Synthesis and evaluation of macrocyclic diarylether heptanoid natural products and their analogs

Bryant, Vashti C.; Kumar, G. Suresh; Nyong, Abijah M.; Natarajan, Amarnath

doi:10.1016/j.bmcl.2011.11.025

Cited by 30 publications

(22 citation statements)

References 18 publications

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“…Recent studies by us also suggest that the quinoxaline urea analog 13–197 inhibits the constitutively active form of IKKβ which is an emerging target for therapeutic development (28–30). In cell-based NF-κB driven dual luciferase assay, the potency of 13-197 is comparable to the reported NF-κB inhibitors, Parthenolide, Curcumin and Noscapine (37). Considering IKKβ and the NF-κB pathway are constitutively active in the therapy-resistant MCL, we speculated that 13-197 might be a therapeutic option for refractory MCL.…”

Section: Introductionmentioning

confidence: 60%

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Chaturvedi

Rajule

Shukla

et al. 2013

Molecular Cancer Therapeutics

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Mantle cell lymphoma (MCL) is one of the most aggressive B cell non-Hodgkin lymphomas with a median survival of about five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB and mTOR pathways are constitutively active in refractory MCL leading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis in MCL cells including therapy-resistant cells compared to control cells. Furthermore, we observed down-regulation of IκBα phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB regulated genes such as cyclin D1, Bcl-XL and Mcl-1 were down-regulated in 13-197-treated cells. 13-197 also inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL bearing NOD-SCID mice compared to vehicle treated mice; indeed, 13-197 significantly increased the survival of MCL transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading suppression of proliferation and increased apoptosis in malignant MCL cells including reduction in tumor burden in mice.

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Section: Introductionmentioning

confidence: 60%

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Chaturvedi

Rajule

Shukla

et al. 2013

Molecular Cancer Therapeutics

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“…Induction of apoptosis was measured using caspase 3/7 activity assay (normalized for cell number using alamarBlue). 24 Camptothecin (50 μM) and a Bayer IKKβ inhibitor IKK2VII (10 μM) 25 a compound with a well characterized target were used as controls in this screen. Camptothecin increases the stability of Noxa protein which, competes with the Mcl-1-Bak complex to release free bak and thereby induce apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Perturbing pro-survival proteins using quinoxaline derivatives: A structure–activity relationship study

Rajule

Bryant

Lopez

et al. 2012

Bioorganic & Medicinal Chemistry

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In HeLa cells the combinatorial knockdown of Bcl-xL and Mcl-1 is sufficient to induce spontaneous apoptosis. Quinoxaline derivatives were screened for the induction of Mcl-1 dependent apoptosis using a cell line without functional Bcl-xL. Quinoxaline urea analog 1h was able to specifically induce apoptosis in an Mcl-1 dependent manner. We demonstrate that even small changes to 1h results in dramatic los of activity. In addition, 1h and ABT-737 synergistically inhibit cell growth and induce apoptosis. Our results also suggest that 1h could have therapeutic potential against ABT-737 refractory cancer.

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“…3 Macrocyclic diarylheptanoids belong to a chemical class of bioactive naturally occurring phytochemicals, which display a characteristic diphenyl ether motif linked by a seven carbon bridge. 7 Since acerogenin A, the first member in the cyclic diarylheptanoid class, was isolated and reported by the Nagai group in 1976, 8 diverse diarylheptanoids 9-16 have been isolated and found to mediate a variety of biological activities (Figure 1). One such example, engelhardione was recently isolated from the roots of Engelhardia roxburghiana and reported to show potent antituberculosis activity with a minimum inhibitory concentration (MIC) of 0.2 μg ml −1 .…”

Section: Introductionmentioning

confidence: 99%

Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents

Shen¹,

Maddox²,

Adhikari³

et al. 2013

J Antibiot

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The natural product engelhardione is an underexplored chemotype for developing novel treatments for bacterial infections; we therefore explored this natural product scaffold for chemical diversification and structure-activity relationship studies. Macrocyclic engelhardione and structural regioisomers were synthesized using a series of aldol condensations and selective hydrogenations to generate the 1,7-diarylheptan-3-one derivatives, followed by microwave-assisted intramolecular Ullmann coupling to afford a series of macrocyclic diaryl ether analogs. An extended macrocyclic chemical library was then produced by oxime formation, reductive amination, and O-alkylation. Antibacterial evaluation revealed that the reductive amination derivatives 7b and 7d showed moderate activities (minimum inhibitory concentrations: 12.5-25 μg ml−1) against Mycobacterium tuberculosis and Gram-positive pathogens, as well as anti-Gram-negative activity against an efflux impaired E. coli strain. These results provide validated leads for further optimization and development.

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Synthesis and evaluation of macrocyclic diarylether heptanoid natural products and their analogs

Cited by 30 publications

References 18 publications

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Perturbing pro-survival proteins using quinoxaline derivatives: A structure–activity relationship study

Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents

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