Synthesis, Antitumor Evaluation and Crystal Structure of Hydroxyurea Derivatives

Abstract

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...

3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides Potently Inhibit HIV-1 Integrase and RNase H

“…The synthesis started from commercially available hydroxyurea 5 which was O -benzylated with BnBr in the presence of KOH under reflux to provide 1-(benzyloxy)urea 6 in high yield. 29 Cyclocondensation of 1-(benzyloxy)urea 2 and diethyl malonate provided six-membered heterocycle compound 3-(benzyloxy)-6-hydroxypyrimidine-2,4(1H,3H)-dione 7 in moderate yield under microwave irradiation (150 °C, 20 min) or under conventional heating (reflux, overnight). 30 Compound 7 was converted to key intermediate 3-(benzyloxy)-6-chloropyrimidine-2,4(1H,3H)-dione 8 by reacting with POCl 3 in the presence of BnEt 3 NCl.…”

Synthesis and Anticancer Evaluation of Benzyloxyurea Derivatives

“…Inhibition of cell-proliferation was measured by the improved MTT assay. 6,24) The inhibitory potency (IC 50 ) of tested compounds are given in Table 1. In general, some target compounds showed good inhibitory effects on L1210 and K562, especially 4a, 4b, 4d, 4e, 4g, 4q, 4c′ and 4f′.…”

“…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.…”

“…[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.…”

Synthesis and antitumor evaluation of some 1,3,4-oxadiazole-2(3H)-thione and 1,2,4-triazole-5(1H)-thione derivatives

“…After culturing for 12 h at 37°C and 5% CO 2 , cells were incubated with samples for 24 h using five concentrations at 10-fold dilutions (10 -3 -10 -7 mol/ml) for each test compound. MTT was added at a terminal concentration of 5 lg/ml and incubated with the cells for 4 h. The formazan crystals were dissolved in DMSO (100 ll) in each well and the optical density was measured at 570 nm (for the absorbance of MTT formazan) (Mai et al, 2010). The IC 50 was calculated using the Bacus Laboratories Incorporated Slide Scanner (Bliss) software.…”