Design, synthesis, and evaluation of isoindolinone-hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors

Lee, Shoukou; Shinji, Chihiro; Ogura, Kiyoshi; Shimizu, Motomu; Maeda, Satoko; Sato, Minoru; Yoshida, Minoru; Hashimoto, Yuichi; Miyachi, Hiroyuki

doi:10.1016/j.bmcl.2007.06.038

Cited by 49 publications

(17 citation statements)

References 21 publications

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“…synthesized and evaluated hydroxamic acid derivatives, bearing a 4-(3-pyridyl)phenyl group as a cap structure which exhibited potent HDAC inhibitory activity. [6]…”

Section: Hydroxamic Acid As Anticancermentioning

confidence: 99%

Hydroxamic acid - A novel molecule for anticancer therapy

Pal¹,

Saha²

2012

J Adv Pharm Technol Res

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Hydroxamic acid is a potent moiety not only in the field of cancer therapy but also as a mutagenic agent. Among the various derivatives of hydroxamic acid, SAHA (Suberoylanilide Hydroxamic Acid) is considered as a potent anticancer agent. Scientists from the different corner synthesized different hydroxamic acid moieties with some straight chain oxazole, thiadiazole, biphenyl moieties in the terminal position. Acetylation and deacetylation of histones of the core proteins of nucleosomes in chromatin play an important role in the regulation of gene expression. The level of acetylation of histones is established and maintained by two classes of enzymes, histone acetyltransferase and histone deacetylases, which have been identified as transcriptional coactivators and transcriptional corepressors, respectively. There is increasing evidence that aberrant histone acetylation has been linked to various malignant diseases. Great efforts are currently underway for the design of more potent and less toxic candidates for the treatment of cancer. In recent years, hydroxamic acid derivatives have attracted increasing attention for their potential as highly efficacious in combating various etiological factors associated with cancer. Our main intention to draw an attention is that this single functional moiety has not only fit in the receptor but also create a diversified activity.

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“…synthesized and evaluated hydroxamic acid derivatives, bearing a 4-(3-pyridyl)phenyl group as a cap structure which exhibited potent HDAC inhibitory activity. [6]…”

Section: Hydroxamic Acid As Anticancermentioning

confidence: 99%

Hydroxamic acid - A novel molecule for anticancer therapy

Pal¹,

Saha²

2012

J Adv Pharm Technol Res

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“…These compounds possess a lot of pharmacological activities such as anxiolytic/anticonvulsant, TNFα-inhibitory, antiangiogenic, 5-HT antagonistic/antidepressant [26–30], PARP-1-inhibitory [31], histone deacetylase inhibitory [32] and cytotoxic activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

Giofrè¹,

Cirmi²,

Mancuso³

et al. 2016

Beilstein J. Org. Chem.

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A series of spiro[isoindole-1,5-isoxazolidin]-3(2H)-ones has been synthesized by 1,3-dipolar cycloaddition of N-benzylnitrone with isoindolin-3-methylene-1-ones. The regio- and stereoselectivity of the process have been rationalized by computational methods. The obtained compounds show cytotoxic properties and antiproliferative activity in the range of 9–22 μM. Biological tests suggest that the antitumor activity could be linked to the inhibition of the protein–protein p53-MDM2 interaction. Docking measurements support the biological data.

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“…Among these, there are compounds with acetylenic and phthalimide groups, as well as isoindoline‐1,3‐diones. Regarding the last ones, isoindoline heterocycles have demonstrated potential in medicinal chemistry as they exhibit activity toward diverse biological targets, such as selective ER‐β (estrogen receptor) ligands , selective ETA (endothelin‐A) antagonists , agents for various purposes including reducing inflammatory cytokine levels , reducing tumor necrosis factor α (TNF‐α) levels , blocking α‐adrenergic receptor , as HDAC (histone deacetylase) inhibitors , as multidrug resistance reversal agents , and as anticonvulsant agents . Therefore, they have been used in the treatment of diverse diseases such as Alzheimer's disease and anxiety disorders , osteoporosis , cardiovascular diseases , rheumatoid arthritis, inflammation , autoimmune disease , and cancer .…”

Section: Introductionmentioning

confidence: 99%

Isoindoline Derivatives of α‐Amino Acids as Cyclooxygenase 1 and 2 Inhibitors

Percino

Trejo-Muñoz

Díaz-Gandarilla

et al. 2016

Archiv der Pharmazie

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IC50 values were obtained for two series of isoindolines derived from α-amino acids over cyclooxygenase 1 and 2 (COX-1 and COX-2). In order to explain the biological activity observed, a structure-activity relationship (SAR) model was achieved for the tested compounds and 19 reference compounds with known selective inhibitory activity, through the correlation of the binding energies calculated from rigid docking of the best conformations into the catalytic sites of COX-1 and COX-2, as well as their molecular descriptors: Log P, molecular weight (MW), volume (V), and solvation energy (Esol) versus their experimental IC50 values by MLR and LS-SVM methods. The model probed whether the COX-1 and COX-2 inhibitory activities of the isoindolines correlate with steric, hydrophobic, and thermodynamic parameters. The correlation values with MLR for COX-1 and COX-2 (r(2) = 0.4193 and r(2) = 0.5929) were optimized with LS-SVM until r(2) = 0.6818 for COX-1 and r(2) = 0.8985 for COX-2, resulting in a good predictive ability for COX-1 and -2 inhibition with this model. In conclusion, the data suggests that the physicochemical descriptors evaluated have an impact on the inhibitory activity and selectivity of isoindolines over COX-1 and COX-2.

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Design, synthesis, and evaluation of isoindolinone-hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors

Cited by 49 publications

References 21 publications

Hydroxamic acid - A novel molecule for anticancer therapy

Hydroxamic acid - A novel molecule for anticancer therapy

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

Isoindoline Derivatives of α‐Amino Acids as Cyclooxygenase 1 and 2 Inhibitors

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