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...

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