- 8-Alkylmercaptocaffeine derivatives: antioxidant, molecular docking, and in-vitro cytotoxicity studies
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Due to their unique pharmacological characteristics, methylxanthines are known as therapeutic agents in a fascinating range of medicinal scopes. In this report, we aimed to examine some biological effects of previously synthesized 8-alkylmercaptocaffeine derivatives. Cytotoxic and antioxidative activity of 8-alkylmercaptocaffeine derivatives were measured in malignant A549, MCF7, and C152 cell lines. Assessment of cGMP levels and caspase-3 activity were carried out using a colorimetric competitive ELISA kit. Computational approaches were employed to discover the inhibitory mechanism of synthesized compounds. Among the twelve synthesized derivatives, three compounds (C1, C5, and C7) bearing propyl, heptyl, and 3-methyl-butyl moieties showed higher and more desirable cytotoxic activity against all the studied cell lines (IC50 0.05) and exhibited no marked ameliorating effects on oxidative damage (P > 0.05). Computational studies showed that H-bond formation between the nitrogen atom in pyrazolo[4,3-D] pyrimidine moiety with Gln817 and creating a hydrophobic cavity result in the stability of the alkyl group in the PDE5A active site. We found that synthesized 8-alkylmercaptocaffeine derivatives induced cell death in different cancer cells through the cGMP pathway. These findings will help us to get a deeper insight into the role of methylxanthines as useful alternatives to conventional cancer therapeutics.
- Sargazi, Saman,Shahraki, Sheida,Shahraki, Omolbanin,Zargari, Farshid,Sheervalilou, Roghayeh,Maghsoudi, Saeid,Soltani Rad, Mohammad Navid,Saravani, Ramin
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- MLKL INHIBITORS
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Purine derivatives that inhibit cellular necroptosis and/or human MLKL, pharmaceutical compositions thereof, and methods of treating an MLKL-mediated disorder with an effective amount of the compound or composition. Said MLKL-mediated disorder is pathology associated necroptosis, including ischemia-reperfusion damage, neurodegeneration, and inflammatory diseases such as acute pancreatitis, multiple sclerosis, inflammatory bowel disease, and allergic colitis.
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Paragraph 0180-0181
(2018/09/26)
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- Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein
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We report the development of novel Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitors with single nanomolar potency (compound 15 is also named as TC13172). Using the converting biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we were able to determine that the inhibitors covalently bind to Cysteine86 (Cys-86) of MLKL. This is the first example of the use of LC-MS/MS to identify the binding site of an MLKL inhibitor. The novel MLKL inhibitors provide powerful tools to study the biological function of MLKL and demonstrate that MLKL should be viewed as a druggable target.
- Yan, Bo,Liu, Lei,Huang, Shaoqiang,Ren, Yan,Wang, Huayi,Yao, Zhenglin,Li, Lin,Chen, She,Wang, Xiaodong,Zhang, Zhiyuan
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p. 3637 - 3640
(2017/04/03)
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- Two-step three-component process for one-pot synthesis of 8-alkylmercaptocaffeine derivatives
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A highly efficient, odourless and two-step three-component process for one-pot synthesis of some 8-alkylmercaptocaffeine derivatives has been described. The catalyst-free three-component reaction of alkyl bromides, thiourea, and 8-bromocaffeine gave 8-alkylmercaptocaffeine products in excellent to quantitative yields. In addition, the impact of parameters on sample reaction is discussed.
- Rad, M. N. Soltani,Maghsoudi
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p. 70335 - 70342
(2016/08/06)
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- Copper-catalyzed direct thiolation of xanthines and related heterocycles with disulfides
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A novel copper-catalyzed, base-free direct thiolation of xanthines and related heterocycles is described, featuring the use of inexpensive Cu(OAc) 2·H2O as the catalyst, O2 as a clean and cheap oxidant, and easy-to-handle
- He, Zuying,Luo, Fang,Li, Yinglong,Zhu, Gangguo
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supporting information
p. 5907 - 5910
(2013/10/21)
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- Thio- and aminocaffeine analogues as inhibitors of human monoamine oxidase
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In a recent study it was shown that 8-benzyloxycaffeine analogues act as potent reversible inhibitors of human monoamine oxidase (MAO) A and B. Although the benzyloxy side chain appears to be particularly favorable for enhancing the MAO inhibition potency
- Booysen, Hermanus P.,Moraal, Christina,Terre'Blanche, Gisella,Petzer, Anél,Bergh, Jacobus J.,Petzer, Jacobus P.
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experimental part
p. 7507 - 7518
(2012/01/03)
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