The Effect of Vicinal Difluorination on the Conformation and Potency of Histone Deacetylase Inhibitors

Ariawan, A. Daryl; Mansour, F. A.; Richardson, Nicole L.; Bhadbhade, Mohan; Ho, Junming; Hunter, Luke

doi:10.3390/molecules26133974

Cited by 4 publications

(7 citation statements)

References 30 publications

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“…In the paper by Ariawan et al [ 42 ], the effect of vicinal difluorination in the chemical structure of the hydroxamate-based HDACis vorinostat and scriptaid was investigated ( Scheme 11 ). The authors found that the introduction of fluorine substituents does not have a positive effect on the potency to inhibit HDAC.…”

Section: Biological Significance and Purpose Of Fluorination In Hdacismentioning

confidence: 99%

“…Even though liquids are easier to handle than gases, it can be considered a disadvantage to work with liquid reagents compared to solids as an alternative. The DexoFluor used for the synthesis of HDACis in the work of Ariawan et al [ 42 ] is subject to this limitation to a certain extent. Fortunately, crystalline solids have now also been described as an improvement on DeoxoFluor for deoxyfluorination [ 97 ].…”

Section: Issues Of Fluorinationmentioning

confidence: 99%

“…A potential strategy for attaching fluorine atoms to the linker chain of difluorinated SAHA analogues was published by Ariawan et al [ 42 ]. Several methods exist to introduce two fluorine atoms into hydroxamic acids ( Scheme 11 ).…”

Section: Introduction Of the Chemical Modification Generating Fluorin...mentioning

confidence: 99%

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The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

et al. 2023

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In recent years, histone deacetylases (HDACs) have emerged as promising targets in the treatment of cancer. The approach is to inhibit HDACs with drugs known as HDAC inhibitors (HDACis). Such HDACis are broadly classified according to their chemical structure, e.g., hydroxamic acids, benzamides, thiols, short-chain fatty acids, and cyclic peptides. Fluorination plays an important role in the medicinal–chemical design of new active representatives. As a result of the introduction of fluorine into the chemical structure, parameters such as potency or selectivity towards isoforms of HDACs can be increased. However, the impact of fluorination cannot always be clearly deduced. Nevertheless, a change in lipophilicity and, hence, solubility, as well as permeability, can influence the potency. The selectivity towards certain HDACs isoforms can be explained by special interactions of fluorinated compounds with the structure of the slightly different enzymes. Another aspect is that for a more detailed investigation of newly synthesized fluorine-containing active compounds, fluorination is often used for the purpose of labeling. Aside from the isotope 19F, which can be detected by nuclear magnetic resonance spectroscopy, the positron emission tomo-graphy of 18F plays a major role. However, to our best knowledge, a survey of the general effects of fluorination on HDACis development is lacking in the literature to date. Therefore, the aim of this review is to highlight the introduction of fluorine in the course of chemical synthesis and the impact on biological activity, using selected examples of recently developed fluorinated HDACis.

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Section: Biological Significance and Purpose Of Fluorination In Hdacismentioning

confidence: 99%

Section: Issues Of Fluorinationmentioning

confidence: 99%

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The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

et al. 2023

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“… 9 , 10 One key advantage of HDAC is their relatively lower rate of side effects. Moreover, most side effects associated with HDAC inhibitors are primarily observed with pan-HDAC inhibitors, 11 indicating that subtype-selective HDAC inhibitor may have fewer adverse effects. Tucidinostat, an oral subtype-selective HDAC inhibitor, received approval from the National Medical Products Administration in China in November 2019 for use in combination with aromatase inhibitors in postmenopausal patients with locally advanced or metastatic breast cancer who have experienced relapse or progression on endocrine therapy.…”

Section: Introductionmentioning

confidence: 99%

Tucidinostat Plus Exemestane as a Neoadjuvant in Early-Stage, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer

Zhao,

Li,

et al. 2024

The Oncologist

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Background To assess the efficacy and safety of tucidinostat plus exemestane as a neoadjuvant strategy in early-stage breast cancer. Methods This prospective, open-label, single-arm phase II trial enrolled patients with stage II-III breast cancer with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative. Eligible patients received tucidinostat plus exemestane, and then breast-conserving surgery (BCS) or modified radical mastectomy. Results Among 20 enrolled patients, 3 of them achieved preoperative endocrine prognostic index (PEPI) score of 0. Additionally, complete cell cycle arrest was observed in 7, radiologic objective response rate in 10, and disease control rate in 20 patients, pathological complete response in 1 patient, and 5 patients performed BCS. Ki67 suppression from baseline to surgery was observed in 17 of patients, with the Ki67 change ratio of −73.5%. Treatment-emergent adverse event included neutropenia, leukopenia, thrombocytopenia, lymphopenia, hypoalbuminemia, aspartate aminotransferase elevation, glutamyl transpeptidase elevation, anemia, and alanine aminotransferase elevation. Conclusions Despite the rate of PEPI score 0 was not high, tucidinostat plus exemestane as a neoadjuvant therapy might be well tolerated and showed promising clinical responses in patients with early hormone receptor-positive, HER2-negative breast cancer. To clarify the safety and efficacy of this strategy, further investigation is warranted. Clinical Trial Registration ChiCTR2100046678.

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“…[3][4][5][6][7][8][9][10][11] The most extensively developed mode of intermolecular alkene difunctionalization is vicinal 1,2-difunctionalization, Figure 1A, for which there are many prominent and useful transformations reported, [12][13][14][15][16][17][18][19][20][21][22] including in the synthesis of complex molecules, such as pharmaceuticals and natural products. [23][24][25][26][27][28] Geminal alkene difunctionalization has also received attention, with several innovative transformations and strategies recently reported in the literature. [29][30][31][32][33][34] This variety of functionalization highlights the versatility of alkenes and their utility in providing access to useful chemical space.…”

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confidence: 99%

Alkene 1,3‐Difluorination via Transient Oxonium Intermediates

Dean,

Randle,

Lacey

et al. 2024

Angewandte Chemie

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The 1,3‐difunctionalization of unactivated alkenes is an under‐explored transformation that leads to moieties that are otherwise challenging to prepare. Herein, we report a hypervalent iodine‐mediated 1,3‐difluorination of homoallylic (aryl) ethers to give unreported 1,3‐difluoro‐4‐oxy groups with moderate to excellent diastereoselectivity. The transformation proceeds through a different mode of reactivity for 1,3‐difunctionalization, in which a regioselective addition of fluoride opens a transiently formed oxonium intermediate to rearrange an alkyl chain. The optimized protocol is scalable and shown to proceed well with a variety of functional groups and substitution on the alkenyl chain, hence providing ready access to this fluorinated, conformationally controlled moiety.

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The Effect of Vicinal Difluorination on the Conformation and Potency of Histone Deacetylase Inhibitors

Cited by 4 publications

References 30 publications

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

Tucidinostat Plus Exemestane as a Neoadjuvant in Early-Stage, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer

Alkene 1,3‐Difluorination via Transient Oxonium Intermediates

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