4% of a mobile phase modifier such as tetrahydrofuran, dioxane or tert-butyl methyl ether. Isocratic and gradient elution conditions are compared. The influence of pH on the efficiency and resolution of the separation was also considered. The developed method was applied to the determination of luotonins in pooled human serum samples by gradient elution RP-HPLC using a simple cleanup procedure. The proposed chromatographic method exhibits satisfactory analytical figures of merit, with LOD from 1.0 x 10(-10) to 2.0 x 10(-10) M, intraday and interday precision below 6% except for the concentration level closest to LOD, and good agreement between experimental and theoretical concentrations. Therefore, the developed method is suitable, reliable, rapid, and simple.

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Section: Introductionmentioning

confidence: 99%

Liquid chromatographic analysis of the anticancer alkaloid luotonin A and some new derivatives in human serum samples

González‐Ruiz

Mussardo

Corda

et al. 2010

J of Separation Science

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“…The N-aryl ketone motif [Mitscher, 2005;Gomez et al, 2007;Nacro et al, 2007;Tse-Dinh, 2007;Wiener et al, 2007;Teicher, 2008] is also associated in the literature with various structural classes of topoisomerase inhibitors. Topoisomerase I inhibitors such as topotecan, camptothecin and congeners and 2-pyridone DNA gyrase inhibitors feature the N-aryl ketone.…”

Section: Discussionmentioning

confidence: 99%

Possible structural and functional determinants contributing to the clastogenicity of pharmaceuticals

Snyder

2010

Environ and Mol Mutagen

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The battery of regulatory genotoxicity studies required in support of new drug registration has remained largely static since its inception some thirty years ago. The Ames mutagenicity assay still forms the foundation for this testing being highly reproducible and, for the most part, transparent. The same is not necessarily true of in vitro mammalian chromosome aberration assays since there is a fairly large and growing number of molecules without clear structural genotoxicity alerts (DEREK, MCASE), which are negative in Ames testing but positive in aberration studies, often only at high concentrations and/or cytotoxicity. Interpretation and risk assessment of these positive results can be problematic since there is no clear understanding of the process that generates them. The present paper builds on our previous observations suggesting that non covalent drug/DNA interactions, which are not adequately modeled in computational programs, may help explain some of these unexpected positive results. In particular, it is suggested that N-dimethyl groups and certain pyridine/piperidine aryl ketones may play a contributory role in genotoxicity, perhaps via DNA intercalation and topoisomerase inhibition. Clastogenicity arising from topoisomerase inhibition would be expected to be a threshold phenomenon and, as such, may carry a distinctly reduced risk relative to clastogenicity associated with covalent drug/DNA interactions.

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“…[38][39][40][41][42][43] As a part of our research on biologically important natural products, we herein described a simple one-pot procedure for the preparation of 1 as well as related alkaloids 3, 4 and 5 in multi-gram quantity.…”

Section: )mentioning

confidence: 99%

“…10,12) Nevertheless, the biological importance of 4(3H)-quinazolinone and related compounds still spurred the development of a new and simple synthetic method for theses compounds. [38][39][40][41][42][43] As a part of our research on biologically important natural products, we herein described a simple one-pot procedure for the preparation of 1 as well as related alkaloids 3, 4 and 5 in multi-gram quantity.…”

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confidence: 99%

One-Pot Synthesis of Simple Alkaloids: 2,3-Polymethylene-4(3<i>H</i>)-quinazolinones, Luotonin A, Tryptanthrin, and Rutaecarpine

Jahng

Kim

et al. 2008

Chem. Pharm. Bull.

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2,3-Trimethylene-4(3H)-quinazolinone (deoxyvasicinone, 1aa) 1) and 2,3-tetramethylene-4(3H)-quinazolinone (mackinazolinone, 1ba) 2,3) are not only the alkaloids isolated from Peganum and Mackinlaya species, respectively, but are also prepared chemically before the isolation from natural sources. [4][5][6] The establishment of a simple and efficient synthetic method for these alkaloids has long been a challenging subject. [7][8][9][10][11][12][13][14][15][16][17][18][19][20] In addition, these substances are a part of the family of intriguing alkaloids that include the bronchodilator vasicinone (2a) from Adhatoda vasica, 21) antiendotoxic isaindigotone (2b) from Isatis indigotica, 22) topoisomerase Idependent cytotoxic luotonin A (3) from Peganum nigellastrum, 23) antibiotic tryptanthrin (4) from yeast (Candida lipolytica) 24,25) and later from cannon ball tree (Cououpita guianensis), 26) anti-inflammatory rutaecarpine (5) 27) from Evodia rutaecarpa, and related alkaloids (Fig. 1). 28)Since Niementowski's preparation of 4(3H)-quinazolinone by fusing anthranilic acid with formamide, 29) several methods attempting the synthesis of modified quinazolinones have been reported. 1,[30][31][32][33] Although most of these are applicable to acyclic amides, methods for cyclic amides, especially without an aryl group, are somewhat limited. [34][35][36][37] These limitations have led to the continuous development of new procedures for cyclic amides, such as cyclocondensation of isatoic anhydride with lactams, 12) metal catalyzed reductive N-heterocyclization of N-(2-nitrobenzoyl)lactams in the presence of CO,13,14) reaction of 2-aminobenzamide with succinic anhydride, 15) intramolecular aza-Wittig reaction of N-(2-azidobenzoyl)lactams, 9,16) condensation of anthranilic acid with O-alkyllactims 6,[18][19][20] or S-alkyllactims, 8) reaction of anthranilic acid with SOCl 2 followed by cyclization with lactams, 17) cyclization of iminochlorides generated from lactam and methyl anthranilate, 11) solid-phase synthesis, 7,9) and microwave assisted synthesis.10,12) Nevertheless, the biological importance of 4(3H)-quinazolinone and related compounds still spurred the development of a new and simple synthetic method for theses compounds. [38][39][40][41][42][43] As a part of our research on biologically important natural products, we herein described a simple one-pot procedure for the preparation of 1 as well as related alkaloids 3, 4 and 5 in multi-gram quantity.Although an earlier study revealed that iminoketene (8), generated from the reaction of anthranilic acid (6) and SOCl 2 , underwent cycloaddition to cyclic iminols, which are tautomers of the corresponding lactams (9), to yield 1 in 70-82% yield, 19) we sometimes have been unable to repeat the reactions.44) Whenever we failed to generate the desired products, imine compounds (10) were isolated as major products (Chart 1). Although we could convert these imines (10) to the desired 2,3-tri-and 2,3-tetramethylene-4(3H)-quinazolinones by employing polyphosphoric acid-catalyzed deh...

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Synthesis and topoisomerase poisoning activity of A-ring and E-ring substituted luotonin A derivatives

Cited by 41 publications

References 70 publications

Liquid chromatographic analysis of the anticancer alkaloid luotonin A and some new derivatives in human serum samples

Liquid chromatographic analysis of the anticancer alkaloid luotonin A and some new derivatives in human serum samples

Possible structural and functional determinants contributing to the clastogenicity of pharmaceuticals

One-Pot Synthesis of Simple Alkaloids: 2,3-Polymethylene-4(3<i>H</i>)-quinazolinones, Luotonin A, Tryptanthrin, and Rutaecarpine

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