Hydroxyurea spectrometer at 400 MHz and 500MHz, Samples were

   Hydroxyurea (HU)
was prepared in 1860 and later further research were indicated that it can suppressed
the leukocyte formation 1 and FDA approved it for the treatment of cancer in
1967 2. It is used for the treatment of psoriasis, melanoma, chronic myelocytic
leukemia, sickle cell anemia, sickle-ß-thalassemia
and recurrent metastatic ovarian
cancer 3, 4, 5.  HU is an
antimetabolite, which inhibit the ribonucleotide reductase (RNR), and result in
to decrease the deoxy ribonucleotides 6. RNR enzymes act by its tyrosyl free
radicals 7 and react with one electron reductants such as HU to produce
normal tyrosine residue and inhibition of RNR by hydroxyurea result in stop of
cell proliferation 8, 9. HU, now is used in chemotherapy of cancer, has short
half-life (1.9—3.9 h) due to its small molecular weight (MW=76.06) and high
polarity (Clog Po/w=1.80) in which result in to using a high dosage of drug
(20—30 mg/kg daily), with high side effect and the rapid development of
resistance. It was indicated that pharmacophore (RC=ONHOH) is critical for
activity of HU; substituting R by methyl decreases significantly its
effectiveness and benzene ring in R position increases cytotoxic effect 10.
Antileukemia effect of guanidine derivatives of HU are same as HU and substituting
hydroxyl in ortho of aromatic ring decreases IC50 of component 11.

Based on our proposed molecular mechanism action, HU is
converted into its oxidized form and subsequently tightly interacts with the
Tyr-176, and inhibits the radical generation and subsequently inhibits the RNR
enzyme 12. Here in our ongoing research we have design and synthesized new lipophilic
analogues of HU to improve its pharmacokinetic and pharmacodynamics profiles.

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Material and Methods

   All required chemicals
and solvents were purchased from Sigma-Aldrich and Merck companies. Melting
points were measured on an electrothermal IA 9300 capillary Melting Point
Apparatus.  NMR spectra were recorded on
a Bruker spectrometer at 400 MHz and 500MHz, Samples were measured in DMSO-d6
solution in 5-mm NMR tubes. Chemical shifts, ?, are given in
ppm and referenced to tetramethylsilane (TMS). IR-spectra were recorded on a
FT-IR Shimadzu spectrometer for samples dispersed in KBr pellets.

Designed compounds 3-7 were synthesized in two steps
(scheme 1), in the first steps, using phenyl chloroformate and hydroxylamine
hydrochloride in the mixture of water and diethyl ether as solvents, the
carbamate intermediate 2 was prepared 13. In the Second step, the
carbamate was reacted with the appropriate aromatic amines to produce the
desired compounds.  For preparation of the
compound 9, hydroxysemicarbazide 8 was reacted with 3-?(Benzyloxy)?benzaldehyde
to achieve the desire compound.