Synthesis and Anticancer Evaluation of Benzyloxyurea Derivatives

Abstract

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...

Palladium(II)‐Catalyzed Acetoxime Directed ortho‐Arylation of Aromatic Alcohols

“…The key to make this protocol successful depends on the reduction of acetoxime by Raney Ni catalyst 14. Alternatively, hydrolysis of acetoxime could obtain hydroxylamine derivatives 21…”

“…[14] Alternatively,h ydrolysis of acetoxime could obtain hydroxylamine derivatives. [21] Based on the above results and pioneering studies, [3f,g,h, 5a, 16, 18d, 22] the mechanism of acetoxime-directed orthoarylationr eaction is proposed as depicted in Scheme 5.To begin with, the Pd II species A,w hich is bound by amino acid ligand,c oordinates with the substrate 1 ands ubsequently activates the ortho-CÀHb ond, forming as ix-membered exo-palladacycle intermediate B. [14] Transmetalation with Ar-BPin 2 produces intermediate C, [18d, 3h] followed by reductive elimination, releases the target molecule 3,w ith concomitant generation of Pd 0 species D.R eoxidation with 2equiv of Ag I regenerates the active Pd II species A foranother catalytic cycle.…”

1-(4-Hexylbenzoyl)-3-methylthiourea

“…The thiourea structure is similar to the urea, except that the S atom in thiourea replaces the O atom on urea. In previous studies, urea was widely used in drug discovery research, for example as anticancer [1,2], anti-tuberculosis [3,4], antimalarial [5,6] and analgesic [7]. Thiourea was also widely used in new drug discovery research, such as anticancer and antitumor [8][9][10][11][12], antibacterial, antimicrobial and anti-tuberculosis [13][14][15][16][17][18], soluble epoxide hydrolase (sEH) inhibitor [19] and antiviral [20].…”

Syntheses and Biological Evaluation of Novel Hydroxamic Acid Derivatives Containing Purine Moiety as Histone Deacetylase Inhibitors

“…Of target compounds, one is both 6-substituted purine hydroxamic acids and 6-substituted purine hydroxycarbamides containing hydroxyurea pharmacophore. Our group has made great efforts to develop novel hydroxycarbamides to evaluate their anticancer activity, [32][33][34][35] and found that some hydroxycarbamides possessed potent antitumor activity. To explore the possibility of synergistic effects, we introduced aliphatic diamines to 6-position of purine as linker and synthesized 6-substituted purine hydroxycarbamides, namely, 6-substituted purine hydroxamic acids.…”