Design, synthesis and biological evaluation of novel HDAC inhibitors with improved pharmacokinetic profile in breast cancer

Yao, Dahong; Li, Chenyang; Jiang, Jin; Huang, Jian; Wang, Jinhui; He, Zhendan; Zhang, Jin

doi:10.1016/j.ejmech.2020.112648

Cited by 31 publications

(11 citation statements)

References 27 publications

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“…Gold score protocol was used as the score function, and the other parameters were set as default. The results were processed by PyMoL …”

Section: Methodsmentioning

confidence: 99%

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Discovery of Anti-TNBC Agents Targeting PTP1B: Total Synthesis, Structure–Activity Relationship, In Vitro and In Vivo Investigations of Jamunones

et al. 2021

J. Med. Chem.

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Twenty-three natural jamunone analogues along with a series of jamunone-based derivatives were synthesized and evaluated for their inhibitory effects against breast cancer (BC) MDA-MB-231 and MCF-7 cells. The preliminary structure− activity relationship revealed that the length of aliphatic side chain and free phenolic hydroxyl group at the scaffold played a vital role in anti-BC activities and the methyl group on chromanone affected the selectivity of molecules against MDA-MB-231 and MCF-7 cells. Among them, jamunone M (JM) was screened as the most effective anti-triple-negative breast cancer (anti-TNBC) candidate with a high selectivity against BC cells over normal human cells. Mechanistic investigations indicated that JM could induce mitochondria-mediated apoptosis and cause G0/G1 phase arrest in BC cells. Furthermore, JM significantly restrained tumor growth in MDA-MB-231 xenograft mice without apparent toxicity. Interestingly, JM could downregulate phosphatidylinositide 3kinase (PI3K)/Akt pathway by suppressing protein-tyrosine phosphatase 1B (PTP1B) expression. These findings revealed the potential of JM as an appealing therapeutic drug candidate for TNBC.

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“…Gold score protocol was used as the score function, and the other parameters were set as default. The results were processed by PyMoL …”

Section: Methodsmentioning

confidence: 99%

“…The results were processed by PyMoL. 55 Western Blotting Analysis. The in vitro effect of JM on protein expression was examined in MDA-MB-231 and MCF-7 cells.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Discovery of Anti-TNBC Agents Targeting PTP1B: Total Synthesis, Structure–Activity Relationship, In Vitro and In Vivo Investigations of Jamunones

et al. 2021

J. Med. Chem.

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“…Class-IIb HDAC inhibitors were identified in a research study aimed to ameliorate the Vorinostat pharmacokinetic profile [37]. Indeed, this molecule has a very short half-life in humans (21-58 min), and the main metabolic biotransformation comprise glucuronidation, alkyl chain β-oxidation, and hydrolysis of both hydroxamate and amide moieties [38].…”

Section: Hydroxamatesmentioning

confidence: 99%

HDAC Inhibitors for the Therapy of Triple Negative Breast Cancer

et al. 2022

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Triple negative breast cancer (TNBC) is an urgent as well as huge medical challenge, which is associated with poor prognosis and responsiveness to chemotherapies. Since epigenetic changes are highly implicated in TNBC tumorigenesis and development, inhibitors of histone deacetylases (HDACIs) could represent a promising therapeutic strategy. Although clinical trials involving single HDACIs showed disappointing results against TNBC, recent studies emphasize the high potential impact of HDACIs in controlling TNBC. In addition, encouraging results stem from new compounds designed to obtain isoform selectivity and/or polypharmacological HDAC approach. The present review provides a discussion of the HDACIs pharmacophoric models and of the structural modifications, leading to compounds with a potent activity against TNBC progression.

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“…A series of novel histone deacetylase inhibitors using a substituted quinazoline was designed and synthesized as the capping group, attaching 3, 5-dimethyl pentyl as a potential metabolic site protector. One of representatives was proposed as an oral histone deacetylase inhibitor with a potential capacity of treating breast cancer [22]. There is evidence indicating that novel 1,2,3-triazole-quinazolines can be used as anti-proliferative agents displaying the extracellular signal-regulated kinase inhibitory activity [23].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of cerebroprotective activity of novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives containing residues of amino acids and dipeptides

2022

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Neurodegenerative processes of the central nervous system are an important socially significant problem of modern society. They cause many diseases, such as Alzheimer's disease and cerebral ischemia, which significantly reduce the quality of human life and can lead to disability or death. The aim of this study was to synthesize novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives with the remains of neuroactive amino acids and dipeptides in order to investigate their cerebroprotective properties. As a result of the study, 13 novel 6,7-dimetho-xyquinazolin-4(3H)-one derivatives were synthesized. Cerebral ischemia in rats was reproduced by irreversible right-sided occlusion of the middle cerebral artery using the Tamura method, and the area of brain necrosis was evaluated. Cognitive functions were evaluated in the Y-maze test. Among the studied quinazolinone derivatives, compounds 3i, 3j and 3k have the most pronounced cerebrotropic activity, which is not inferior to ethylmethylhydroxypyridine succinate in terms of pharmacological activity, making them promising objects for further research.

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Design, synthesis and biological evaluation of novel HDAC inhibitors with improved pharmacokinetic profile in breast cancer

Cited by 31 publications

References 27 publications

Discovery of Anti-TNBC Agents Targeting PTP1B: Total Synthesis, Structure–Activity Relationship, In Vitro and In Vivo Investigations of Jamunones

Discovery of Anti-TNBC Agents Targeting PTP1B: Total Synthesis, Structure–Activity Relationship, In Vitro and In Vivo Investigations of Jamunones

HDAC Inhibitors for the Therapy of Triple Negative Breast Cancer

Synthesis and evaluation of cerebroprotective activity of novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives containing residues of amino acids and dipeptides

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