الفهرس 
AbstractOnly 14 pages are availabe for public view
 |  | from | 244 |  |  |
| | | from | 244 | | |
Abstract
This thesis comprises four chapters. The first one is an introduction which consists of a brief survey of cytotoxic activity of compounds containing pyrazolo[3,4-d]pyrimidine nucleus and the new approaches in their synthesis.
The second chapter deals with the aim of the work and the Schemes for the preparation of starting materials and the new required pyrazolopyrimidine containing compounds.
The third chapter clarifies the theoretical discussion of the experimental work for the preparation of the starting materials Ia-d- III.
Compound III was cyclized either through the reaction with hydrazine hydrate or stirring with different primary amines to afford IV and Va-c, sequentially.
On the other hand, acid hydrolysis of II yielded VI. Reacting VI with diethylmalonate afforded 6-ethoxycarbonylmethylpyrazolopyrimidine derivative VII. Hydrazinolysis of VII gave the acid hydrazide VIII.
Moreover, compound VI was cyclized to give pyrazolopyrimidine derivative IX using chloroacetyl chloride.
Formation of pyrazole ring at position 4 in pyrazolopyrimidine system in compounds Xa-d and XI was prepared from compound IV. The reaction of IV with ethyl acetoacetate or different aromatic aldehydes afforded XII and XIIIa-d, respectively.
On the other hand, compound Vb was reacted with formic acid, acetic anhydride or ethoxymethylenemalononitrile and/or ethoxyethylidenemalononitrile giving XIVa&b.
Also, compounds XVa-e, XVIa&b, XVII, XVIII, XIX, XX, XXI and XXII were synthesized from the reaction of Vb with different aromatic aldehydes , isothiocyanate derivatives, diethyloxalate, diethylmalonate, chloroacetyl chloride, ethyl cyanoacetate, sodium nitrite and oxalyl chloride, sequentially.
Moreover, reacting the acid hydrazide VIII with different aromatic aldehyds and carbon disulfide afforded XXIIIa-e and XXIV, respectively. Reaction of XXIV with different alkylating agents afforded XXVa-d, while reacting XXIV with hydrazine hydrate gave XXVI. Also, compound VIII was subjected to diazotization conditions to yield XXVII. Phthalimido derivative XXVIII was obtained upon reacting VIII with phthalic anhydride.
Additionally, reaction of VIII with Phenyl isothiocyanate afforded XXIX. Cyclization of XXIX either in acidic medium or under basic condition yielded XXX and XXXI, respectively. While, XXXII was obtained from the reaction of VIII and ethyl isothiocyanate. The reaction of VIII with arylidene derivatives gave the unexpected products XXXIIIa-c.
Compound IX was subjected to nucleophilic substitution reactions to afford compounds XXXIVa-d from which XXXVa-d were prepared. Also XXXVIa-c and XXXVIIa-c were prepared from IX. Alkylation of compound IX was occurred to yield XXXVIIIa&b. Substitution of chlorine atom in IX with thiol group in XXXIX, then alkylating the thiol group with different alkylating agents or chloroacetanilide derivatives yielded XXXXa&b and XXXXIa&b, respectively.
The structure elucidation of the new compounds was supported by element analyses, IR, 1H NMR, 13C H NMR in addition to mass spectral data.
Additionally, a brief account on the docking study was explained through the binding conformations in comparison with the experimental results.
The fourth chapter consists of the experimental part of this work which contains the detailed procedures used for the synthesis of the starting compounds Ia-d-III, the intermediates IV,Vb and VI-IX, in addition to the target new pyrazolopyrimidine compounds Va&c, Xa-d-XIIIa-d and XVb-e-XXXXIa&b, in addition to physical properties and detailed data obtained from element and spectral analysis of these compounds. It also includes the in-vitro anticancer activity of thirty-nine compounds of newly synthesized derivatives compared with methotrexate as a standard cytotoxic agent. Compounds XXXIVb, XXXVIIIa, XXXXb and XXXXIa&b showed the highest in-vitro cytotoxic activity. This chapter also demonstrates the correlation between the results of molecular docking study and the anticancer evaluation. There was some sort of consistency between the docking studies prediction and the in-vitro biological cytotoxic evaluation.
This thesis comprises four chapters. The first one is an introduction which consists of a brief survey of cytotoxic activity of compounds containing pyrazolo[3,4-d]pyrimidine nucleus and the new approaches in their synthesis.
The second chapter deals with the aim of the work and the Schemes for the preparation of starting materials and the new required pyrazolopyrimidine containing compounds.
The third chapter clarifies the theoretical discussion of the experimental work for the preparation of the starting materials Ia-d- III.
Compound III was cyclized either through the reaction with hydrazine hydrate or stirring with different primary amines to afford IV and Va-c, sequentially.
