Design, synthesis and preliminary evaluation of a series of histone deacetylase inhibitors carrying a benzodiazepine ring

Guandalini, Luca; Balliu, Manjola; Cellai, Cristina; Martino, Maria Vittoria; Nebbioso, Angela; Mercurio, Ciro; Carafa, Vincenzo; Bartolucci, Gianluca; Dei, Silvia; Manetti, Dina; Teodori, Elisabetta; Scapecchi, Serena; Altucci, Lucia; Paoletti, Francesco; Romanelli, Maria Novella

doi:10.1016/j.ejmech.2013.05.017

Cited by 17 publications

(12 citation statements)

References 26 publications

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“…The rationale for generating a series of BDZ‐hydroxamate hybrids with HDACi activity was previously described , and some specific properties of chiral compounds (S)‐8 and (R)‐8 (Fig. A) were reported in a recent medicinal chemistry study . Briefly, the 5‐phenyl‐1,4‐benzodiazepine ring containing a chiral centre in position three was used as the cap and joined with a suberoyl moiety ending with an hydroxamic function like that of SAHA .…”

Section: Resultsmentioning

confidence: 99%

“…Regarding SAHA and (S)‐8, these compounds carry the same suberoyl chain ending with an hydroxamic moiety such as the zinc‐chelating group but differ in the cap. SAHA has a small achiral hydrophilic anilido group, while in (S)‐8 there is a bulky lipophilic phenyl‐1,4‐benzodiazepine ring containing a chiral centre in position 3, which is important for activity . These structural differences may explain why the two HDACis display distinct pro‐apoptotic mechanisms in solid cancer models: SAHA‐mediated effects depend mainly on accumulation of ROS and are counteracted by antioxidants , while effects of (S)‐8 rely on activation of caspase cascade and hence are contrasted by pan‐caspase inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…The 1,4‐benzodiazepine ring (5‐phenyl‐1,3‐dihydro‐2‐oxo‐benzo[e][1,4]‐diazepine) was used as the cap of novel hydroxamic‐based HDACi . (S) and (R) N1‐hydroxy‐N8‐(1‐methyl‐2‐oxo‐5‐phenyl‐2,3‐dihydro‐1H‐benzo[e][1,4]‐diazepin‐3‐yl)octanediamide [(S)‐8] and [(R)‐8] were obtained as reported previously where they are labelled with the number 8. The chiral compounds (S)‐8 and (R)‐8 (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Compounds and reagents used in the study The 1, [16] where they are labelled with the number 8. The chiral compounds (S)-8 and (R)-8 ( Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we reported a series of new HDACi characterized by a 1,4‐benzodiazepine ring (BDZ) hybridized with either SAHA or oxamflatin to yield compounds capable of inducing H3/H4 histone acetylation in cell‐based‐assays; and especially one, termed (S)‐2, displayed interesting anticancer properties towards various subtypes of cultured and primary acute myeloid leukaemia cells and prostate adenocarcinoma cells . In the meantime, we kept screening BDZ‐hybrids against various cancer models and another compound, namely (S)‐8, has recently emerged during a medicinal chemistry study because of its high activity over a panel of cell‐based assays . The present work concern the effects of (S)‐8 against human metastatic melanoma cell lines derived from highly lethal neoplasms which are often resistant to most treatments .…”

Section: Introductionmentioning

confidence: 99%

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HDAC‐inhibitor (S)‐8 disrupts HDAC6‐PP1 complex prompting A375 melanoma cell growth arrest and apoptosis

Balliu

Guandalini

Romanelli

et al. 2014

J Cellular Molecular Medi

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Histone deacetylase inhibitors (HDACi) are agents capable of inducing growth arrest and apoptosis in different tumour cell types. Previously, we reported a series of novel HDACi obtained by hybridizing SAHA or oxamflatin with 1,4-benzodiazepines. Some of these hybrids proved effective against haematological and solid cancer cells and, above all, compound (S)-8 has emerged for its activities in various biological systems. Here, we describe the effectiveness of (S)-8 against highly metastatic human A375 melanoma cells by using normal PIG1 melanocytes as control. (S)-8 prompted: acetylation of histones H3/H4 and α-tubulin; G0/G1 and G2/M cell cycle arrest by rising p21 and hypophos-phorylated RB levels; apoptosis involving the cleavage of PARP and caspase 9, BAD protein augmentation and cytochrome c release; decrease in cell motility, invasiveness and pro-angiogenic potential as shown by results of wound-healing assay, down-regulation of MMP-2 and VEGF-A/VEGF-R2, besides TIMP-1/TIMP-2 up-regulation; and also intracellular accumulation of melanin and neutral lipids. The pan-caspase inhibitor Z-VAD-fmk, but not the antioxidant N-acetyl-cysteine, contrasted these events. Mechanistically, (S)-8 allows the disruption of cytoplasmic HDAC6-protein phosphatase 1 (PP1) complex in A375 cells thus releasing the active PP1 that dephosphorylates AKT and blocks its downstream pro-survival signalling. This view is consistent with results obtained by: inhibiting PP1 with Calyculin A; using PPP1R2-transfected cells with impaired PP1 activity; monitoring drug-induced HDAC6-PP1 complex re-shuffling; and, abrogating HDAC6 expression with specific siRNA. Altogether, (S)-8 proved very effective against melanoma A375 cells, but not normal melanocytes, and safe to normal mice thus offering attractive clinical prospects for treating this aggressive malignancy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Compounds and reagents used in the study The 1, [16] where they are labelled with the number 8. The chiral compounds (S)-8 and (R)-8 ( Fig.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

HDAC‐inhibitor (S)‐8 disrupts HDAC6‐PP1 complex prompting A375 melanoma cell growth arrest and apoptosis

Balliu

Guandalini

Romanelli

et al. 2014

J Cellular Molecular Medi

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Hydroxamates

2018

Privileged Structures in Drug Discovery

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Dual HDAC–BRD4 inhibitors endowed with antitumor and antihyperalgesic activity

et al. 2022

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Histone deacetylases (HDAC) are enzymes that regulate the concentration of acetylated histones which, in turns, interact with the bromodomain (BRD) of BET (Bromodomain and Extracellular domain) proteins to affect transcriptional activity. Simultaneous blockade of both epigenetic players has shown synergistic effects in a variety of cancer cell lines. In this paper we report the design, synthesis and activity of new dual inhibitors, obtained by adding a methyltriazole moiety to some HDAC inhibitors carrying a benzodiazepine core, which were previously developed by us. An Alphascreen FRET assay showed that the compounds were able to interact with BRD4-1 and BRD4-2 proteins, with some selectivity for the latter, while the HDAC inhibiting properties were measured by means of an immunoprecipitation assay. The antiproliferative activity was tested on C26 adenocarcinoma, SSMC2 melanoma and SHSY5Y neuroblastoma cells. Interestingly, both compounds were endowed with antihyperalgesic activity in the mouse Spared Nerve Injury (SNI) model.

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Design, synthesis and preliminary evaluation of a series of histone deacetylase inhibitors carrying a benzodiazepine ring

Cited by 17 publications

References 26 publications

HDAC‐inhibitor (S)‐8 disrupts HDAC6‐PP1 complex prompting A375 melanoma cell growth arrest and apoptosis

HDAC‐inhibitor (S)‐8 disrupts HDAC6‐PP1 complex prompting A375 melanoma cell growth arrest and apoptosis

Hydroxamates

Dual HDAC–BRD4 inhibitors endowed with antitumor and antihyperalgesic activity

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