Design, Synthesis, and Biological Evaluation of 14-Substituted Aromathecins as Topoisomerase I Inhibitors

Cinelli, Maris A.; Morrell, Andrew; Dexheimer, Thomas S.; Scher, Evan S.; Pommier, ﻿Yves; Cushman, Mary

doi:10.1021/jm800259e

Cited by 74 publications

(64 citation statements)

References 49 publications

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“…Luotonin is cytotoxic toward leukemia cell lines and produces an effect similar to CPT, as tested by a cleavage/ religation equilibrium assay and by the effect observed in a Saccharomyces cerevisiae strain lacking yeast Top1, but harboring human Top1 (Cagir et al , 2003 ). This finding has brought to the synthesis of several modified and substituted luotonins, some of which have greater antiproliferative activity than the parent compound (Cagir et al , 2004 ;Dallavalle et al , 2004 ), and to the synthesis of aromathecins, compounds with similarities to the natural product obtained from hybrids between indenoisoquinolines and CPT (Cinelli et al , 2008 ).…”

Section: Compounds That Target Top1mentioning

confidence: 99%

Interaction between natural compounds and human topoisomerase I

Castelli

Coletta²,

D’Annessa³

et al. 2012

Biological Chemistry

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Eukaryotic topoisomerase I (Top1) is a monomeric enzyme that catalyzes the relaxation of supercoiled DNA during important processes including DNA replication, transcription, recombination and chromosome condensation. Human Top1 I is of significant medical interest since it is the unique cellular target of camptothecin (CPT), a plant alkaloid that rapidly blocks both DNA and RNA synthesis. In this review, together with CPT, we point out the interaction between human Top1 and some natural compounds, such us terpenoids, flavonoids, stilbenes and fatty acids. The drugs can interact with the enzyme at different levels perturbing the binding, cleavage, rotation or religation processes. Here we focus on different assays that can be used to identify the catalytic step of the enzyme inhibited by different natural compounds.

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Section: Compounds That Target Top1mentioning

confidence: 99%

Interaction between natural compounds and human topoisomerase I

Castelli

Coletta²,

D’Annessa³

et al. 2012

Biological Chemistry

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“…As such, the system is a “hybrid” of the camptothecin and indenoisoquinoline systems. Although initial attempts to develop aromathecins were less than fruitful,29 subsequent efforts led to the synthesis of the more promising 14-substituted aromathecins 30. These compounds, substituted with amino alcohols and nitrogen heterocycles, possess both greater anti-top1 and antiproliferative activity than rosettacin and a greater ability to inhibit top1 than 22-hydroxyacuminatine.…”

Section: Introductionmentioning

confidence: 99%

“…Molecular modeling and crystallography8 indicate that the lactam region of the indenoisoquinoline system (where these substituents are located) overlaps spatially with both the 7-position of camptothecin and the 14-position of the aromathecin system in their respective ternary cleavage complexes. These substituents likely project into the DNA major groove in the cleavage complex 30. This spatial overlap suggests a significant degree of structure-activity relationship overlap between these two systems 8.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: Investigating the hypothesis of shared structure–activity relationships

Cinelli

Cordero

Dexheimer

et al. 2009

Bioorganic & Medicinal Chemistry

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The aromathecin topoisomerase I (top1) inhibitors offer promising scaffolds for the development of novel cancer chemotherapeutics. They are “composites” of the camptothecin and indenoisoquinoline top1 inhibitors. Interestingly, some structure-activity-relationship (SAR) overlap between the aromathecins and the indenoisoquinolines has been observed. For both classes, placement of certain polar groups in similar regions of the heteroaromatic system improves top1 inhibitory and antiproliferative activities. A series of water-soluble aromathecins substituted at position 14 with diaminoalkanes of various lengths has been prepared. These compounds all possess similar antiproliferative potency, but a general trend is observed: aromathecins with longer diaminoalkane substituents (> 6 carbons) possess lower anti-top1 activity than their smaller counterparts (2–4 carbons), presumably as a result of unfavorable hydrophobic interactions. This trend is also noted with the indenoisoquinolines, revealing additional SAR overlap that supports the hypothesis that there is a “universal” top1 inhibitor SAR.

