الفهرس 
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Abstract
English abstract
Natural products have been used to treat many diseases since ancient times. Modern medicine includes hundreds of preparations that were discovered and developed from natural sources, of both terrestrial and marine origin.
(Part I):
Phytochemical study of Pulicaria Undulata extract led to the isolation of six known compounds elucidated as Xanthoxyline (1), Stigmasterol (2), Oleanolic acid (3), Salvigenin (4), Rhamnetin (5) and Dihydroquercetin 4‵-methyl ether (6) using 1D NMR spectroscopic techniquesas well as comparison with the literature data; compound 3and 4 are first reported in Pulicaria genus. In vitro cytotoxicity of the total extract and isolated compounds were evaluated against breast cancer cell line (MCF-7) and in vivo antiproliferative activity against Ehrlich’s ascites carcinoma (EAC) were assessed; Pulicaria Undulata extract and the isolates showed significant reduction in tumor weight, decreased both serum VEGF-B levels and VEGFR2 expression significantly compared to control EAC group suggesting an antiangiogenic activity through inhibition of VEGF signaling. Besides, they displayed reduction of CD34 expression confirming their antiangiogenic effect. Moreover, the potential affinity of isolated compounds tohuman estrogen nuclear receptor-alpha (hER-α), the most recognized modulator of VEGFR-2expression, was virtually estimated through molecular modeling studies. The bioflavonoids, salvigenin, rhamnetin and dihydroquercetin 4‵-methyl ether showed the highest docking ranks while possessing preferential binding with hER-α critical residues. Based on the provided data, the isolated compounds illustrated promising inhibitors of VEGF-stimulated angiogenesis which could be a possible mechanism for their anticancer activity.
(Part II):
Boiassay-guided fractionation of Notarchus indicus methanol extract afforded one new nucleoside derivative along with eight known compounds; identified asCholesterol (7), Thymine (8), Uracil(9), Bursatellin(10), Thymidine(11), 2’-Deoxyuridine(12), Notarchoside(13), 3-O-methyl d-glucose (14)and d-glucose (15). Structure elucidation was achieved using spectroscopic techniques, including 1D, 2D NMR, LC/MS (HRESIMS) as well as comparison with the literature data;This is the first report of these compounds in genus Notarchus and the first evidence of the presence of (13) as a new natural uridine derivative.In vitro cytotoxicity assay of the total extract and the isolated compounds was tested against two cancer cell lines, MCF-7 and HepG2. Compounds 10, 11, 12, 13 and 14 showed variable promising cytotoxicity against (MCF-7) with IC50 9.9±0.18, 34.5±0.11, 34.0±0.15, 20.0±0.25, 38.5±0.16 µg/mL respectively and against (HepG2) cell line with IC50 44.5±0.25, 43.0±0.22, 48.0±0.31, 37.0±0.18 , 21.0±0.21 µg/mL respectively compared to doxorubicin as positive control. Molecular docking experiments showed high affinity of bursatellin (10) to COX-2, a widely upregulated enzyme in many cellular carcinomas, and notarchoside (13) to thymidylate synthase, an essential enzyme in DNA synthesis; which could be possible mechanisms for their anticancer activity; Our findings suggest that Notarchus indicus active metabolites are promising anticancer agents.
Keywords:Pulicaria undulata; Flavonoids; Ehrlich’s ascites carcinoma;VEGF modulator; angiogenesis; Sea hares; Notarchus indicus; nucleosides; bursatellin; molecular docking; cytotoxic activity.