Synthesis and Preliminary Cytotoxicity Studies of 1-[1-(4,5-Dihydrooxazol- 2-yl)-1H-indazol-3-yl]-3-phenylurea and 3-phenylthiourea Derivatives.

BACKGROUND: N-substituted 3-amino-1H-indazoles represent an interesting class of biologically active compounds. Among them, derivatives containing phenylurea moiety are of particular interest. Such compounds have been found to possess inhibitory activity against cancer cell growth. Additionally, various oxazoline-containing compounds have also been designed as potential anticancer agents. OBJECTIVE: The aim of this work was to obtain a new class of N-substituted 3-amino-1H-indazole derivatives with cytotoxic activity towards cancer cells. METHOD: Two series of 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-phenylurea and 3- phenylthiourea derivatives 7-17 and 18-22, respectively, were prepared and screened for their potential in vitro cytotoxic activities against lung carcinoma LCLC-103H cell line using a crystal violet microtiter plate assay. RESULTS: All the urea derivatives, except the compound 8, were inactive at a concentration of 20 µM attainable in cancer cells, while the thiourea derivatives showed a pronounced cancer cell growth inhibitory effects. The most potent 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-ptolylthiourea (19) exhibited cytotoxicity on the lung cancer LCLC-103H and cervical cancer SISO cell lines at a concentration of 10 µM. Moreover, compound 19 displayed cytostatic activity against pancreas cancer DAN-G cell line. CONCLUSION: The 1-[1-(4,5-dihydrooxazol-2-yl)-1H-indazol-3-yl]-3-phenylthiourea derivatives described herein may serve as a useful scaffold for the search for novel anticancer agents.

Renal function and lipid metabolism in pregnant renal transplant recipients.

OBJECTIVE: To estimate renal function and lipid metabolism in pregnant renal transplant recipients. STUDY DESIGN: The study covered 64 women during the third trimester of pregnancy including 33 renal transplant recipients (the study group) and 31 healthy women (the control group). Serum concentrations of uric acid, urea, creatinine, electrolytes, total protein, albumin, acid-base balance and blood cell count were examined to assess renal function. Moreover, the levels of the following lipid metabolism parameters were estimated: (1) total lipids (TL), (2) total LDL fraction (TLDL), (3) total cholesterol (TCh), (4) free cholesterol (fCh), (5) free/total cholesterol (fCh/TCh) ratio, (6) phospholipids (PhL), (7) total cholesterol/phospholipids (fCh/PhL) ratio, (8) triglycerides (TG), (9) HDL-cholesterol (HDL-Ch), (10) LDL-cholesterol (LDL-Ch) and (11) LDL-Ch/HDL-Ch ratio. 'The effect of immunosuppressants (cyclosporine, prednisone and azathioprine) on serum lipid levels was estimated in the study group. The mean maternal age, gestational age and BMI did not differ in both groups. RESULTS: Pregnant renal transplant recipients presented mild renal insufficiency during the third trimester resulting in the increase in serum level of uric acid (P<0.001), urea (P<0.001), creatinine (P<0.001), and Cl- (P<0.001). Proteinuria (1.19+/-1.9 g/24 h) leading to hypoproteinemia (P<0.001) and hypoalbuminemia (P<0.05) confirmed renal function impairment in the study group. Additionally, the diagnosis of renal insufficiency was supported by mild acidosis reflected by a drop in pH (P<0.001). standard HCO3- (P<0.001) and base excess (P<0.001). The women with renal grafts presented vital lipid metabolism disturbances illustrated by the elevated levels of: (1) TL by 72% (P<0.001), (2) TLDL by 21% (P<0.001), (3) TCh by 16% (P<0.001), (4) fCh by 34% (P<0.001), (5) fCh/TCh ratio by 21% (P<0.001), (6) PhL by 28% (P<0.001), (7) TG by 53% (P<0.001), (8) LDL-Ch by 13% (P<0.05) and (9) LDL-Ch/HDL-Ch ratio by 23% (P<0.001). No difference in HDL-Ch level between the two groups was found. Hyperlipidemia in pregnant kidney recipients was associated with immunosuppressive treatment and depended on cyclosporine treatment regimen. Treatment with azathioprine and prednisone was associated with elevated serum levels of examined lipids. CONCLUSION: Serum lipid abnormalities are significantly influenced by the administered dosages of immunosuppressants.