Synergistic TRAIL Sensitizers from <i>Barleria alluaudii</i> and <i>Diospyros maritima</i>

Whitson, Emily L.; Sun, Han; Thomas, Christopher G.; Henrich, Curtis J.; Sayers, Thomas J.; McMahon, James B.; Griesinger, Christian; McKee, Tawnya C.

doi:10.1021/np200805z

Cited by 18 publications

(10 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to all the 2‐ O ‐alkylated naphthoquinones bearing an ester functionality inside the chain, those with a free OH group at C‐5 showed higher activities. This supports the proposal of other research groups that a free OH group at C‐5 is important for the activity of substituted naphthoquinones 8,10,27,28. Comparison between 2q and 4e seems to suggest that further glycolate groups increase the activity.…”

Section: Mechanism Of Actionsupporting

confidence: 89%

Synthesis and Cytotoxic Activity of a Small Naphthoquinone Library: First Synthesis of Juglonbutin

et al. 2014

View full text Add to dashboard Cite

A synthetic protocol has been designed to synthesize grecoketidone (2k), 5‐hydroxylapachol (2g), and the recently discovered natural products juglonbutin (2o) and its derivatives, leading to a small library of different 1,4‐naphthoquinones with the intention of finding new active compounds. Within our collection, 2‐O‐alkylated naphthoquinones with an ester functionality in the side‐chain and a free OH group at C‐5 showed the best activities. Compounds 2f, 2m, and 2n showed GI50 values against 12 tumor cell lines in the lower micromolar range and juglonbutin (2o) showed remarkably efficient inhibition of the glycogen synthase kinase 3β with an IC50 value of 2.03 μM. Furthermore, studies on the mode of action of the most active cytotoxic compounds have been carried out. To the best of our knowledge, this is the first report on the synthesis of juglonbutin (2o) and its biological activity.

show abstract

Section: Mechanism Of Actionsupporting

confidence: 89%

Synthesis and Cytotoxic Activity of a Small Naphthoquinone Library: First Synthesis of Juglonbutin

et al. 2014

View full text Add to dashboard Cite

show abstract

“… 1 , 2 , 3 , 4 , 6 , 10 High-throughput screening of natural product libraries 11 followed by isolation and characterization of active components has yielded a number of natural products able to sensitize resistant cancer cells to TRAIL. 12 , 13 A series of TRAIL-sensitizing withanolides from the indigenous South American plant Physalis peruviana have now been identified, including four not previously identified as TRAIL sensitizers. Withanolides comprise a family of C 28 plant steroids many of which induce apoptosis in several tumor cell lines.…”

mentioning

confidence: 99%

Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation

et al. 2015

View full text Add to dashboard Cite

Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects.

show abstract

“…Eleven examples of real‐world CASE studies were examined using DFT analysis of J ‐couplings. Table shows structures that were elucidated by ACD/SE using the FSG algorithm.…”

Section: Resultsmentioning

confidence: 99%

Enhancing computer‐assisted structure elucidation with DFT analysis of J‐couplings

Buevich

Elyashberg²

2020

Magnetic Reson in Chemistry

View full text Add to dashboard Cite

Computer-assisted structure elucidation (CASE) is the class of expert systems that derives molecular structures primarily from one-dimensional and twodimensional nuclear magnetic resonance data. Contemporary CASE systems, including Advanced Chemistry Development/Structure Elucidator (ACD/SE), consider cross-peaks in heteronuclear multiple bond coherence (HMBC) and correlation spectroscopy (COSY) spectra as two-or three-bond correlations by default. However, four and more bond correlations (nonstandard correlations [NSCs]) could be present in these spectra too. The indiscriminate addition of NSCs to the CASE computations is prohibitively expensive. To address this problem, the ACD/SE program performs a logical analysis of observed correlations and determines the minimum number of NSCs. Guided by this information, a more efficient fuzzy structure generation (FSG) algorithm is subsequently applied. Until now, the FSG algorithm was utilized without any verification of the reliability of found NSCs. Here, we report a verification method for NSCs based on the relationship between NSCs and J-couplings computed with high accuracy density functional theory (DFT) methods. We used the example of strychnine to show that 41 (32%) of 8-Hz HMBC crosspeaks were NSCs and were consistent with 4-6 J CH couplings greater than 0.3 Hz. This cutoff value was largely confirmed by the analysis of NSCs in 11 realworld natural products elucidated by ACD/SE. Additionally, utilizing the example of the CASE study of cleospinol A, we showed that the DFT-computed J-couplings of NSCs can distinctively differentiate the correct structure among six proposed isomers. The proposed approach of NSC verification should further improve the robustness of CASE analysis and can help reveal potential problems with reported experimental data.

show abstract

Synergistic TRAIL Sensitizers from Barleria alluaudii and Diospyros maritima

Cited by 18 publications

References 36 publications

Synthesis and Cytotoxic Activity of a Small Naphthoquinone Library: First Synthesis of Juglonbutin

Synthesis and Cytotoxic Activity of a Small Naphthoquinone Library: First Synthesis of Juglonbutin

Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation

Enhancing computer‐assisted structure elucidation with DFT analysis of J‐couplings

Contact Info

Product

Resources

About