Cyclopropene Cycloadditions with Annulated Furans: Total Synthesis of (+)- and (−)-Frondosin B and (+)-Frondosin A

Oblak, E. Zachary; VanHeyst, Michael D.; Jin, Li; Wiemer, Andrew J.; Wright, Dennis L.

doi:10.1021/ja413106t

Cited by 58 publications

(36 citation statements)

References 45 publications

(31 reference statements)

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“…Cell lines were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA) and cultured as described [25]. Cells were grown at 37 °C with 5% CO 2 in RPMI-1640 medium (Thermo Fisher Scientific) with 1x Penicillin-Streptomycin (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis

Jin

Falcone

Holstein

et al. 2016

Pharmacological Research

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Tropolones, such as β-thujaplicin, are small lead-like natural products that possess a variety of biological activities. While the β-substituted natural products and their synthetic analogs are potent inhibitors of human cancer cell growth, less is known about their α-substituted counterparts. Recently, we synthesized a series of α-substituted tropolones including 2-hydroxy-7-(naphthalen-2-yl)cyclohepta-2,4,6-trien-1-one (α-naphthyl tropolone). Here, we evaluate the antiproliferative mechanisms of α-naphthyl tropolone and the related α-benzodioxinyl analog. The α-substituted tropolones inhibit growth of lymphocytic leukemia cells, but not healthy blood cells, with nanomolar potency. Treatment of leukemia cell lines with the tropolone dose-dependently induces apoptosis as judged by staining with annexin V and propidium iodide and Western blot analysis of cleaved caspase 3 and 7. Moreover, pre-treatment of cells with the caspase inhibitor Z-VAD-FMK inhibited the apoptotic effects of the tropolone in two lymphocytic lines. Caspase inhibition also blocked elevated histone acetylation caused by the tropolone, indicating that its effects on histone acetylation are potentiated by caspases. In contrast, α-naphthyl tropolone upregulated p53 expression and phosphorylation of Akt and mTOR in a manner that was not rescued by caspase inhibition. The effects of tropolone were blocked by co-incubation with high levels of free extracellular iron but not by pre-loading with iron. Additionally, dose and time dependent reduction in ex vivo viability of cells from leukemia patients was observed. Taken together, we demonstrate that α-substituted tropolones upregulate DNA damage repair pathways leading to caspase-dependent apoptosis in malignant lymphocytes.

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Section: Methodsmentioning

confidence: 99%

Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis

Jin

Falcone

Holstein

et al. 2016

Pharmacological Research

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“…HuT-78 and Molt-4 were cultured as described previously at 37 °C with 5% CO 2 . 47 HuT-78 cells were grown in Hyclone RPMI-1640 medium supplemented with 10% FBS and the addition of 1× penicillin/streptomycin. Molt-4 cells were grown in Hyclone RPMI-1640 medium supplemented with 10% fetal clone III.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

Gromek

deMayo

Maxwell

et al. 2016

Bioorganic & Medicinal Chemistry

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Santacruzamate A (SCA) is a natural product isolated from a Panamanian marine cyanobacterium, previously reported to have potent and selective histone deacetylase (HDAC) activity. To optimize the enzymatic and cellular activity, 40 SCA analogues were synthesized in a systematic exploration of the zinc-binding group (ZBG), cap terminus, and linker region. Two cap group analogues inhibited proliferation of MCF-7 breast cancer cells, with analogous increased degranulation of cytotoxic T cells (CTLs), while one cap group analogue reduced CTL degranulation, indicative of suppression of the immune response. Additional testing of these analogues resulted in reevaluation of the previously reported SCA mechanism of action. These analogues and the resulting structure-activity relationships will be of interest for future studies on cell proliferation and immune modulation.

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“…The reported sodium ethanethiolate deprotection of 13 was also unfruitful, as only the monodeprotected product was formed. A significant improvement was made through a two-step oxidative (AgO, HNO 3 )/ reductive (Pd/C, H 2 ) sequence, following the procedure reported by Wright et al 28 in the synthesis of (+)-frondosin A. Under these reaction conditions, the dihydroquinone 14 was obtained in 82% yield.…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis of (±)-Aureol by Bioinspired Rearrangements

et al. 2015

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Cyclopropene Cycloadditions with Annulated Furans: Total Synthesis of (+)- and (−)-Frondosin B and (+)-Frondosin A

Cited by 58 publications

References 45 publications

Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis

Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis

Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

Synthesis of (±)-Aureol by Bioinspired Rearrangements

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