Date of Award

2006

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Environmental Science

First Advisor

Dr.Ibrahim Abdou

Second Advisor

Dr.Ahmed M almdhdi

Third Advisor

Dr.Hazem A.H.Kataya

Abstract

Abstract

3-Deazapyrimidine nucleosides have been shown to exhibit great potential as pro drug for use in medicine especially as antagonists to cancer tumors and the HIV-virus. Recent research has focused on the design, synthesis and characterization of novel nucleoside analogues.

Fluoropyridinone and their corresponding nucleoside derivatives have been synthesized and characterized to induce the activity against tumors. 4, 6-diaryl-3-cyano-2(1H)-pyridinones (82a-i) and their nucleosides were prepared. A trifluoromethyl group was introduced into the pyridinone ring system to study its effect on different tumor cells. The glycoside analogues (83a-e, 85a-e, 87a-e and 88a-d) have been synthesized in good yield via the reaction between pyridinone derivatives and an activated hexapyranosyl sugar to give N-nucleosides (83a-e, 85a-e, 87a-e and 88a-d) as the sole product. In our biological screening, it was found that the fluorine and trifluoromethyl derivatives of the pyridine ring enhance the biological activity. Moreover, the novel non-nucleoside derivatives (89a-d) are found to be more active than the corresponding N-nucleosides. This enhancement in biological properties is due to the presence of the fluorine groups on the pyridine ring.

Computer aided Quantum Mechanics (QM) calculations using density functional theory (DFT) were used to study the reactivity of 3-deazapyrimidines with activated sugar molecules. Gaussian 98 was employed for the calculation of geometries and energies. Charge density gas phase calculations were performed at the B3LYP level with the 6-31G basis set. The data obtained from QM calculations supports our experimental results by showing higher charge density on the pyridine N-atom than on the oxygen atom at C-2. HOMO-LUMO charge density studies of the isolated compounds are fully consistent with the spectroscopic results.

Structure-Activity Relationships (SAR) of nucleosides (83a-e, 85a-e, 87a-e and 88a-d) and other non-nucleosides (89a-d) showed an interesting biological activity. Structure-activity relationships studies of 3-deazapyrimidine derivatives were used to determine the parts of the structure that are responsible for its biological activity and its side effects according to the nature of the substituents. The results have shown that 2-thiophene at the 4-position has the highest activity among all analogues. In addition, the aryl group at the 6-position has shown similar activities. For example, 4-(thiophen-2-yl)-6-phenyl-3-cyano-2(1H)-pyridinones (82d) and 4-(thiophen-2-yl)-6-(p-chlorophenyl)-3-cyano-2(1H)-pyridinones (82e) have shown the same activity at lower and higher concentrations. This result indicates that aryl groups at the 6-position have the same effects, based on the results obtained from biological screening. Meanwhile, nucleosides containing the glucopyranosyl ring system showed higher activity than the galactose isomer. For example, compounds (83a-e) have shown better activity than the corresponding galactoside analogues (87a-e). All free nucleosides showed higher activity due to the solubility factor, where the low soluble acetylated derivatives showed good activities.

2-Thiophene present at the 4-position showed promising biological activity in both nucleosides and non-nucleosides. Meanwhile, more interesting results were obtained from the non-nucleoside analogues (89a-d). SAR has explained these results as follows:

The solubility factor might not be the dominant factor because even the low soluble non-nucleoside (89a) was found to have the highest potential activity.

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