Synthesis and Biological Evaluation of Antitumor‐Active Arglabin Derivatives

Csuk, René; Heinold, Anke; Siewert, Bianka; Schwarz, Štefan; Barthel, Alexander; Kluge, Ralph; Ströhl, Dieter

doi:10.1002/ardp.201100065

Cited by 26 publications

(21 citation statements)

References 29 publications

(29 reference statements)

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“…86 In a recent study involving arglabin ( 203 ), amine ( 205-206, 210-212 ), thiol derivatives ( 208-209 ), and other derivatives involving small structural changes ( 204 , 207 ) to the exocyclic methylene-γ-lactone and periphery of the molecule were prepared; their biological activities were analyzed (Figure 23). 79c The Michael adducts were all active at low micromolar IC 50 values (2-20 μM) for cytotoxicity to cervical, lung, melanoma, ovarian, colon, thyroid, and breast cancer cell lines, similar to the parent compound, where as the structural changes ( 204 , 207 , data not shown) abolished activity altogether (Table 5). …”

Section: αβ-Unsaturated Esters and Lactonesmentioning

confidence: 87%

“…Reduction of the exocyclic methylene routinely eliminates biological activity, with some exceptions, even at high micromolar concentrations. 79 Several reviews have covered the biological importance and therapeutic potential of α-methylene-γ-lactone-containing compounds. 80 Therefore, the thiol reactivity of these Michael acceptors with cysteines and GSH will be the focus here.…”

Section: αβ-Unsaturated Esters and Lactonesmentioning

confidence: 99%

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Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

et al. 2016

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Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogs possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

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Section: αβ-Unsaturated Esters and Lactonesmentioning

confidence: 87%

Section: αβ-Unsaturated Esters and Lactonesmentioning

confidence: 99%

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

et al. 2016

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“…Arborescin (30) was generated from arglabin (2) by hydrogenation. [18] Bhat et al also www.eurjoc.org obtained amino analogues of ludartin (31), a potent and selective cytotoxic agent, [19] by use of a Michael addition at the exocyclic double bond of the α-methylene γ-lactone as a key step (Scheme 3). Less common guaianolides have been used in the synthesis of several derivatives with fascinating structural diversity.…”

Section: Guaianolide Strategiesmentioning

confidence: 99%

Trends in the Synthesis and Functionalization of Guaianolides

2015

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Guaianolides constitute a large and diverse group of biologically active sesquiterpenes. Guaianolide and seco‐guaianolides can also be used as, for example, scaffolds for the development of new active molecules that are readily accessible by synthetic methods. Nevertheless, these lactones often have complex structures that make their synthesis difficult. The aim of this microreview is to provide an overview of the developments in guaianolide synthesis by the two major synthetic strategies: semi‐synthesis and total synthesis. Partial and total syntheses of guaianolides are described, with particular emphasis placed on the methods reported in the last decade. The methods discussed include rearrangements, cycloadditions, ring‐closing metathesis, the use of transition‐metal catalysts, photochemical reactions, and other recently developed techniques as key steps.

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“…Many STLs exhibit important pharmaceutical properties. For example, thapsigargin from Thapsia laciniata has been used in clinical trials to treat advanced solid tumors (Drew et al, 2013), and arglabin from Artemisia glabella has been shown to selectively inhibit the growth of lung, liver and ovarian cancer cells but to exert fewer side effects on normal cells (Csuk et al, 2012). Xanthanolides are bicyclic STLs in which a five carbon-membered γ-lactone ring is fused to a seven carbon-membered carbocycle (Supplementary Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Comparative Transcriptome Analysis Identifies Putative Genes Involved in the Biosynthesis of Xanthanolides in Xanthium strumarium L.

Gou

Chen

et al. 2016

Front. Plant Sci.

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Xanthium strumarium L. is a traditional Chinese herb belonging to the Asteraceae family. The major bioactive components of this plant are sesquiterpene lactones (STLs), which include the xanthanolides. To date, the biogenesis of xanthanolides, especially their downstream pathway, remains largely unknown. In X. strumarium, xanthanolides primarily accumulate in its glandular trichomes. To identify putative gene candidates involved in the biosynthesis of xanthanolides, three X. strumarium transcriptomes, which were derived from the young leaves of two different cultivars and the purified glandular trichomes from one of the cultivars, were constructed in this study. In total, 157 million clean reads were generated and assembled into 91,861 unigenes, of which 59,858 unigenes were successfully annotated. All the genes coding for known enzymes in the upstream pathway to the biosynthesis of xanthanolides were present in the X. strumarium transcriptomes. From a comparative analysis of the X. strumarium transcriptomes, this study identified a number of gene candidates that are putatively involved in the downstream pathway to the synthesis of xanthanolides, such as four unigenes encoding CYP71 P450s, 50 unigenes for dehydrogenases, and 27 genes for acetyltransferases. The possible functions of these four CYP71 candidates are extensively discussed. In addition, 116 transcription factors that are highly expressed in X. strumarium glandular trichomes were also identified. Their possible regulatory roles in the biosynthesis of STLs are discussed. The global transcriptomic data for X. strumarium should provide a valuable resource for further research into the biosynthesis of xanthanolides.

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Synthesis and Biological Evaluation of Antitumor‐Active Arglabin Derivatives

Cited by 26 publications

References 29 publications

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Trends in the Synthesis and Functionalization of Guaianolides

Comparative Transcriptome Analysis Identifies Putative Genes Involved in the Biosynthesis of Xanthanolides in Xanthium strumarium L.

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