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“…78 To conclude, we have developed an efficient procedure for the synthesis of dihydroisoindol-1-one derivatives containing a terpenoid fragment. These compounds attract interest as potential biologically active substances, and they can be used for the synthesis of analogs of pharmacologically important pentacyclic alkaloids of the aromathecin series [15,16].…”

Section: V-viiimentioning

confidence: 99%

Synthetic transformations of higher terpenoids: XXIII. Synthesis of diterpenoid-based dihydroisoindolones

et al. 2010

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Vilsmeier-Haak reaction of phlomisoic acid methyl ester gave a mixture of 15-and 16-formyllabdanoids. In addition, methyl 2-formyldodecahydrophenanthro[1,2-b]furan-6-carboxylate was isolated, and its structure was determined by X-ray analysis. Reductive amination of 16-formyllabdanoid with benzylamine or α-amino acid methyl esters led to the formation of labdanoid furfurylamines which reacted with maleic anhydride to produce N-substituted 4-oxo-10-oxa-3-azatricyclo[5.2.1.0 1,5 ]dec-8-ene-6-carboxylic acids. Acylation of labdanoid furfurylamines with (E)-but-2-enoyl chloride afforded the corresponding unsaturated amides which were converted into 10-oxa-3-azatricyclo[5.2.1.0 1,5 ]dec-8-en-4-ones via intramolecular Diels-Alder reaction. Treatment of the oxa adducts with boron trifluoride-diethyl ether complex gave dihydroisoindol-1-one derivatives containing a diterpene fragment. * For communication XXII, see [1].Heterocyclic dihydroisoindol-1-one system constitutes a structural fragment of a number of polycyclic alkaloids with benzoindolizino[1,2-b]quinoline, isoindolo[1,2-b][3]benzoazepine, and isoindolo[1,2-b][3]-oxazepine skeletons, which exhibit diverse biological activity [2]. In the recent years, various synthetic dihydroisoindolone derivatives have been extensively studied. For example, N-piperazinyl-substituted isoindolones were proposed as novel pharmacologically active compounds selective for serotonin and dopamine receptors [3]. Dihydroisoindolones having a piperazine substituent on C 4 constitute a group of selective urotensin II receptor antagonists [4]. Effective antiviral [5] and antitumor agents [6] were found among dihydroisoindolone derivatives. Taking the above into account, the present work was aimed at synthesizing functionalized dihydroisoindolones containing a labdanoid fragment.A convenient procedure for the synthesis of functionally substituted dihydroisoindolones is based on transformations of nitrogen-containing oxatricyclic compounds, 2-substituted 3a,6-epoxy-2,3,7,7a-tetrahydroisoindol-1-ones. The latter can be obtained in high yield by intramolecular Diels-Alder reaction of N-alkyl(aryl)-N-furfurylacrylamides [7]. As starting compound for the synthesis of terpenoid dihydroisoindol-1-ones we selected an accessible furan diterpenoid, phlomisoic acid methyl ester (I); its preparation from lambertianic acid was described previously [8].Vilsmeier-Haak formylation of phlomisoic acid methyl ester (I) gave a mixture of three compounds, 16-formyllabdatrienoate II, 15-formyllabdatrienoate III, and 2-formylmarginatafuran IV in 79, 8, and 2% yield, respectively (Scheme 1). The products were isolated as individual substances by column chromatography, followed by recrystallization from appropriate solvent. The structure of compound IV was confirmed by X-ray analysis. It is seen that the VilsmeierHaak reaction of furan diterpenoid I involves mainly the furan ring; compound IV formed as a result of formylation at the double bond in the octahydronaphthalene fragment was isolated in a poor yield. It sho...

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Design, Synthesis, and Biological Evaluation of 14-Substituted Aromathecins as Topoisomerase I Inhibitors

Cited by 74 publications

References 49 publications

Interaction between natural compounds and human topoisomerase I

Interaction between natural compounds and human topoisomerase I

Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: Investigating the hypothesis of shared structure–activity relationships

Synthetic transformations of higher terpenoids: XXIII. Synthesis of diterpenoid-based dihydroisoindolones

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