Design strategies, structure activity relationship and mechanistic insights for purines as kinase inhibitors

Sharma, Sahil; Singh, Jagjeet; Ojha, Ritu; Singh, Harbinder; Kaur, Manpreet; Bedi, Preet Mohinder Singh; Nepali, Kunal

doi:10.1016/j.ejmech.2016.02.018

Cited by 58 publications

(26 citation statements)

References 183 publications

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“…(Liu et al , 2014; Liu et al , 2013). Molecular SARs have been extensively and successfully used in the field of drug discovery and development (Akhtar et al , 2016; Cordomi et al , 2016; Monteiro et al , 2016; Putz et al , 2016; Sharma et al , 2016). Likewise the ultimate goal of developing nano-SARs is to enable prediction of toxicity based on ENM intrinsic physicochemical properties and thus enable safer by design development of commercial ENMs.…”

Section: Intrinsic Properties Of Ienmsmentioning

confidence: 99%

The role of the food matrix and gastrointestinal tract in the assessment of biological properties of ingested engineered nanomaterials (iENMs): State of the science and knowledge gaps

et al. 2016

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Many foods contain appreciable levels of engineered nanomaterials (ENMs) (diameter < 100 nm) that may be either intentionally or unintentionally added. These ENMs vary considerably in their compositions, dimensions, morphologies, physicochemical properties, and biological responses. From a toxicological point of view, it is often convenient to classify ingested ENMs (iENMs) as being either inorganic (such as TiO2, SiO2, Fe2O3, or Ag) or organic (such as lipid, protein, or carbohydrate), since the former tend to be indigestible and the latter are generally digestible. At present there is a relatively poor understanding of how different types of iENMs behave within the human gastrointestinal tract (GIT), and how the food matrix and biopolymers transform their physico-chemical properties and influence their gastrointestinal fate. This lack of knowledge confounds an understanding of their potential harmful effects on human health. The purpose of this article is to review our current understanding of the GIT fate of iENMs, and to highlight gaps where further research is urgently needed in assessing potential risks and toxicological implications of iENMs. In particular, a strong emphasis is given to the development of standardized screening methods that can be used to rapidly and accurately assess the toxicological properties of iENMs.

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Section: Intrinsic Properties Of Ienmsmentioning

confidence: 99%

The role of the food matrix and gastrointestinal tract in the assessment of biological properties of ingested engineered nanomaterials (iENMs): State of the science and knowledge gaps

et al. 2016

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“…They also modulate CRH−R1 and act as inhibitors of Hsp90, sulfotransferase, leukotriene A4 hydrolase, and kinases phosphodiesterases . Furthermore, there are reports available regarding their role in enzyme inhibition, as antihyperglycemic, antifungal and antibacterial agents . According to a report, WHO stresses for research on purines as potential antimycobacterial agents .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 6‐[4‐(4‐Propoxyphenyl)piperazin‐1‐yl]‐9H‐purine Derivatives as Antimycobacterial and Antifungal Agents: In Vitro Evaluation and In Silico Study

Nadaf

Najare

Garbhagudi

et al. 2020

Chemistry & Biodiversity

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A series of novel alkyl substituted purines were synthesized. 6-[4-(4-Propoxyphenyl)piperazin-1-yl]-9H-purine was used as the key starting material, which was synthesized via a multistep protocol and finally subjected for Nalkylation with various alkyl halides with an aim to get prospective antimicrobial agents. The structures of the novel compounds were established by substantiating them through spectral techniques like 1 H-NMR, 13 C-NMR, FT-IR and EI-MS. They were explored for antitubercular activity against Mycobacterium tuberculosis H37RV. Furthermore, they were checked for their antimicrobial activity concerning bacterial and fungal strains. The title compounds exhibited considerable antimicrobial activity without any significant toxicity. In silico studies depicted their good binding profile against Mycobacterium tuberculosis enoyl reductase (InhA; PDB ID: 4TZK) and Candida albicans dihydrofolate reductase (PDB ID: 1AI9). The title compounds obeyed Lipinski's parameters and have exhibited good drug-like properties.

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“…In addition to the aforementioned, the purine nucleus has been used as a fragment in the development of ligands against a host of biological targets. Most of this work has been done on the design of purine derivatives such as kinase inhibitors, because the dysregulation of these proteins is implicated in several processes of carcinogenesis [17,27]. The substitution pattern of the purine ring has been explored, and therefore it is anticipated that introduction of substituents at the C-2, C-6, and N-9 positions will afford compounds with enhanced binding affinity and selectivity toward kinases [17,27].…”

Section: Introductionmentioning

confidence: 99%

“…Most of this work has been done on the design of purine derivatives such as kinase inhibitors, because the dysregulation of these proteins is implicated in several processes of carcinogenesis [17,27]. The substitution pattern of the purine ring has been explored, and therefore it is anticipated that introduction of substituents at the C-2, C-6, and N-9 positions will afford compounds with enhanced binding affinity and selectivity toward kinases [17,27]. Some purine-based compounds which target these proteins have been synthesized, and considering the essential role of some kinases in the regulation of the cell cycle or proliferation signaling, have transformed these compounds into new and potential anticancer agents [17,27,28].…”

Section: Introductionmentioning

confidence: 99%

“…The substitution pattern of the purine ring has been explored, and therefore it is anticipated that introduction of substituents at the C-2, C-6, and N-9 positions will afford compounds with enhanced binding affinity and selectivity toward kinases [17,27]. Some purine-based compounds which target these proteins have been synthesized, and considering the essential role of some kinases in the regulation of the cell cycle or proliferation signaling, have transformed these compounds into new and potential anticancer agents [17,27,28]. Some examples of 2,6,9-trisubstituted purine with these biological properties are compounds III [29] and IV [30] (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

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Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

Salas

Zárate

Kryštof

et al. 2019

IJMS

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We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

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Design strategies, structure activity relationship and mechanistic insights for purines as kinase inhibitors

Cited by 58 publications

References 183 publications

The role of the food matrix and gastrointestinal tract in the assessment of biological properties of ingested engineered nanomaterials (iENMs): State of the science and knowledge gaps

The role of the food matrix and gastrointestinal tract in the assessment of biological properties of ingested engineered nanomaterials (iENMs): State of the science and knowledge gaps

Synthesis of 6‐[4‐(4‐Propoxyphenyl)piperazin‐1‐yl]‐9H‐purine Derivatives as Antimycobacterial and Antifungal Agents: In Vitro Evaluation and In Silico Study

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

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