Hydroxyurea (HU)was prepared in 1860 and later further research were indicated that it can suppressedthe leukocyte formation 1 and FDA approved it for the treatment of cancer in1967 2. It is used for the treatment of psoriasis, melanoma, chronic myelocyticleukemia, sickle cell anemia, sickle-ß-thalassemiaand recurrent metastatic ovariancancer 3, 4, 5. HU is anantimetabolite, which inhibit the ribonucleotide reductase (RNR), and result into decrease the deoxy ribonucleotides 6. RNR enzymes act by its tyrosyl freeradicals 7 and react with one electron reductants such as HU to producenormal tyrosine residue and inhibition of RNR by hydroxyurea result in stop ofcell proliferation 8, 9. HU, now is used in chemotherapy of cancer, has shorthalf-life (1.9—3.9 h) due to its small molecular weight (MW=76.06) and highpolarity (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 ofresistance. It was indicated that pharmacophore (RC=ONHOH) is critical foractivity of HU; substituting R by methyl decreases significantly itseffectiveness and benzene ring in R position increases cytotoxic effect 10.Antileukemia effect of guanidine derivatives of HU are same as HU and substitutinghydroxyl in ortho of aromatic ring decreases IC50 of component 11.Based on our proposed molecular mechanism action, HU isconverted into its oxidized form and subsequently tightly interacts with theTyr-176, and inhibits the radical generation and subsequently inhibits the RNRenzyme 12. Here in our ongoing research we have design and synthesized new lipophilicanalogues of HU to improve its pharmacokinetic and pharmacodynamics profiles.Material and Methods All required chemicalsand solvents were purchased from Sigma-Aldrich and Merck companies. Meltingpoints were measured on an electrothermal IA 9300 capillary Melting PointApparatus.
NMR spectra were recorded ona Bruker spectrometer at 400 MHz and 500MHz, Samples were measured in DMSO-d6solution in 5-mm NMR tubes. Chemical shifts, ?, are given inppm and referenced to tetramethylsilane (TMS). IR-spectra were recorded on aFT-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 hydroxylaminehydrochloride in the mixture of water and diethyl ether as solvents, thecarbamate intermediate 2 was prepared 13.
In the Second step, thecarbamate was reacted with the appropriate aromatic amines to produce thedesired compounds. For preparation of thecompound 9, hydroxysemicarbazide 8 was reacted with 3-?(Benzyloxy)?benzaldehydeto achieve the desire compound.