405-79-8Relevant articles and documents
Modulation of DNA damage response by targeting ATM kinase using newly synthesized di-phenoxy acetamide (DPA) analogs to induce anti-neoplasia
Al-Ostoot, Fares Hezam,Sherapura, Ankith,Malojirao, Vikas H.,Thirusangu, Prabhu,Al-Muhimeed, Tahani I.,Khanum, Shaukath Ara,Prabhakar
, p. 1344 - 1360 (2021/06/14)
Background: Imbalance and instability in the structure of the DNA have become major characteristics of cancer. In response to DNA damage, DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), plays a pivotal role in the modulation of regulatory regions responsible for inhibition of apoptosis, thereby neoplastic progression. Methods: A new series of DPA (7a–t) were synthesized, characterized. Anti-proliferative studies to identify the lead compound were carried out by LDH and MTT assay. Apoptosis/DNA damage was measured through FACS, Annexin-v staining, TUNEL and Comet assay. Elucidation of molecular mechanism through immunoblot and further validation of the drug effect through in vivo approaches. Results: Initial in vitro anti-proliferative screening of Compounds DPA (7a–t) against multiple cancer cell lines identified Compound DPA (7n) as a potent cytotoxic molecule with IC50 value of 4.3?μM. Down the line, in vitro and in vivo evaluation of Compound DPA (7n) inferred that it has apoptotic inducing potentiality. Further, evaluation of molecular mechanism inferred that Compound DPA (7n) effectively modulates ATM phosphorylation only, eventually altering downstream signalling pathways. Conclusions: Compound DPA (7n) emerged as a potent proapoptotic and anti-neoplastic agent by inhibiting ATM kinase activity both in vitro and in vivo. The conferring results ascertain that the drug could be developed as a new ATM kinase inhibitor with anti-cancer capacity. Graphic abstract: [Figure not available: see fulltext.]
Synthesis, crystal structure characterization, DFT calculations, Hirshfeld surface analysis and 3D energy frameworks of triazole pyridazine derivatives: Theoretical and experimental studies
Al-Ostoot, Fares Hezam,Khanum, Shaukath Ara,M. A., Sridhar,Mohammed, Yasser Hussien Issa,Sallam, Hamdi Hamid
, (2021/09/04)
Recently, pyridazine derivatives have shown considerable biological properties such as anti-tumor and anti-inflammatory activity. The studied compounds 6-chloro-3-[(4-methylphenoxy)methyl][1,2,4] triazolo[4,3-b]pyridazine (8a) and 6-chloro-3-[(4-fluorophenoxy)methyl][1,2,4] triazolo[4,3-b]pyridazine (8b) have been synthesized and characterized by NMR, IR and mass spectral studies, and finally, the structures were confirmed by single crystal X-ray diffraction technique. The compounds 8a and 8b have crystallized in the same crystal system with different space groups. Density functional theory calculations were performed to compare the theoretical and experimental results obtained from XRD. Further, DFT calculations were employed to determine HOMO-LUMO energy levels, energy gap, softness, hardness, and other quantum chemical parameters of the compounds 8a and 8b. Hirshfeld surface analysis was carried out to distinguish the different intermolecular hydrogen bonds. Energy frameworks for the compounds were constructed through different intermolecular interaction energies to know the dominant interaction energy involved in the molecular packing strength.
ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 1 (ENPP1) MODULATORS AND USES THEREOF
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Paragraph 00631, (2021/07/02)
Provided herein are small molecule modulators of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
Ketoreductase catalyzed stereoselective bioreduction of α-nitro ketones
Wang, Zexu,Wu, Xiaofan,Li, Zhining,Huang, Zedu,Chen, Fener
supporting information, p. 3575 - 3580 (2019/04/14)
We report here the stereoselective bioreduction of α-nitro ketones catalyzed by ketoreductases (KREDs) with publicly known sequences. YGL039w and RasADH/SyADH were able to reduce 23 class I substrates (1-aryl-2-nitro-1-ethanone (1)) and ten class II substrates (1-aryloxy-3-nitro-2-propanone (4)) to furnish both enantiomers of the corresponding β-nitro alcohols, with good-to-excellent conversions (up to >99%) and enantioselectivities (up to >99% ee) being achieved in most cases. To the best of our knowledge, KRED-mediated reduction of class II α-nitro ketones (1-aryloxy-3-nitro-2-propanone (4)) is unprecedented. Select β-nitro alcohols, including the synthetic intermediates of bioactive molecules (R)-tembamide, (S)-tembamide, (S)-moprolol, (S)-toliprolol and (S)-propanolol, were stereoselectively synthesized in preparative scale with 42% to 90% isolated yields, showcasing the practical potential of our developed system in organic synthesis. Finally, the advantage of using KREDs with known sequence was demonstrated by whole-cell catalysis, in which β-nitro alcohol (R)-2k, the key synthetic intermediate of hypoglycemic natural product (R)-tembamide, was produced in a space-time yield of 178 g L?1 d?1 as well as 95% ee by employing the whole cells of a recombinant E. coli strain coexpressing RasADH and glucose dehydrogenase as the biocatalyst.
