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Hydroxyurea (HU) has been used in cancer chemotherapy for many years. It has been of manifold pharmacological interest, so it has been used for the treatment of melanoma, chronic myelocytic leukemia, and recurrent, metastatic, or inoperable ovarian cancer. HU is also used in therapy of squamous cell carcinomas in the head and neck and relapsed metastasis ovarian cancer, 1) and people have found that it has certain effect on sickle cell anemia, 2) beta-thalassemia, 3) and psoriasis.4) It is also reported that HU has been used for the treatment of AIDS in combination with didanosine, showing no viral rebound after one year treatment.5) HU causes an immediate inhibition of DNA synthesis by acting on the R 2 subunit of the ribonucleotide reductase.6-8) Therapeutic application of HU has several disadvantages such as short half-life (1.9-3.9 h) in patients due to its small molecular size (MWϭ76.06) and extremely polar nature (Clog P o/w ϭ Ϫ1.80), the necessity of using a high dosage (80 mg/kg every third day or 20-30 mg/kg daily), and the rapid development of resistance. 1,[9][10][11] In this study, structure modification of HU based on increasing its hydrophobic nature and molecular size has been adopted to obtain a more potent compound. A series of monosubstituents and disubstituents of HU with different benzyls were synthesized and their structures were elucidated using spectrometry along with X-ray crystal structures analysis for representative compounds. The antitumor activity tests in vitro for human tongue cancer cell line and murine leukemia cell line were evaluated. Results and DiscussionSynthesis The target compounds were prepared using the reaction sequence in Chart 1. The compounds 2a-f were synthesized in good yield by condensation of HU with various benzyls (1a-f) in the presence of potassium hydroxide under reflux. The condensation of 2a-f with HU afforded compounds 3a-f. The chemical structures of the synthesized compounds (2a-f and 3a-f) were confirmed by spectroscopic methods, and exact stereostructures of compounds 2a and 3f have been determined by X-ray crystal structure analysis.X-Ray Crystal Structure Analysis The crystallographic data of 2a are summarized in Table 1. The selected bond lengths, angles and torsion angles are given in Table 2. ORTEP drawings of the compounds 2a and 3f 12) are illustrated in Fig. 1. Crystallographic data and the structure analysis of compound 3f have been outlined in the previous paper.12) Conformations of the C8ϭO2 double bond and N1-O1 bond in 2a are the opposite of each other, similar to that observed in 3f (C1ϭO2 double bond and N1-O1 bond), N-hydroxyurea [13][14][15][16][17] and other hydroxyurea derivates.18) The length of the carbonyl bond (C8ϭO2) in 2a is in the normal range of 1.19-1.23 Å, similar to that observed in 3f, 12) but obviously shorter than N-hydroxyurea, 1-hydroxy-1-methylurea and 1-hydroxy-3-methylurea (Ͼ1.25 Å). This may be related to the hydroxyl etherification. The average distance between the carbon atom and the coordination nitrogen atom i...

In the title hydroxy­urea derivative, C15H14F2N2O2, the dihedral angle between the two benzene rings is 48.64 (19)°. The urea group forms dihedral angles of 48.1 (2) and 79.2 (2)° with the two benzene rings. In the crystal, inversion dimers linked by pairs of N—H⋯O hydrogen bonds occur, and further N—H⋯O links lead to chains of molecules.

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This study investigated the inhibitory mechanism of quercetin in acetylcholinesterase (AChE) and its neuroprotective effects on β-amyloid25–35-induced oxidative stress injury in PC12 cells. Quercetin inhibited AChE in a reversible mixed manner with an IC50 of 4.59 ± 0.27 µM. The binding constant of quercetin with AChE at 25 °C was (5.52 ± 0.05) × 104 L mol−1. Hydrogen bonding and van der Waals forces were the main interactions in forming the stable quercetin–AChE complex. Computational docking revealed that quercetin was dominant at the peripheral aromatic site in AChE and induced enzymatic allosterism; meanwhile, it extended deep into the active center of AChE and destabilized the hydrogen bond network, which caused the constriction of the gorge entrance and prevented the substrate from entering the enzyme, thus resulting in the inhibition of AChE. Molecular dynamics (MD) simulation emphasized the stability of the quercetin–AChE complex and corroborated the previous findings. Interestingly, a combination of galantamine hydrobromide and quercetin exhibited the synergistic inhibition effect by binding to different active sites of AChE. In a β-amyloid25–35-induced oxidative stress injury model in PC12 cells, quercetin exerted neuroprotective effects by increasing the glutathione level and reducing the malondialdehyde content and reactive oxygen species levels. These findings may provide novel insights into the development and application of quercetin in the dietary treatment of Alzheimer’s disease.

A series of novel benzyloxyurea derivatives was designed, synthesized by substituting different benzyls or phenyls on N,N′-positions of the hydroxyurea (HU). These target compounds were evaluated for their anticancer activity in vitro against human leukemia cell line K562 and murine leukemia cell line L1210 in comparison with HU by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Some of the compounds showed promising anticancer activity against the cells. Molecular docking experiments with Saccharomyces cerevisiae R1 domain indicated that 4a and 4f′ have stronger affinity than 4m and 4n. Flow cytometry study showed that compound 4g exerted greater apoptotic activity against K562 cells line than HU.Key words benzyloxyurea derivative; anticancer evaluation; K562; L1210; molecular docking; apoptosis As we all know, because of its low cure rate and high mortality, tumor has become one of the most terrible diseases around the world. Hydroxyurea (HU), as the preferred treatment drug of chronic myelogenous leukemia, could also be used to treat melanoma, tumor of the ovary, human immunodeficiency virus (HIV) infection, β-mediterranean disease and so on. [1][2][3][4][5] But the use of HU is limited by its metabolic and inherent cytotoxicity. [6][7][8][9] Eukaryotic ribonucleoside reductase (RR) catalyzes nucleoside diphosphate conversion to deoxynucleoside diphosphate. Crucial for rapidly dividing cells, RR is an attractive therapeutic target of cancer, and over the past years, many chemotherapeutics inhibiting different subunits of RR have been developed and tested clinically for their anticancer activities and anti-HIV activities.10-13) HU is the first RR inhibitor applied to the clinic, and is utilized for the therapeutic of neoplasms because of its influences on the DNA replication of cancer cells. 1,14) To overcome the drawbacks of HU, numerous medicinal chemistry efforts have been made to design and synthesize novel HU derivatives. 9,[15][16][17][18] In previous paper, we reported HU monosubstituents and disubstituents with benzyls at N-positions of HU. 6,19) The results indicated that the stronger hydrophobic nature of the HU derivatives might favor the cytotoxic activity and benzyl groups at the N-position of HU were associated with enhanced cytotoxic activity. The disadvantages associated with HU's physicochemical properties, e.g., very high hydrophilicity (log P: −1.80) and small molecular size, may be overcomed by the structural modification. This background prompted us to further explore more novel benzyloxyurea derivatives with different substituents at N,N′-positions of HU. In this study, a series of novel benzyloxyurea derivatives substituted with different benzyls or phenyls at N,N′-position of HU were synthesized. The target compounds were evaluated for their anticancer activity in vitro against human leukemia cell line K562 and murine leukemia cell line L1210 in comparison with HU by the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay. Meanwhile, the...

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