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1

Natural products as potential inhibitors of FLT3 for acute myeloid leukemia: HTVS, docking, and molecular dynamic simulation

Salah Salsabeel, Sami Najat, Ali Sarah, Khalid Teemah-Alrahman, Alnajjar Radwan

Scientiae Radices

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2023

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Vol. 2, Iss. 4

325--346

EN

Cancer is one the most common health issues worldwide, with cancer-related mortality of 9.5 million in 2018, with an expectation to become 29.5 by 2040. Among others, acute myeloid leukemia (AML) is common among older people. FLT3 mutations are one of the most common genetic aberrations found in Acute Myeloid Leukemia and are associated with poor prognosis. Herein, we attempt to identify natural compounds as potential candidates to treat AML by targeting the FLT3 kinase domain using in silico approaches. The COCONUT database, which contains 407,270 natural compounds, was HTVS against the FLT3 kinase domain active site, and promising compounds were subject to molecular docking. Finally, frontier compounds were validated further using molecular dynamic simulation. In total, ten compounds were identified with docking scores higher than Quizartinib (-11.606 kcal/mol), with the best three compounds showing a docking score of -18.052, -15.772, and -16.767 kcal, respectively, and compound 2 showing excellent stability in molecular dynamic simulation.

2

Synthesis and anticancer evaluation of some coumarin and azacoumarin derivatives

Bakare Safyah B.

Polish Journal of Chemical Technology

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2021

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Vol. 23, nr 2

27--34

EN

Coumarin and its nitrogen analogue 1-aza coumarin are a class of lactones and lactams, respectively, which are indispensable heterocyclic units to both chemists and biochemists. 1-Aza coumarin derivatives, which ultimately metabolize as the corresponding 8-hydroxy coumarins in the biological system are therefore found to be very good anti-inflammatory, anti-cancer, and analgesic agents. A series of hybrid substituted coumarin and azacoumarin-3-carboxylic acid derivatives (8-methoxycoumarin-3-carboxylic acid (4a), 8-methoxyazacoumarin-3-carboxylic acid (4b), 5-bromo-8-methoxycoumarin-3-carboxylic acid (5a), 5-bromo-8-methoxyazacoumarin-3-carboxylic acid (5b), 2-acetoxy-5-bromo-8-methoxyquinoline-3-carboxylic acid (6), and 5,7-di(phenylazo)-8-methoxycoumarin-3-carboxylic acid (7) were synthesized and structurally proved using spectral and elemental analysis data. Substituted coumarin-3-carboxylic acid (4a and 5a) and Substituted azacoumarin-3-carboxylic acid (4b, 5b and 6) were tested for their in vitro cytotoxic activity against MCF-7 and HepG-2 cell lines.

3

Phenolic constituents, antimicrobial, antioxidant, and anticancer activities of ethyl acetate and n-butanol extracts of Senna italica

Khalaf Omar M., Ghareeb Mosad A., Saad Amal M., Madkour Hassan M. F., El-Ziaty Ahmed K., Abdel-Aziz Mohamed S.

Acta Chromatographica

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2019

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Vol. 31, no. 2

138--145

EN

Different solvent extracts of the aerial parts of Senna italica (Mill.) were investigated for their chemical constituents and biological activities. Moreover, bio-guided fractionation led to isolation and identification of six compounds, namely: physcion (1), emodin (2), 2-methoxy-emodin-6-O-β-d-glucopyranoside (3), 1-hydroxy-2-acetyl-3-methyl-6-hydroxy-8-methoxynaphthalene (tinnevellin) (4), quercetin 3-O-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside (rutin) (5), and 1,6,8-trihydroxy-3-methoxy-9,10-dioxo-9,10-dihydroanthracene (6). The chemical structures of these compounds were established via 1D and 2D 1H- and 13C-NMR spectroscopy. Ethyl acetate and n-butanol extracts as well as compound 3 were evaluated for their anticancer activity against tumor cell lines. The tested extracts showed a moderate to weak activity, while compound 3 showed a moderate activity against human liver cancer (Hep G2) and breast cancer (MCF-7) cell lines with IC50 values of 57.5 and 42.3 μg/mL, respectively. Both ethyl acetate and n-butanol extracts exhibited antimicrobial activities with different strengths, i.e., ethyl acetate exhibited antimicrobial activity against seven test microbes while n-butanol extract showed antimicrobial activity against all tested microbes. This is the first report for the isolation of compound 3 as a new compound from S. italica growing in Egypt.

