(+)-Myristinins A and D from Knema elegans, which Inhibit DNA Polymerase β and Cleave DNA

Deng, Junwen; Starck, Shelley R.; Li, Shisheng; Hecht, Sidney M.

doi:10.1021/np058064g

Cited by 54 publications

(28 citation statements)

References 33 publications

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“…Structurally, these natural products are chalcone‐flavanone dimers, epimeric at C4 and implicating arylation of the chalcone with a 4‐hydroxyl catechin isomer. This is an example of a rarely observed carbon–carbon bond connection within natural polyphenolics . Compounds 64 and 65 were reported to exhibit moderate aromatase activities of 1.8 and 3.3 µM, respectively.…”

Section: Chalcones and Chalconoids As Aismentioning

confidence: 84%

“…This is an example of a rarely observed carbon-carbon bond connection within natural polyphenolics. 57 Compounds 64 and 65 were reported to exhibit moderate aromatase activities of 1.8 and 3.3 µM, respectively. From a structureactivity viewpoint, it is noted that both derivatives lack the presence of a C4-hydroxyl unit on the aromatic amino acid-derived unit and have a methoxy substituent at C6′.…”

Section: Chalcones and Chalconoids As Aismentioning

confidence: 99%

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Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Nielsen

McNulty

2018

Medicinal Research Reviews

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The discovery of biologically active polyphenolic natural products, including chalcones, stilbenes, flavanones, and isoflavones as steroidal mimics has proven to be a subject of considerable importance in medicine. Some of these natural compounds have been shown to modulate key human metabolic processes via steroidal hormone receptors, or to inhibit crucial enzymes involved in the biosynthesis of steroidal hormones themselves. Isoflavone polyphenolics such as genistein are well known for this "phytoestrogenic" biological activity. This review focuses on the ability of select polyphenolics and their synthetic derivatives to function as steroidal mimics in the inhibition of the enzyme aromatase, thereby lowering production of endogenous estrogen growth hormones. The discovery of potent, natural product-based aromatase inhibitors (AIs) as hit compounds has led to the introduction of steroidal-based irreversible inhibitors, such as exemestane and reversible AIs such as anastrozole and letrozole, now standard therapy in the treatment of estrogen receptor-positive breast cancer and other hormone related indications. Pursuit of this strategy over the last few decades has been largely successful although complications and challenges remain. This review highlights the aromatase activity of natural stilbenes, chalcones, and flavanones and synthetically inspired versions thereof and draws attention to new and under-investigated areas within each class worthy of pursuit.

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Section: Chalcones and Chalconoids As Aismentioning

confidence: 84%

Section: Chalcones and Chalconoids As Aismentioning

confidence: 99%

Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Nielsen

McNulty

2018

Medicinal Research Reviews

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“…Recently, Hecht and colleagues isolated a set of flavinoids [(+)-myristinin A and D], shown in Fig. (5), from knema elegans [71] and later they accomplished the complete chemical synthesis of (+)-myristinin A [72]. These also have potent Polβ inhibitory activity and mediate Cu 2+ -dependent DNA cleavage.…”

Section: Inhibiting Polβ-dependent Dna Synthesismentioning

confidence: 99%

Targeting DNA Polymerase ß for Therapeutic Intervention

Goellner

Svilar²,

Almeida³

et al. 2012

CMP

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DNA damage plays a causal role in numerous disease processes. Hence, it is suggested that DNA repair proteins, which maintain the integrity of the nuclear and mitochondrial genomes, play a critical role in reducing the onset of multiple diseases, including cancer, diabetes and neurodegeneration. As the primary DNA polymerase involved in base excision repair, DNA polymerase β (Polβ) has been implicated in multiple cellular processes, including genome maintenance and telomere processing and is suggested to play a role in oncogenic transformation, cell viability following stress and the cellular response to radiation, chemotherapy and environmental genotoxicants. Therefore, Polβ inhibitors may prove to be effective in cancer treatment. However, Polβ has a complex and highly regulated role in DNA metabolism. This complicates the development of effective Polβ-specific inhibitors useful for improving chemotherapy and radiation response without impacting normal cellular function. With multiple enzymatic activities, numerous binding partners and complex modes of regulation from post-translational modifications, there are many opportunities for Polβ inhibition that have yet to be resolved. To shed light on the varying possibilities and approaches of targeting Polβ for potential therapeutic intervention, we summarize the reported small molecule inhibitors of Polβ and discuss the genetic, biochemical and chemical studies that implicate additional options for Polβ inhibition. Further, we offer suggestions on possible inhibitor combinatorial approaches and the potential for tumor specificity for Polβ-inhibitors.

