Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors

Musso, Loana; Cincinelli, Raffaella; Zuco, Valentina; Zunino, Franco; Nurisso, Alessandra; Cuendet, Muriel; Giannini, Giuseppe; Vesci, Loredana; Pisano, Claudio; Dallavalle, Sabrina

doi:10.1016/j.bmcl.2015.09.006

Cited by 14 publications

(9 citation statements)

References 30 publications

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“…We observed that compounds RN246 (%Ctr of 17.7% and 10.3% in #83 and #110 SC, respectively) and RN422 (%Ctr of 4.41% and -6.2% in #83 and #110 SC, respectively) displayed good activity, while in both the DCs we observed a very low cytotoxic activity. The syntheses of these compounds have been recently published [24,25]. The more efficient compounds able to kill 90% (%Ctr≤10%) of the stem like cells were the tyrosine kinases inhibitors: sunitinib (platelet derived growth factor receptor-PDGFR, vascular endothelial growth factor receptor-VEGFR), erlotinib (against the EGFR kinase) and dasatinib (against the bcrl/abl kinase), while we observed no activity with imatinib (against ABL, KIT, PDGFR kinases).…”

Section: Resultsmentioning

confidence: 68%

A High-throughput Screening of a Chemical Compound Library in Ovarian Cancer Stem Cells

Ricci

Carrassa

Christodoulou

et al. 2018

CCHTS

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Section: Resultsmentioning

confidence: 68%

A High-throughput Screening of a Chemical Compound Library in Ovarian Cancer Stem Cells

Ricci

Carrassa

Christodoulou

et al. 2018

CCHTS

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“…1 ). All of them are also being investigated for the treatment of different types of cancers as well as other diseases, as single agents and in combination therapies [2]. …”

Section: Introductionmentioning

confidence: 99%

Synthesis of ST7612AA1, a Novel Oral HDAC Inhibitor, via Radical Thioacetic Acid Addition

Battistuzzi

Giannini

2016

CBC

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BackgroundIn the expanding field of anticancer drugs, HDAC inhibitors are playing an increasingly important role. To date, four/five HDAC inhibitors have been approved by FDA. All these compounds fit the widely accepted HDAC inhibitors pharmacophore model characterized by a cap group, a linker chain and a zinc binding group (ZBG), able to bind the Zn2+ ion in a pocket of the HDAC active site. Romidepsin, a natural compound, is the only thiol derivative. We have selected a new class of synthetic HDAC inhibitors, the thio-ω(lactam-carboxamide) derivatives, with ST7612AA1 as drug candidate, pan-inhibitor active in the range of single- to two-digit nanomolar concentrations. Preliminary results of a synthetic optimization attempt towards a fast scale-up process are here proposed.MethodsIn the four steps of synthesis, from unsaturated amino acid intermediate to the final product, we explored different synthetic conditions in order to have a transferable process for a scale-up synthetic laboratory.ResultsIn the first step, isobutyl chloroformate was used and, after a simple work up with 1M HCl, 2 (96% yield) was obtained as a white solid, which was used directly in the next step. For thioacetic acid addition to the double bond of intermediate 2, two different routes were possible, with addition reaction in the first (D’) or last step (D). Reactions of 2 to give 5 or of 4 to give ST7612AA1 were both performed in dioxane. Reactions were fast and did not need the usually advised radical quenching with cyclohexene. The corresponding products were obtained in good yields (step D’, 89%; step D, 81%) after a flash chromatography.Conclusion: ST7612AA1, a thiol derivative prodrug of ST7464AA1, is the first of a new generation of HDAC inhibitors, very potent, orally administered, and well tolerated. Here, we have identified a synthetic route, competitive, versatile and easily transferable to industrial processes.

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“…[15] As part of an ongoing research program aimed at studying new histone deacetylase (HDAC) inhibitors, we have developed as eries of hydroxamic acidb ased compounds, characterized by ac innamic spacer capped with as ubstituted phenyl group (compound 1,F igure 1). [17] Among the analogues incorporating alternative ZBGs, we synthesized compound 2 containing af ive-membered cyclic hydroxamic acid. [17] Among the analogues incorporating alternative ZBGs, we synthesized compound 2 containing af ive-membered cyclic hydroxamic acid.…”

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confidence: 99%

“…[16] We recently initiated the search for zinc binding group (ZBG) functionalitiest hat could replace the hydroxamic acid group. [17] Unfortunately,c ompound 2 showedal ack of activity in terms of both HDAC inhibition (IC 50 > 5 mm on HDAC-2 from HeLa cells) and cell growth inhibition (IC 50 > 20 mm against apanel of tumor cell lines). [17] Unfortunately,c ompound 2 showedal ack of activity in terms of both HDAC inhibition (IC 50 > 5 mm on HDAC-2 from HeLa cells) and cell growth inhibition (IC 50 > 20 mm against apanel of tumor cell lines).…”

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confidence: 99%

“…[17] Among the analogues incorporating alternative ZBGs, we synthesized compound 2 containing af ive-membered cyclic hydroxamic acid. [17] Unfortunately,c ompound 2 showedal ack of activity in terms of both HDAC inhibition (IC 50 > 5 mm on HDAC-2 from HeLa cells) and cell growth inhibition (IC 50 > 20 mm against apanel of tumor cell lines). We therefore replaced the hydroxypyrrolidinone moiety with an N-hydroxyoxindole counterpart (compound 3a).…”

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3‐Arylidene‐N‐hydroxyoxindoles: A New Class of Compounds Endowed with Antitumor Activity

et al. 2016

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A series of compounds containing the N-hydroxyoxindole scaffold were synthesized and evaluated for antitumor activity. The compounds showed potent antiproliferative activity against the wild-type p53 IGROV-1 ovarian carcinoma cell line and considerably lower efficacy against the mutant IGROV-1/Pt1 subline that lacks p53 function. The differential response of ovarian carcinoma cells depending on p53 status was also reflected in the varied susceptibility to apoptosis of the treated cell lines. These results support a role for the p53 transcription factor as a determinant of cytotoxicity. The therapeutic potential of the most promising compound of the series was evaluated in the treatment of an IGROV-1 xenograft growing as ascitic tumor in mice. Using intraperitoneal administration, daily treatment with the compound for four weeks produced a significant delay in the onset of ascites.

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Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors

Cited by 14 publications

References 30 publications

A High-throughput Screening of a Chemical Compound Library in Ovarian Cancer Stem Cells

A High-throughput Screening of a Chemical Compound Library in Ovarian Cancer Stem Cells

Synthesis of ST7612AA1, a Novel Oral HDAC Inhibitor, via Radical Thioacetic Acid Addition

3‐Arylidene‐N‐hydroxyoxindoles: A New Class of Compounds Endowed with Antitumor Activity

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