Design and synthesis of phthalimide-type histone deacetylase inhibitors

Shinji, Chihiro; Nakamura, Takanori; Maeda, Satoko; Yoshida, Minoru; Hashimoto, Yuichi; Miyachi, Hiroyuki

doi:10.1016/j.bmcl.2005.07.048

Cited by 50 publications

(27 citation statements)

References 32 publications

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“…(1)), an example of such a molecule, inhibited partially purified HDAC1, 4 and 6 in vitro with IC 50 values of 190, 150 and 250 nM, respectively; demonstrated higher growth inhibition (IC 50 = 75 nM) of the LNCaP human prostate cancer cell line than SAHA; and strongly induced the p21 promoter [23]. Structurally similar, though less potent, phthalimide-type compounds were reported earlier by the same authors [24]. Topotarget has also disclosed a set of hydroxyacrylamides bearing a bicyclic heteroaryl core with potential for the treatment of cancer, psoriasis, neurodegenerative, and inflammatory diseases, as well as fungal, parasitic, bacterial and viral infections [25].…”

Section: N-hydroxyacrylamidessupporting

confidence: 68%

Histone Deacetylase Inhibitors in Cancer Therapy: New Compounds and Clinical Update of Benzamide-Type Agents

Moradei¹,

Vaisburg²,

Martell³

2008

CTMC

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Histone deacetylase (HDAC) inhibitors constitute a novel and growing class of anticancer agents that function by altering intracellular patterns of histone acetylation, the so-called epigenetic "histone code," thereby producing changes in cell cycle arrest, differentiation, and/or apoptosis in tumor cells. This overview describes the chemistry and preliminary characterization of recently disclosed molecules in three major classes of HDAC inhibitors: hydroxamic acids, 2-amino- benzanilides, and cyclic peptides. In addition, results from recent clinical trials on isotype-selective HDAC inhibitors are reviewed. It is clear from the plethora of new molecules and the encouraging results from clinical trials that HDAC inhibitors hold a great deal of promise, particularly as add-on therapy, for the treatment of a variety of solid and hematologic cancers.

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Section: N-hydroxyacrylamidessupporting

confidence: 68%

Histone Deacetylase Inhibitors in Cancer Therapy: New Compounds and Clinical Update of Benzamide-Type Agents

Moradei¹,

Vaisburg²,

Martell³

2008

CTMC

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“…As mentioned above, we have derived various kinds of biologically active compounds derived from thalidomide (1) (Fig. 1) [18,20,[51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70]. In the course of those studies, we noticed that a 2,6-diisopropylphenylphthalimide skeleton was often a good substitute for a thalidomide skeleton.…”

Section: Structural Development Of Tubulin Polymerization Inhibitors mentioning

confidence: 99%

“…Various biologically active compounds have been developed, including TNF-production regulators (including bidirectional ones, pure inhibitors, and pure enhancers) [51,52], androgen antagonists [53][54][55], aminopeptidase inhibitors [56][57][58], -glucosidase inhibitors [59,60], thymidine phosphorylase inhibitors [61], COX inhibitors [27,[61][62][63], nitric oxide synthase (NOS) inhibitors [64,65], histone deacetylase (HDAC) inhibitors [66,67], antiangiogenic agents [68,69], and cell differentiation inducers [70]. As shown in Fig.…”

Section: Thalidomide As a Multi-template For Devel-opment Of Biologicmentioning

confidence: 99%

New Tubulin Polymerization Inhibitor Derived from Thalidomide: Implications for Anti-Myeloma Therapy

Kizaki¹,

Hashimoto²

2008

CMC

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Despite the conventional and high-dose chemotherapy with hematopoietic stem cell transplantation, multiple myeloma eventually relapses, resulting in an incurable hematological malignancy. Therefore, novel therapeutic approaches in clinical settings are desired. Recently, thalidomide was introduced for the treatment of myeloma, and many clinical trials have since confirmed its efficacy in patients with relapsed/refractory or newly diagnosed multiple myeloma. Multiple mechanisms have been proposed to explain thalidomide's anti-myeloma activity. However, the precise mechanism underlying this activity remains unclear, because thalidomide rapidly undergoes spontaneous, nonenzymatic, hydrolytic cleavage to numerous metabolites in vivo. To elucidate the exact anti-myeloma mechanism of thalidomide in vivo, we have performed structural development studies of thalidomide, and obtained various analogs with specific molecular properties. Among these derivatives, we found that a new thalidomide analog, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33), has the most potent anti-myeloma effect with tubulin polymerization inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cells in a dose-dependent manner with IC(50) of 1-10 microM. In contrast, thalidomide itself did not inhibit RPMI8226 cell growth. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 had potent tubulin polymerization inhibiting activity with IC(50) of 8.1 microM, comparable to that of rhizoxin, a known tubulin polymerization inhibitor. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Our data suggest that 5HPP-33 is a promising candidate as a therapeutic agent for multiple myeloma. In addition, the results suggest that thalidomide's tubulin polymerization inhibiting activity might be the mechanism underlying the induction of apoptosis in myeloma cells.

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“…Several ongoing NIH trials are investigating the use of these agents in combination with potent chemotherapeutic agents, aiming at increasing their therapeutic efficiency [4,35]. In addition, several phthalimide-type HDAC inhibitors, prepared during structural developmental studies based on thalidomide, are under investigation [89]. Thalidomide itself is being tried for the treatment of advanced colorectal cancer within a clinical trial by the United States National Cancer Institute: information can be found at their website (http:// www.cancer.gov/cancer_information).…”

Section: Perspectivesmentioning

confidence: 99%

Histone deacetylase inhibitors as a potential therapeutic agent for human cancer treatment

2006

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Recent evidence pointed that remodeling of the chromatin template by inhibition of the enzyme histone deacetylase could be a promising approach for the treatment of human cancer. Alterations in histone acetylation may lead to changes in chromatin structure and transcriptional dysregulation of genes that are implicated in controlling cell cycle progression or pathways regulating cell differentiation and apoptosis. The histone deacetylase (HDAC) inhibitors are currently a new class of antineoplastic agents. They bind DNA tightly to histones, preventing the transcription of several tumor suppression genes without modifying DNA sequence. At present, there are already too many HDAC inhibitors available and hopefully some of them could help substantially in the prevention and treatment of cancer. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to be becoming possible. Several ongoing National Institute of Health (NIH) trials are investigating the use of these agents in combination with potent chemotherapeutic agents, with the aim of increasing their efficiency. Further studies are needed to delineate the optimal dosage, the duration of therapy and possibly the efficacy of other agents able to synergize with HDAC inhibitors in the fight against cancer.

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Design and synthesis of phthalimide-type histone deacetylase inhibitors

Cited by 50 publications

References 32 publications

Histone Deacetylase Inhibitors in Cancer Therapy: New Compounds and Clinical Update of Benzamide-Type Agents

Histone Deacetylase Inhibitors in Cancer Therapy: New Compounds and Clinical Update of Benzamide-Type Agents

New Tubulin Polymerization Inhibitor Derived from Thalidomide: Implications for Anti-Myeloma Therapy

Histone deacetylase inhibitors as a potential therapeutic agent for human cancer treatment

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