4

Ekstaza i udręka, czyli o chemii taksolu

Kacprzak K.

Wiadomości Chemiczne

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1998

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[Z] 52, 11-12

843--870

EN

Taxol (1), highly functionalised complex diterpenoid originally derived from the bark of Pacific yew, has received in recent decade wide attention of scientists in all fields of life sciences and chemistry, after the discovery of its strong and unique anticancer properties. Fast and spectracular career of this molecule is a subject of the present review. The Jarge scale of research on taxol is the consequence of public and commercial response to successful treatment of various cancer diseases and impossibility of solving basic technological and intellectual problems such as: production, drug formulation, structure-activity relationship elucidation. The discussion is divided into following sections: 1. Activity and pharmacological phenomena of taxol. 2. Production of taxol by biotechnological and chemical methods, including synthesis of taxol side chain. 3. Structure-activity relationship (SAR) of taxoids. After Horwitz reported in 1979 a strongly antimitotic activity of taxol, interest in developing the pharmacology and biochemistry of this class of natural products increased. Taxol molecule promotes anticancer activity by enhancing polymerization of tubulin and stabilization of microtubules. This process has the effect of inhibiting the normal dynamic reorganization of the cytoskeleton (with consists of microtubules) that is necessary for interphase and cell division in mitosis. Taxol and taxotere are successfully used for the treatment of a variety of cancers, in particular ovarian and breast cancer. The biggest problem hindering wider application of this drug is its limited availability from natural sources. One kg of Taxus brevifolia bark yields only 100-170 mg of taxol, after long and complicated extraction procedure. Since the yew is slow growing species this method of obtaining the drug is controvertible and unprofitable. An alternative source of taxol is semisynthesis, where natural precursor of taxol 10-deacetylbaccatin (10-DAB) can be extracted from regenerable twigs of popular yew Taxus baccata and after coupling with synthetically prepared side chain can be converted to taxol or taxotere. Taxol has also been prepared by a number of total syntheses but none of these is expected to enter the phase of commercial production. Biotechnological approaches to production by tissue culture or fungi cultivation have been reprted. Studies in the area of taxoids structure-activity relationships have first demonstrated two basic principles. The so-called 'southern' substituents, such as C-2 benzoate and the side chain, are crucial for the activity. 'Northern' substituents at C-7, C-9 and C-10 can be changed without drastic effect on the activity. The role of the substituents at C-1, the oxetane ring and diterpenoid core modifications are less well understood. There are many reports of significant activity of highly transformed taxoids, including those with: modified ABC core, open C-ring structure and aromatic C-ring. These results indicate the possibility of obtaining a synthetic, structurally simplified variant of taxol.

5

Synthesis of some 5-amino-2-methyl-4-nitro-1-phenacylimidazoles

Sobiak S.

Polish Journal of Chemistry

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1998

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Vol. 72, nr 1

78-83

EN

Reaction of 4(5)-bromo-2-methyl-5(4)-nitroimidazole with phenacyl bromide derivatives gave two isomers: 4-bromo-5-niroimidazoles (4a-e) and 5-bromo-4-nitroimidazoles (5a-e). Compounds 5a-e were treated with cyclic secondary amines to afford expected 5-amino-4-nitroimidazole derivatives 6a-c - 10a-b.