Exploring novel capping framework: high substituent pyridine-hydroxamic acid derivatives as potential antiproliferative agents

Hernández-Borja, Fernando; Mercado-Sánchez, Itzel; Alcaraz, Yolanda; García‐Revilla, Marco A.; Gómez, Clarisa Villegas; Ordaz-Rosado, David; Santos-Martínez, Nancy; Garcı́a-Becerra, Rocı́o; Vázquez, Miguel A.

doi:10.1007/s40199-021-00406-8

Cited by 6 publications

(3 citation statements)

References 51 publications

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“…This research was carried out on an in vitro model, where nasopharyngeal carcinoma cells showed that SAHA activates tumor suppressors such as p53 and Rb1 (retinoblastoma protein), while, at the same time, inactivating AMPK (5′ AMP-activated protein kinase) signaling, which leads to apoptosis [ 84 ]. SAHA is highly effective in cell lines with p53 mutations, breast cancer, MDA-MB-231 R280K , BT-474 E285K , and prostate adenocarcinoma PC3 p.K139fs*31 , where the antiproliferative effect was present due to the increased expression of CDKN1A (cyclin-dependent kinase inhibitor 1A encoding p21), while, at the same time, CCND1 (cyclin D1) and TP53 expression levels decreased [ 85 ].…”

Section: Vorinostat (Saha)mentioning

confidence: 99%

Gain of Function (GOF) Mutant p53 in Cancer—Current Therapeutic Approaches

Roszkowska

Piecuch

Sady

et al. 2022

IJMS

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Continuous development of personalized treatments is undoubtedly beneficial for oncogenic patients’ comfort and survival rate. Mutant TP53 is associated with a worse prognosis due to the occurrence of metastases, increased chemoresistance, and tumor growth. Currently, numerous compounds capable of p53 reactivation or the destabilization of mutant p53 are being investigated. Several of them, APR-246, COTI-2, SAHA, and PEITC, were approved for clinical trials. This review focuses on these novel therapeutic opportunities, their mechanisms of action, and their significance for potential medical application.

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Section: Vorinostat (Saha)mentioning

confidence: 99%

Gain of Function (GOF) Mutant p53 in Cancer—Current Therapeutic Approaches

Roszkowska

Piecuch

Sady

et al. 2022

IJMS

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“…Acetylation is one of the important post-translational modifications and is regulated by two key enzymes, namely, histone acetyltransferases (HATs) and histone deacetylases (HDACs) [ 5 ]. The latter, comprising eighteen human HDAC isoforms, are promising targets for anti-cancer therapeutics, as HDAC inhibitors have demonstrated efficacy in inhibiting cancer proliferation by re-expressing suppressed regulatory genes [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of 1,10-phenanthroline-based hydroxamate derivative as dual histone deacetylases/ribonucleotide reductase inhibitor with antitumor activities

Shetty,

Pai,

Dey

et al. 2024

DARU J Pharm Sci

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Background Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) enzymes are commonly observed in various cancers. Researchers are focusing on these enzymes in cancer studies with the aim of developing effective chemotherapeutic drugs for cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in cancer treatment, making it a promising strategy. Objectives The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor. Methods The N1-hydroxy-N8-(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2. Results The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC50 of 16.43 μM. It displayed potent inhibitory activity against HDAC and RR with IC50 values of 10.80 μM and 9.34 μM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of reactive oxygen species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633 kcal/mol, as compared to the standard HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244 kcal/mol against HDAC7. Conclusion The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule. Graphical Abstract

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“…Within N-heterocyclic compounds, 2-pyridones and their derivatives are considered privileged structures due to their frequent presence in drugs with biological activity, such as vasorelaxant, 44 anticancer, 45 a,b antiviral, 46 antifungal, 47 a,b anti-inflammatory, 48 a,b and cardiotonic agents, as well as ACE inhibitors. 49 2-Pyridones have been prepared by means of two main synthetic approaches, 50 heterocycle transformation (Fig.…”

Section: Introductionmentioning

confidence: 99%