The Novel 4-Phenyl-2-Phenoxyacetamide Thiazoles modulates the tumor hypoxia leading to the crackdown of neoangiogenesis and evoking the cell death
Mohammed, Yasser Hussein Eissa,Malojirao, Vikas H.,Thirusangu, Prabhu,Al-Ghorbani, Mohammed,Prabhakar,Khanum, Shaukath Ara
, p. 1826 - 1839 (2017/11/16)
Tumor microenvironment is a complex multistep event which involves several hallmarks that transform the normal cell into cancerous cell. Designing the novel antagonistic molecule to reverse the tumor microenvironment with specific target is essential in modern biological studies. The novel 4-phenyl-2-phenoxyacetamide thiazole analogues 8a-ab were synthesized in multistep process, then screened and assessed for cytotoxic and anti-proliferative effects in vitro against multiple cancer cells of different origin such as MCF-7, A549, EAC and DLA cells which revealed that compound 8f with fluoro and methyl substitute has potential cytotoxic efficacy with an average IC50 value of ? 13 μM. The mechanism of cytotoxicity assessed for anti-tumor studies both in ascites and solid tumor models in-vivo inferred the regressed tumor activity. This is due to changes in the cause of tumor microenvironment with crackdown of neovascularization and evoking apoptosis process as assessed by CAM, corneal vascularization and apoptotic hallmarks in 8f treated cells. The molecular gene studies inferred involvement of HIF-1upregulation and stabilization of p53 which are interlinked in signaling as conferred by immunoblot analysis.
Novel pyrazolone derivatives and corresponding europium(III) complexes: Synthesis and properties research
Li, Dewei,Xiong, Suhao,Guo, Tiantong,Shu, Dehua,Xiao, Haihua,Li, Guizhi,Guo, Dongcai
, p. 28 - 35 (2018/05/24)
A series of pyrazolone derivatives ligands L1?7 were successfully synthesized and validated by 1H NMR and MS, corresponding europium complexes [EuL1?7(NO3)2]NO3·EtOAc were synthesized. Physico-chemistry properties of title complexes were determined by Elemental analysis, Molar conductance, UV absorption spectra, IR spectra and Thermogravimetric analysis. The title complexes exhibit characteristic red fluorescence of Eu3+. The effect of various substituent groups in ligands on the of title Eu3+ complexes is ordered: Cl > -Br > -OCH3 > -F > -CH3 > -H > -NO2, and [EuL6(NO3)2]NO3·EtOAc containing Cl possesses the strongest fluorescence intensity, so does fluorescence quantum yield. The electrochemical properties indicate that energy gap Eg and LUMO energy level are huge affected by substituent groups, and variation trends of LUMO energy level affected by diverse substituent groups are also different. The prepared title europium complexes have potential application prospects in the fields of photoelectric functional materials and life sciences.
The anti-invasive role of novel synthesized pyridazine hydrazide appended phenoxy acetic acid against neoplastic development targeting matrix metallo proteases
Eissa Mohammed, Yasser Hussein,Thirusangu, Prabhu,Zabiulla,Vigneshwaran,B.T, Prabhakar,Khanum, Shaukath Ara
, p. 375 - 386 (2017/09/02)
Neoplastic metastasis is a major process where tumor cells migrate from the primary tumor and colonize at other parts of our body to form secondary tumor. Cancer incidences are rising and novel anti-neoplastic compounds with new mechanism of actions are essential for preventing cancer related deaths. In the current examination, a novel series of pyridazine analogues 6a-l was synthesized and evaluated against metastatic neoplastic cells. Experimental data postulated compound 6j has potential cytotoxic efficacy with prolonged activity against various cancer cells, including A549, HepG2, A498, CaSki and SiHa cells. Moreover, compound 6j arrests the A549 migration and invasions markedly by counteracting matrix metalloproteinase (MMP)-2 and MMP-9 expressions. Also, compound 6j proved its potentiality against Dalton's solid lymphoma progression in-vivo by abridging MVD and MMP expressions. Compound 6j interacts with MMP-2 and MMP-9 by H- bond in-silico, thereby down regulates the MMPs action in tumourigenesis. Altogether, we concluded that compound 6j down regulates MMP-2 and MMP-9 and thereby impairs metastatic cancer cell migration and invasions which can be translated into a potent anti-neoplastic agent.
