Design and synthesis of imidazole based zinc binding groups as novel small molecule inhibitors targeting Histone deacetylase enzymes in lung cancer

Saravanan, Konda Mani; Subramani, Prabhu; Srinivasan, Kannupal; Jayaraj, John Marshal; Gunasekaran, Prasanth; Muthusamy, Karthikeyan; Rajakannan, V.; Ravikumar, Vasulinga T.

doi:10.1016/j.molstruc.2020.128177

Cited by 17 publications

(6 citation statements)

References 20 publications

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“…understanding of the structure of HDACs. Since Somoza et al reported the first crystal structure of HDACs in 2004, to date, most crystal structural information of monomer HDACs is about HDAC8 [57][58][59][60][61]. The global structures of Class I HDACs look similar (Figure 2A) because they all contain a large catalytic domain, which consist of a central parallel β-sheet surrounded by several α-helices linked with loops.…”

Section: Structure and Catalytic Mechanism Of Monomeric Hdacsmentioning

confidence: 99%

“…Structural studies have been particularly useful in understanding and refining the mode of inhibitor binding to Class I HDACs; conversely, inhibitor studies have also promoted our understanding of the structure of HDACs. Since Somoza et al reported the first crystal structure of HDACs in 2004, to date, most crystal structural information of monomer HDACs is about HDAC8 [ 57 , 58 , 59 , 60 , 61 ]. The global structures of Class I HDACs look similar ( Figure 2 A) because they all contain a large catalytic domain, which consist of a central parallel β-sheet surrounded by several α-helices linked with loops.…”

Section: Structures Of Class I Hdacsmentioning

confidence: 99%

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Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

Luo

2020

IJMS

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Class I histone deacetylases (HDACs) are promising targets for epigenetic therapies for a range of diseases such as cancers, inflammations, infections and neurological diseases. Although six HDAC inhibitors are now licensed for clinical treatments, they are all pan-inhibitors with little or no HDAC isoform selectivity, exhibiting undesirable side effects. A major issue with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Except for HDAC8, Class I HDACs (1, 2 and 3) are recruited to large multiprotein complexes to function. Therefore, there are rising needs to develop new, hopefully, therapeutically efficacious HDAC inhibitors with isoform or complex selectivity. Here, upon the introduction of the structures of Class I HDACs and their complexes, we provide an up-to-date overview of the structure-based discovery of Class I HDAC inhibitors, including pan-, isoform-selective and complex-specific inhibitors, aiming to provide an insight into the discovery of additional HDAC inhibitors with greater selectivity, specificity and therapeutic utility.

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Section: Structure and Catalytic Mechanism Of Monomeric Hdacsmentioning

confidence: 99%

Section: Structures Of Class I Hdacsmentioning

confidence: 99%

Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

Luo

2020

IJMS

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“…The imidazole and its derivatives can either work as a friend or foe for the epigenetic enzymes. Our previous research emphasizes that the heterocyclic imidazole derivatives intervene in classic HDAC enzyme activity and inhibit their operations in the lung cancer cell lines [8]. But the class III, HDAC is the most active form in orchestrating the progression and suppression of the various disease [9].…”

Section: Introductionmentioning

confidence: 99%

In-Silico and In-Vitro Functional Validation of Imidazole Derivatives as Potential Sirtuin Inhibitor

Dindi,

Sadiq,

Al-Ghamdi

et al. 2023

Preprint

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Sirtuins are a family of Class III epigenetic modifying enzymes involved in regulating cellular processes through the removal of acetyl groups from proteins. They rely on NAD+ as a coenzyme in contrast with classical HDACs (Class I, II, and IV) that depends on Zn+ for their activation, linking their function to cellular energy levels. There are seven mammalian sirtuin isoforms (SIRT1-7), each located in different subcellular compartments. Sirtuins act as master regulators of cellular homeostasis, responding to changes in nutrient availability and energy status. They play vital roles in diverse physiological and pathological conditions, making them promising therapeutic targets for various diseases, including cancer, neurodegenerative disorders, and metabolic diseases. High levels of SIRT6 are involved in the cancer progression of many tumor types and our previous studies revealed that sirtuin 6 was highly expressed in NSCLC cells and its inhibition potentially favored apoptosis and cell cycle arrest. Sirt6 emerged as a promising target and inhibitors of natural and synthetic sources are highly warranted. Imidazole derivatives are often investigated as sirtuin regulators due to their ability to interact with the binding site and modulate their activity. Imidazole bestows many possible substitutions on its ring and neighboring atoms, to design and synthesize derivatives with specific target selectivity and improved pharmacokinetic properties, optimizing drug development. We recently developed imidazole-based derivatives that potentially inhibited classical HDAC enzymes. Therefore, we evaluated the Sirtuin inhibition activity of our in-house compound comprised of imidazole derivatives and the strongest inhibition was observed with Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl) acetate against Sirt6 by in-silico and protein expression studies. Our results suggested that Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl) acetate could be a potential novel sirt6 inhibitor.

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“…Kandasamy et al. recently reported the synthesis of zinc binding groups based on imidazole inhibitors that target lung cancer [ 14 ]. Recently green synthesis of an ionic liquid is reported based on imidazole [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Khodja et al recently reported a series of imidazole derivative's design, synthesis and biological evaluation [13]. Kandasamy et al recently reported the synthesis of zinc binding groups based on imidazole inhibitors that target lung cancer [14]. Recently green synthesis of an ionic liquid is reported based on imidazole [15].…”

Section: Introductionmentioning

confidence: 99%

Conformational analysis and quantum descriptors of two new imidazole derivatives by experimental, DFT, AIM, molecular docking studies and adsorption activity on graphene

Kumar

Mary

Pradhan³

et al. 2020

Heliyon

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1-[2-(2-hydroxy-3-methoxy-5-(4-methoxyphenylazo)benzaldeneamino)ethyl]-3-methyl-3H-imidazole (HMY) and 1-[2-(2-hydroxy-3-methoxy-5-(4-methylphenylazo)benzaldene amino)ethyl]-3-methyl-3H-imidazole (HMM) were synthesized and characterized using spectral analysis. Conformational analysis has been achieved using potential energy scan for different rotable bonds for obtaining the lowest energy conformer. Conformer with minimum energy is obtained along the dihedral angle N30-C31-C34-N37. QTAIM analysis gives nature and strength of hydrogen bonding interactions. UV-Vis, electrostatic potential and chemical descriptors are analyzed. Interaction of HMY and HMM with graphene is analyzed in terms of SERS activity. Chemical reactivity descriptors were investigated for graphene-drug systems. NLO activity of parent drugs and its graphene complexes show good activity. The wavenumber downshift of different modes is noted. Title molecules exhibit inhibitory activity against cytochrome C peroxidase. Interactions with graphene sheets are theoretically predicted for the title compounds.

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Design and synthesis of imidazole based zinc binding groups as novel small molecule inhibitors targeting Histone deacetylase enzymes in lung cancer

Cited by 17 publications

References 20 publications

Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

In-Silico and In-Vitro Functional Validation of Imidazole Derivatives as Potential Sirtuin Inhibitor

Conformational analysis and quantum descriptors of two new imidazole derivatives by experimental, DFT, AIM, molecular docking studies and adsorption activity on graphene

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