الفهرس 
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Abstract
This thesis aims to the synthesis and biological activity of new thieno[2,3-d]pyrimidine derivatives and their nucleosides.
Gewald thiophene synthesis allows for a facile synthetic entry to the class of thienopyrimidine. The compound methyl N-(3-ethoxycarbonyl-5,6-dihydro-4H-cyclopenta[b]thien-2-yl) dithiocarbamate (II) was used as starting material in this study. It was obtained by reacting the ethyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3carboxylate (I) with carbon disulfide, sodium hydroxide and dimethyl sulfate in DMSO (Scheme 1).
Scheme 1
Refluxing of methyl N-(3-ethoxycarbonyl-5,6-dihydro-4H-cyclopenta[b]thien-2-yl)dithiocarbamate (II) with ethylamine, in dichloromethane led to the formation of the thioureido derivative III [1] (Scheme 2).
Scheme 2
Aqueous alkaline hydrolysis of the thioureido derivative III followed by acidification led to the formation of the cyclized product IV in 76 % yield. Next, the potassium salt of compound IV were treated with methyl iodide to give the corresponding compound V.Treatment of compound V with hydrazine hydrate or piperidine in ethanol under reflux gave products VI (a, b) respectively (Scheme 3).
Scheme 3
It was interesting to explore the capability of compound VIa towards ring closure reactions using different reagents Thus, compound VIa reacted with sodium nitrite in acetic acid, carbon disulfide , triethyl orthoformate, benzoyl chloride and acetic anhydride to afforded compounds VIIa, VIIb, VIIc, VIId and VIIe, respectively (Scheme 4).
Scheme 4
Arylidene derivatives VIII(a, b) were prepared by condensing of VIa with certain aldehydes namely p-chlorobenzaldehyde and p-nitrobenzaldehyde in boiling ethanol with a few drops of acetic acid .Cyclization of VIII(a, b) was carried out on refluxing with FeCl3 giving thienotriazolopyrimidine derivatives IX(a, b) (Scheme 5).
Scheme 5
Furthermore, sugar hydrazones XI (a, b) was synthesized through the reaction of compound VIa with D-glucose Xa and D-xylose Xb in ethanol solution containing catalytic drops of acetic acid. Treatment of compounds XI (a, b) with acetic anhydride in the presence of pyridine at ambient temperature provided per-O-acetylated sugar hydrazones XII (a, b). Heating hydrazones XI (a ,b) in acetic anhydride at 100ºC provided the respective acyclic nucleosides analogs XIII(a, b) (Scheme 6).
Scheme 6
Reaction of compound XIV with p-chlorobenzaldehyde and p-nitrobenzaldehyde furnished the corresponding hydrazones XV (a, b) (Scheme 7).
Scheme 7
Similarly, heating compound XIV with monosaccharaides like D-glucose Xa, and D-xylose Xb in ethanol with small amount of acetic acid for 8h yielded our products XIVI(a, b). Acylation of products XIVI (a, b) using acetic anhydride and pyridine furnished the O-acetyl derivatives XIVII (a, b) (Scheme 8).
Scheme 8
All new compounds were confirmed by analytical and spectroscopic features [TLC, IR, 1H-NMR, 13C-NMR and MS and microanalysis].
Finally, The twelve selected products V, VIa, VIb, XIa, XIb, Xa, XIIa, XIIIb, XIVIa, XIVIb, XIVIIa and XIVIIb were investigated in vitro for their anticancer effect using (MTT) method against two human cancer cell lines, hepatocellular carcinoma (HepG-2), and breast cancer (MCF-7). The better cytotoxic effect was given by compounds VIa and XIa. Compounds V and XIIIa demonstrated a good viability against the two human tumor cell lines, whereas, the rest of the compounds had moderate to weak activities relative to the positive control.