Synthesis and Biological Activity of Ethyl 4-Alkyl-2-(2-(substituted phenoxy)acetamido)thiazole-5-carboxylate
Mo, Wenyan,Shi, Yanxia,He, Junbo,Li, Baoju,Peng, Hao,He, Hongwu
, p. 183 - 187 (2016/02/10)
(Chemical Equation Presented) A series of novel ethyl 4-(methyl or trifluoromethyl)-2-(2-(substituted phenoxy)acetamido)thiazole-5-carboxylates 7a, 7b, 7c, 7d, 7e and 8f, 8g, 8h, 8i, 8j, 8k, 8l, 8m, 8n, 8o, 8p, 8q, 8r were synthesized, and their structures were confirmed by IR, 1H-NMR, MS spectra and elemental analysis. The results of preliminary bioassays show that some of the title compounds exhibit moderate to good herbicidal activities. Compared with the fluorine free compounds 7a, 7b, and 7e, the compounds bearing fluorine 8g, 8j, and 8q showed higher herbicidal activities with 70-100% inhibition against Capsella bursa-pastoris, Amaranthus restroflexus, and Eclipta prostrata at the dosage of 150 g/ha, which indicated that the trifluoromethyl on the thiazole ring was beneficial for the herbicidal activity. Furthermore, compounds 8f, 8g, 8h, 8i, 8j, 8k, 8l, 8m, 8n, 8o, 8p, 8q, 8r were tested for fungicidal activity against Pseudoperonospora cubensis at 500 μg/mL. Compounds 8f and 8q showed the best fungicidal activity with more than 80% inhibition.
Synthesis and properties of coumarin derivatives and their terbium complexes
Meng, Defen,Xu, De,Li, Dong,Dai, Ming,Li, Guizhi,Guo, Dongcai
, p. 5269 - 5280 (2016/06/01)
A series of coumarin derivatives obtained from salicylaldehyde and phenol were synthesized. Their corresponding terbium complexes were prepared and characterized by elemental analysis, EDTA titrations, molar conductivity, UVvis spectra, IR spectra, and thermal analysis. The luminescent properties and electrochemical properties of the terbium complexes were also investigated. The results showed that all the terbium complexes exhibited characteristic emissions of terbium ions. The introduction of electron-donating groups can improve the luminescent properties, decrease the HOMO and LUMO energy levels of the terbium complex, while electron-withdrawing groups can weaken the luminescent properties, and increase the HOMO and LUMO energy levels of terbium complex.
Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A1and A2Areceptor antagonists
Harmse, Rozanne,van der Walt, Mietha M.,Petzer, Jacobus P.,Terre'Blanche, Gisella
supporting information, p. 5951 - 5955 (2016/12/03)
Based on a previous report that a series of 8-(phenoxymethyl)-xanthines may be promising leads for the design of A1adenosine receptor antagonists, selected novel and known 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine and 1,3,7-trimethyl-8-(phenoxymethyl)-xanthine analogs were synthesized and evaluated for their A1and A2Aadenosine receptor affinity. Generally, the study compounds exhibited affinity for both the A1and A2Aadenosine receptors. Replacement of the 1,3-dimethyl-substition with a 1,3-diethyl-substition pattern increased A1and A2Abinding affinity. Overall it was found that para-substitution on the phenoxymethyl side-chain of the 1,3-diethyl-xanthines decreased A1affinity except for the 4-Br analog (4f) exhibiting the best A1affinity in the submicromolar range. On the other hand A2Aaffinity for the 1,3-diethyl-xanthines were increased with para-substitution and the 4-OCH3(4b) analog showed the best A2Aaffinity with a Kivalue of 237?nM. The 1,3-diethyl-substituted analogs (4a, and 4f) behaved as A1adenosine receptor antagonists in GTP shift assays performed with rat whole brain membranes expressing A1adenosine receptors. This study concludes that para-substituted 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine analogs represent novel A1and A2Aadenosine receptor antagonists that are appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's and Alzheimer's disease.