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“…The addition of vinyl-and aryl-based nucleophiles to this class of electrophiles give rise to chiral chromene products [10] that could readily be utilized in the synthesis of benzopyrancontaining natural products (Scheme 1) such as epigallocatechin-3-gallate, a nutraceutical with potent antioxidant properties, [11] procyanidin B2, a proapoptotic polyphenol, [12] myristinin A, an inhibitor of DNA polymerase B, [13] and the antibacterial fungal metabolite aposphaerin A. [14] A general synthetic method to access this structural class in enantioenriched form would be attractive.…”

mentioning

confidence: 99%

Enantioselective Addition of Boronates to Chromene Acetals Catalyzed by a Chiral Brønsted Acid/Lewis Acid System

2010

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Chiral α,β-dihydroxy carboxylic acids catalyze the enantioselective addition of alkenyl-and aryl boronates to chromene acetals. The optimal carboxylic acid is a tartaric acid amide, easily synthesized via a 3-step procedure. The reaction is enhanced by the addition of Lanthanide triflate salts such as cerium(IV)-and ytterbium(III) triflate. The chiral Brønsted acid and metal Lewis acid may be used in as low as 5 mol % relative to acetal substrate. Optimization of the reaction conditions can lead to yields >70% and enantiomeric ratios as high as 99:1. Spectroscopic and kinetic mechanistic studies demonstrate an exchange process leading to a reactive dioxoborolane intermediate leading to enantioselective addition to the pyrylium generated from the chromene acetal.Boronates exhibit wide-ranging utility in synthesis. [1] As carbon donors in cross coupling reactions [2] and metal-based nucleophiles in π addition reactions, [3] their utility is characterized by their ease of preparation, stability towards isolation and storage, and predictable reactivity patterns to afford valuable products. [4] In a seminal discovery Petasis demonstrated how boronates could be activated towards addition to iminiums. [5] However, an elusive area of reactivity is the addition of vinyl and aryl boronates to carbonyls and oxoniums.[6] While less reactive than imines and iminiums, carbonyl-based electrophiles would significantly expand the utility of boronates in synthesis. Coincident with our interest in new reaction methodology [7] we sought to expand the repertoire of nucleophilic boronate reactions to enantioselective addition to acetals.[8] We identified 2-alkoxy-2H-chromenes as our first substrate class for investigation [Eq. (1) The addition of vinyl and aryl based nucleophiles to this class of electrophiles give rise to chiral chromene products [10] that could readily be utilized in the synthesis of benzopyran containing natural products (Figure 1) We initiated our study by investigating the addition of boronate 5 to 2-ethoxy-2H-chromene 4 (Table 1). A brief survey of Lewis acids failed, providing none of the desired addition product when used in catalytic amount and led to substantial decomposition of the chromene 4. We postulated that organic acids would serve as mild catalysts for the formation of the pyrylium, thereby promoting the reaction. Indeed, the use of acetic acid and trifluoroacetic acid provided the desired addition product 6 in modest yields ( Encouraged by these preliminary results, we explored the use of available chiral acids. (+)-Mandelic acid 9 and dihydroxy acid 10 were nominally successful at promoting the enantioselective addition reaction (entries 3 & 4). However, the use of catalytic N-Boc amino acids derived from L-serine and L-threonine resulted in a more selective reaction. Notably, L-threonine 12 afforded the product in lower selectivity than L-serine 11 (entries 5 & 6); enantioselectivity that returned upon use of the epimeric allo-L-threonine (entry 7). Theses results led us to consider ...

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(+)-Myristinins A and D from Knema elegans, which Inhibit DNA Polymerase β and Cleave DNA

Cited by 54 publications

References 33 publications

Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Targeting DNA Polymerase ß for Therapeutic Intervention

Enantioselective Addition of Boronates to Chromene Acetals Catalyzed by a Chiral Brønsted Acid/Lewis Acid System

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