Synthesis of cinnoline derivatives as anticancer agents / Marwa Sobhy Ahmed Hassan ; Supervisied Manal Mostafa Kandeel , Aliaa Mohamed Kamal , Bassem Heshmat Naguib

Thesis (M.Sc.) - Cairo University -Faculty of Pharmacy - Department of Organic Chemistry

The present thesis comprises four chapters. The first chapter is an introduction which is composed of two parts. The first part is a brief literature survey on the synthesis of cinnoline, pyrimidocinnoline and triazepinocinnoline derivatives. The second part is a survey covering topoisomerase I inhibitors as one of the recent fields of research, some reported cinnoline derivatives with anticancer activity and mechanisms of anticancer activity of some reported cinnoline derivatives. The second chapter demonstrates the aim of the work, along with the Schemes that had been carried out to obtain new cinnoline derivatives. The third chapter explains the theoretical discussion of the experimental work used for the preparation of the newly synthesized compounds, together with explanation of their spectroscopic data. Scheme of starting materials, reveals the preparation of the root compounds viz. 4-amino-6-substituted cinnoline-3-carboxamides (IIa,b), 4- amino-6-substituted cinnoline-3-carbohydrazides (Va,b) and their corresponding acids IIIa,b and esters IVa,b are presented. Scheme 1, compounds IIa,b were refluxed with acetic anhydride to yield pyrimidocinnoline derivatives VIa,b. However, the reaction of IIa,b with certain phenacyl bromides gave 4-(2-aryl-2-oxoethylamino)-6-substituted cinnoline-3- carboxamides (VIIa-g) rather than diazepinocinnolines A. Scheme 2, cyclization of the hydrazides Va,b with acetic acid gave triazepinocinnoline derivatives VIIIa,b. On the other hand, reacting Vb with different aromatic acids gave unexpectedly triazepinocinnoline derivatives IXa,b instead of the oxadiazolylcinnoline derivatives B. Moreover, heating Vb with the appropriate aromatic aldehyde yielded the corresponding arylidene derivatives Abstract vii Xa-d. Cyclization of the latter Xa with acetic anhydride gave unexpectedly pyrimidocinnoline derivative XI instead of oxadiazolylcinnoline derivative C. Scheme 3, cyclization of the hydrazide Vb with carbon disulphide yielded the triazepinocinnoline derivative XII instead of the expected pyrimidocinnoline derivative XIII. However, triazepinocinnoline derivative XII underwent thermal isomerization upon refluxing with xylene (high boiling point solvent) to give the more thermodynamically stable pyrimidocinnoline derivative XIII

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