4,5,6,7-Tetrahydro-isoxazolo-[4,5-c]-pyridines as a new class of cytotoxic Hsp90 inhibitors

Baruchello, Riccardo; Daniele, Simona; Marchetti, Paolo; Rondanin, Riccardo; Mangiola, Stefania; Costantini, Cristiana; Meli, Maria; Giannini, Giuseppe; Vesci, Loredana; Carollo, Valeria; Brunetti, Tiziana; Battistuzzi, Gianfranco; Tolomeo, Manlio; Cabri, Walter

doi:10.1016/j.ejmech.2014.01.056

Cited by 16 publications

(19 citation statements)

References 33 publications

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“…A derivative thereof, bearing a HA residue bound to the C-3 amide portion, blocks HSP90 and HDAC6 (Figure 2). Compound 29 is 500-fold more active against HDAC6 than against HDAC1 and cytotoxic against CML cells in the sub-micromolar range [63].…”

Section: Reviewmentioning

confidence: 99%

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Drugging the HDAC6–HSP90 interplay in malignant cells

Krämer

Mahboobi

Sellmer

2014

Trends in Pharmacological Sciences

117

128

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Section: Reviewmentioning

confidence: 99%

“…Nexturastat A [27], C1A [28] or 8b [32] are further examples for the most prominent group of inhibitors, containing a HA as ZBG (J -M). Compound 29, also bearing a HA as a ZBG has been designed as a chimeric, dual HSP90 and HDAC6 inhibitor [63] (M).…”

Section: Structure Of Hdaci and Achievement Of Specificity For Hdac6mentioning

confidence: 99%

Drugging the HDAC6–HSP90 interplay in malignant cells

Krämer

Mahboobi

Sellmer

2014

Trends in Pharmacological Sciences

117

128

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“…Some other synthetic compounds, including the derivatives used in the present study and containing an isoxazole nucleus, have recently shown potent and selective inhibition of HSP90 ( 12 , 13 ). The presence of the heterocyclic nucleus seems to exert an important role in the docking of these derivatives to the ATP-binding site of HSP90 ( 14 ).…”

Section: Introductionmentioning

confidence: 87%

Pro‑apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth <em>in vitro</em>

et al. 2020

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In order to develop potential anticancer agents stimulating apoptosis, novel 3,4-isoxazolediamide and 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]-pyridine derivatives have been synthetized. The original structures of geldanamycin and radicicol, which are known natural heat shock protein (HSP) inhibitors, were deeply modified because both of them exhibit several drawbacks, such as poor solubility, hepatotoxicity, intrinsic chemical instability or deprivation of the in vivo activity. This novel class of synthetic compounds containing the isoxazole nucleus exhibited potent and selective inhibition of HSP90 in previous studies. Biological assays (focusing on in vitro antiproliferative effects and pro-apoptotic activity) in human erythroleukemic K562 cells (as a model system referring to tumor cells grown in suspension), glioblastoma U251-MG and glioblastoma temozolomide (TMZ)-resistant T98G cell lines (two model systems referring to tumor cells grown attached to the flask), were performed. Almost all isoxazole derivatives demonstrated significant antiproliferative and pro-apoptotic activities, showing induction of both early and late apoptosis of K562 cells. Different effects were observed on the glioma U251-MG and T98G cells, depending on the structure of the analogues. Antiproliferative and pro-apoptotic activities in K562 cells were associated with the activation of the erythroid differentiation program. The present study demonstrated that 3,4-isoxazolediamide and 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]-pyridine derivatives should be considered for in vivo studies focusing on the development of anticancer drugs acting, at least partially, via activation of apoptosis.

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“…9) displayed high affinity and potent antiproliferative activity. Baruchello et al (2014) reported Hsp90 and HDAC6 inhibitory activity of 4,5,6,7-tetrahydro-isoxazolo-[4,5-c] pyridine compounds and evaluated for antiproliferative activity. The N-5 substitution with a 2,4-resorcinol carboxamide appeared to be crucial for activity.…”

Section: Biological Activitiesmentioning

confidence: 99%

The synthetic and therapeutic expedition of isoxazole and its analogs

2018

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Isoxazole, constituting an important family of five-membered heterocycles with one oxygen atom and one nitrogen atom at adjacent positions is of immense importance because of its wide spectrum of biological activities and therapeutic potential. It is, therefore, of prime importance that the development of new synthetic strategies and designing of new isoxazole derivatives should be based on the most recent knowledge emerging from the latest research. This review is an endeavor to highlight the progress in the chemistry and biological activity of isoxazole derivatives which could provide a low-height flying bird's eye view of isoxazole derivatives to the medicinal chemists for the development of clinically viable drugs using this information.

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4,5,6,7-Tetrahydro-isoxazolo-[4,5-c]-pyridines as a new class of cytotoxic Hsp90 inhibitors

Cited by 16 publications

References 33 publications

Drugging the HDAC6–HSP90 interplay in malignant cells

Drugging the HDAC6–HSP90 interplay in malignant cells

Pro‑apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth <em>in vitro</em>

The synthetic and therapeutic expedition of isoxazole and its analogs

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4,5,6,7-Tetrahydro-isoxazolo-[4,5-c]-pyridines as a new class of cytotoxic Hsp90 inhibitors

Cited by 16 publications

References 33 publications

Drugging the HDAC6–HSP90 interplay in malignant cells

Drugging the HDAC6–HSP90 interplay in malignant cells

Pro‑apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth <em>in&nbsp;vitro</em>

The synthetic and therapeutic expedition of isoxazole and its analogs

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Product

Resources

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Pro‑apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth <em>in vitro</em>