Solid phase-assisted synthesis and screening of a small library of N-(4-hydroxyphenyl)retinamide (4-HPR) analogs

Mershon, Serena M.; Anding, Allyson L.; Chapman, Jason S.; Clagett‐Dame, Margaret; Stonerock, Laura A.; Curley, Robert W.

doi:10.1016/j.bmcl.2006.10.050

Cited by 20 publications

(18 citation statements)

References 18 publications

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“…42) were used. The MC2678 and -2677 compounds do not display HDAC inhibition (data not shown) and MC2677 has been previously described to inhibit the growth of a number of tumor cell lines, including prostate, head and neck, squamous carcinoma, and neuroblastoma (42,43). In contrast to MC2392 and MS-275, MC2678 and MC2677 are unable to induce a proliferation arrest of NB4 cells (Fig.…”

Section: Mc2392 Induces Cell Death In Apl Cellsmentioning

confidence: 74%

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

et al. 2014

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HDAC inhibitors (HDACi) are widely used in the clinic to sensitize tumorigenic cells for treatment with other anticancer compounds. The major drawback of HDACi is the broad inhibition of the plethora of HDAC-containing complexes. In acute promyelocytic leukemia (APL), repression by the PML-RARa oncofusion protein is mediated by an HDAC-containing complex that can be dissociated by pharmacologic doses of all trans retinoic acid (ATRA) inducing differentiation and cell death at the expense of side effects and recurrence. We hypothesized that the context-specific close physical proximity of a retinoid and HDACi-binding protein in the repressive PML-RARa-HDAC complex may permit selective targeting by a hybrid molecule of ATRA with a 2-aminoanilide tail of the HDAC inhibitor MS-275, yielding MC2392. We show that MC2392 elicits weak ATRA and essentially no HDACi activity in vitro or in vivo. Genome-wide epigenetic analyses revealed that in NB4 cells expressing PML-RARa, MC2392 induces changes in H3 acetylation at a small subset of PML-RARa-binding sites. RNA-seq reveals that MC2392 alters expression of a number of stress-responsive and apoptotic genes. Concordantly, MC2392 induced rapid and massive, caspase-8-dependent cell death accompanied by RIP1 induction and ROS production. Solid and leukemic tumors are not affected by MC2392, but expression of PML-RARa conveys efficient MC2392-induced cell death. Our data suggest a model in which MC2392 binds to the RARa moiety and selectively inhibits the HDACs resident in the repressive complex responsible for the transcriptional impairment in APLs. Our findings provide proof-of-principle of the concept of a context-dependent targeted therapy. Cancer Res; 74(8); 2328-39. Ó2014 AACR.

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Section: Mc2392 Induces Cell Death In Apl Cellsmentioning

confidence: 74%

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

et al. 2014

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“…The 4-HPR metabolites 4-oxo-4-HPR and 4-MPR were prepared as described previously (11,12). The yellow solid 4-oxo-4-MPR was synthesized analogously to 4-oxo-4-HPR by reaction of 4-methoxyaniline with 4-oxoretinoic acid activated as its acid chloride: UV (methanol) max 376 nm (⑀ 60,000); 1 and a 250 ϫ 4.6 mm Ultrasphere ODS column with 85% methanol/water at 1 ml/min showed a retention time of 7 min with a minor amount (6%) of the 13-cis isomer at 5.8 min and no other impurities.…”

Section: Methodsmentioning

confidence: 99%

Identification of Dihydroceramide Desaturase as a Direct in Vitro Target for Fenretinide

Rahmaniyan

Curley

Obeid

et al. 2011

Journal of Biological Chemistry

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110

114

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The dihydroceramide desaturase (DES) enzyme is responsible for inserting the 4,5-trans-double bond to the sphingolipid backbone of dihydroceramide. We previously demonstrated that fenretinide (4-HPR) inhibited DES activity in SMS-KCNR neuroblastoma cells. In this study, we investigated whether 4-HPR acted directly on the enzyme in vitro. N-C8:0-D-erythrodihydroceramide (C 8 -dhCer) was used as a substrate to study the conversion of dihydroceramide into ceramide in vitro using rat liver microsomes, and the formation of tritiated water after the addition of the tritiated substrate was detected and used to measure DES activity. NADH served as a cofactor Sphingolipids are known to be modulators of various cell functions. They are not only components of cell membranes but also play a role in cell survival, apoptosis, senescence, and differentiation (1, 2). Ceramide, a central molecule in the metabolism of sphingolipids and glycosphingolipids, is involved in these regulatory cellular events. Intracellulary, ceramide is generated by different pathways. De novo synthesis of ceramide starts with condensation of L-serine with palmitoylCoA. Further reduction and subsequent N-acylation generates dihydroceramide. Ceramide is finally generated by introduction of the 4,5-double bond into dihydroceramide by dihydroceramide desaturase (DES) 2 (3). The DES enzyme was characterized previously, and an in vitro assay was developed to determine its activity (4). In subsequent studies, a family of sphingolipid ⌬4-desaturases (homologs of the Drosophila melanogaster degenerative spermatocyte gene 1 (des-1)) were identified via a bioinformatics approach (5). These proteins contain three His-containing consensus motifs that are characteristic of a group of membrane fatty acid desaturases. The human homolog of des-1 is now referred to as DEGS-1, although it was first cloned in 1997 and named as membrane lipid desaturase because its physiologic substrate was not determined at the time (6). DEGS-1 is the only dihydroceramide desaturase reported to be present in human cells, and its mouse homolog (mDES1) was shown to have desaturase activity (7). hDES2, the human homolog of the mouse DES2 (mDes2) gene, like mDES2 has dihydroceramide hydroxylase activity (8). Although mDES2 has been reported to have both desaturase and hydroxylase activity, no desaturase activity was detected in HEK 293 human embryonic kidney cells overexpressing hDES2 (8). In this work, we refer to enzyme as DES in experiments with rat liver microsomes and as DEGS-1 in experiments with human SMS-KCNR cells.We previously developed an assay to evaluate the in situ activity of DEGS-1 using cell-permeable dihydroceramidoids (dhCCPS analogs) (9). We showed in these studies that the

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“…Fenretinide (4 hydroxypropyl phenyl retinamide, 4HPR) is a synthetic amide derivative of all-trans-retinoic acid [33,34] applied in the chemoprevention and in the treatment of many types of malignancies including neuroblastoma, breast, prostate and pancreas cancers. Moreover 4HPR has been proposed for the treatment of many skin tumours (e.g.…”

Section: Introductionmentioning

confidence: 99%

Gelified reverse micellar dispersions as percutaneous formulations

Esposito

Ravani

Mariani

et al. 2016

Journal of Drug Delivery Science and Technology

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Solid phase-assisted synthesis and screening of a small library of N-(4-hydroxyphenyl)retinamide (4-HPR) analogs

Cited by 20 publications

References 18 publications

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

Identification of Dihydroceramide Desaturase as a Direct in Vitro Target for Fenretinide

Gelified reverse micellar dispersions as percutaneous formulations

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