- Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with DNA damage and apoptosis inducing abilities
-
A series of novel β-carboline-based hydroxamate derivatives (8a-n) as HDAC inhibitors have been designed and synthesized. Most of these compounds displayed potent histone deacetylase inhibitory effects and good antiproliferative activity with IC50/s
- Liu, Ji,Wang, Tingting,Wang, Xinyang,Luo, Lin,Guo, Jing,Peng, Yanfu,Xu, Qibing,Miao, Jiefei,Zhang, Yanan,Ling, Yong
-
-
Read Online
- Plasticity in designing PROTACs for selective and potent degradation of HDAC6
-
HDAC6 (histone deacetylase 6) catalyses the deacetylation of non-histone substrates, and plays important roles in cell migration, protein degradation and other cellular processes. Here we report that CRBN-recruiting PROTAC NH2, which introduces pomalidomi
- Yang, Haiyan,Lv, Wenxing,He, Ming,Deng, Haiteng,Li, Haitao,Wu, Wei,Rao, Yu
-
-
Read Online
- Reductive Amination Revisited: Reduction of Aldimines with Trichlorosilane Catalyzed by Dimethylformamide─Functional Group Tolerance, Scope, and Limitations
-
Aldimines, generated in situ from aliphatic, aromatic, and heteroaromatic aldehydes and aliphatic, aromatic, and heteroaromatic primary or secondary amines, can be reduced with trichlorosilane in the presence of dimethylformamide (DMF) as an organocatalys
- Campbell, Joanna L. P.,Davies, Christopher D.,Ho?ek, Jan,Ko?ovsky, Pavel,Kysilka, Ond?ej,Popov, Kirill K.,Pour, Milan
-
p. 920 - 943
(2022/01/27)
-
- SELECTIVE HISTONE DEACETYLASE 6 INHIBITORS
-
The present disclosure provides methods, pharmaceutical compositions, and kits comprising histone deacetylase (HD AC) inhibitors of formula I, or a pharmaceutically acceptable salt thereof, wherein R1, R2, L1, L2, m, n, p, X, Y, and Z are as defined in the specification, including methods of increasing the sensitivity of cancer cells to the cytotoxic effects of radiotherapy and/or chemotherapy in a subject.
- -
-
Page/Page column 0232-0233
(2022/01/01)
-
- Rational Design of Suprastat: A Novel Selective Histone Deacetylase 6 Inhibitor with the Ability to Potentiate Immunotherapy in Melanoma Models
-
Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using in silico simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms. In vitro characterization of Suprastat demonstrates subnanomolar HDAC6 inhibitory potency and a hundred- to a thousand-fold HDAC6 selectivity over the other HDAC isoforms. In vivo studies reveal that a combination of Suprastat and anti-PD1 immunotherapy enhances antitumor immune response, mediated by a decrease of protumoral M2 macrophages and increased infiltration of antitumor CD8+ effector and memory T-cells.
- Noonepalle, Satish,Shen, Sida,Ptá?ek, Jakub,Tavares, Maurício T.,Zhang, Guiping,Stránsky, Jan,Pavlí?ek, Ji?í,Ferreira, Glaucio M.,Hadley, Melissa,Pelaez, Guido,Ba?inka, Cyril,Kozikowski, Alan P.,Villagra, Alejandro
-
p. 10246 - 10262
(2020/11/02)
-
- Synthesis and Pharmacological Evaluation of Selective Histone Deacetylase 6 Inhibitors in Melanoma Models
-
Only a handful of therapies offer significant improvement in the overall survival in cases of melanoma, a cancer whose incidence has continued to rise in the past 30 years. In our effort to identify potent and isoform-selective histone deacetylase (HDAC) inhibitors as a therapeutic approach to melanoma, a series of new HDAC6 inhibitors based on the nexturastat A scaffold were prepared. The new analogues 4d, 4e, and 7b bearing added hydrophilic substituents, so as to establish additional hydrogen bonding on the rim of the HDAC6 catalytic pocket, exhibit improved potency against HDAC6 and retain selectivity over HDAC1. Compound 4d exhibits antiproliferative effects on several types of melanoma and lymphoma cells. Further studies indicates that 4d selectively increases acetylated tubulin levels in vitro and elicits an immune response through down-regulating cytokine IL-10. A preliminary in vivo efficacy study indicates that 4d possesses improved capability to inhibit melanoma tumor growth and that this effect is based on the regulation of inflammatory and immune responses.
- Tavares, Maurício T.,Shen, Sida,Knox, Tessa,Hadley, Melissa,Kutil, Zsófia,Ba?inka, Cyril,Villagra, Alejandro,Kozikowski, Alan P.
-
supporting information
p. 1031 - 1036
(2017/10/18)
-
- 1,3,4-OXADIAZOLE DERIVATIVE COMPOUNDS AS HISTONE DEACETYLASE 6 INHIBITOR, AND THE PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
-
The present invention relates to novel compounds having histone deacetylase 6 (HDAC6) in-hibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, the use thereof for the preparation of therapeutic medicaments, pharmaceutical compositions containing the same, a method for treating diseases using the composition, and methods for preparing the novel compounds. The novel compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof according to the present invention have histone deacetylase (HDAC) inhibitory activity and are effective for the prevention or treatment of HDAC6-mediated diseases, including infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and be-havioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; diseases of the musculoskeletal system and connective tissue; or congenital malformations, de? formations and chromosomal abnormalities.
- -
-
Paragraph 2962-2964
(2017/02/28)
-
- Design and Synthesis of C3-Substituted β-Carboline-Based Histone Deacetylase Inhibitors with Potent Antitumor Activities
-
A series of hydroxamic acid histone deacetylase (HDAC) inhibitors in which the β-carboline motif has been incorporated were designed and synthesized. The effect of substitution at the C3 amide on HDAC inhibition and antiproliferative activities was invest
- Ling, Yong,Feng, Jiao,Luo, Lin,Guo, Jing,Peng, Yanfu,Wang, Tingting,Ge, Xiang,Xu, Qibing,Wang, Xinyang,Dai, Hong,Zhang, Yanan
-
p. 646 - 651
(2017/05/15)
-
- SELECTIVE HISTONE DEACTYLASE 6 INHIBITORS
-
Disclosed are selective histone deactylase inhibitors (HDACi) that having Formula I. Specifically, the disclosed subject matter relates to compounds having activity as selective HDAC6 inhibitors, methods of making and using the compounds, and compositions comprising the compounds. In still further aspects, the disclosed subject matter relates to methods for treating oncological disorders in a patient. Methods of making and using these inhibitors for the treatment of cancer, in particular melanoma are also disclosed.
- -
-
Page/Page column 42; 43
(2015/02/25)
-
- SELECTIVE HISTONE DEACTYLASE 6 INHIBITORS
-
Disclosed are selective histone deactylase inhibitors (HDACi) that having Formula (I). Methods of making and using these inhibitors for the treatment of cancer, in particular melanoma are also disclosed.
- -
-
Page/Page column 36
(2013/09/26)
-
- Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth
-
The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ~600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.
- Bergman, Joel A.,Woan, Karrune,Perez-Villarroel, Patricio,Villagra, Alejandro,Sotomayor, Eduardo M.,Kozikowski, Alan P.
-
p. 9891 - 9899
(2013/01/16)
-