On the other hand, acid hydrolysis of II yielded VI. Reacting VI with diethylmalonate afforded 6-ethoxycarbonylmethylpyrazolopyrimidine derivative VII. Hydrazinolysis of VII gave the acid hydrazide VIII.
Moreover, compound VI was cyclized to give pyrazolopyrimidine derivative IX using chloroacetyl chloride.
Formation of pyrazole ring at position 4 in pyrazolopyrimidine system in compounds Xa-d and XI was prepared from compound IV. The reaction of IV with ethyl acetoacetate or different aromatic aldehydes afforded XII and XIIIa-d, respectively.
On the other hand, compound Vb was reacted with formic acid, acetic anhydride or ethoxymethylenemalononitrile and/or ethoxyethylidenemalononitrile giving XIVa&b.
Also, compounds XVa-e, XVIa&b, XVII, XVIII, XIX, XX, XXI and XXII were synthesized from the reaction of Vb with different aromatic aldehydes , isothiocyanate derivatives, diethyloxalate, diethylmalonate, chloroacetyl chloride, ethyl cyanoacetate, sodium nitrite and oxalyl chloride, sequentially.
Moreover, reacting the acid hydrazide VIII with different aromatic aldehyds and carbon disulfide afforded XXIIIa-e and XXIV, respectively. Reaction of XXIV with different alkylating agents afforded XXVa-d, while reacting XXIV with hydrazine hydrate gave XXVI. Also, compound VIII was subjected to diazotization conditions to yield XXVII. Phthalimido derivative XXVIII was obtained upon reacting VIII with phthalic anhydride.
Additionally, reaction of VIII with Phenyl isothiocyanate afforded XXIX. Cyclization of XXIX either in acidic medium or under basic condition yielded XXX and XXXI, respectively. While, XXXII was obtained from the reaction of VIII and ethyl isothiocyanate. The reaction of VIII with arylidene derivatives gave the unexpected products XXXIIIa-c.
Compound IX was subjected to nucleophilic substitution reactions to afford compounds XXXIVa-d from which XXXVa-d were prepared. Also XXXVIa-c and XXXVIIa-c were prepared from IX. Alkylation of compound IX was occurred to yield XXXVIIIa&b. Substitution of chlorine atom in IX with thiol group in XXXIX, then alkylating the thiol group with different alkylating agents or chloroacetanilide derivatives yielded XXXXa&b and XXXXIa&b, respectively.
The structure elucidation of the new compounds was supported by element analyses, IR, 1H NMR, 13C H NMR in addition to mass spectral data.
Additionally, a brief account on the docking study was explained through the binding conformations in comparison with the experimental results.
The fourth chapter consists of the experimental part of this work which contains the detailed procedures used for the synthesis of the starting compounds Ia-d-III, the intermediates IV,Vb and VI-IX, in addition to the target new pyrazolopyrimidine compounds Va&c, Xa-d-XIIIa-d and XVb-e-XXXXIa&b, in addition to physical properties and detailed data obtained from element and spectral analysis of these compounds. It also includes the in-vitro anticancer activity of thirty-nine compounds of newly synthesized derivatives compared with methotrexate as a standard cytotoxic agent. Compounds XXXIVb, XXXVIIIa, XXXXb and XXXXIa&b showed the highest in-vitro cytotoxic activity. This chapter also demonstrates the correlation between the results of molecular docking study and the anticancer evaluation. There was some sort of consistency between the docking studies prediction and the in-vitro biological cytotoxic evaluation.
This thesis comprises four chapters. The first one is an introduction which consists of a brief survey of cytotoxic activity of compounds containing pyrazolo[3,4-d]pyrimidine nucleus and the new approaches in their synthesis.
The second chapter deals with the aim of the work and the Schemes for the preparation of starting materials and the new required pyrazolopyrimidine containing compounds.
The third chapter clarifies the theoretical discussion of the experimental work for the preparation of the starting materials Ia-d- III.
Compound III was cyclized either through the reaction with hydrazine hydrate or stirring with different primary amines to afford IV and Va-c, sequentially.
On the other hand, acid hydrolysis of II yielded VI. Reacting VI with diethylmalonate afforded 6-ethoxycarbonylmethylpyrazolopyrimidine derivative VII. Hydrazinolysis of VII gave the acid hydrazide VIII.
Moreover, compound VI was cyclized to give pyrazolopyrimidine derivative IX using chloroacetyl chloride.
Formation of pyrazole ring at position 4 in pyrazolopyrimidine system in compounds Xa-d and XI was prepared from compound IV. The reaction of IV with ethyl acetoacetate or different aromatic aldehydes afforded XII and XIIIa-d, respectively.
On the other hand, compound Vb was reacted with formic acid, acetic anhydride or ethoxymethylenemalononitrile and/or ethoxyethylidenemalononitrile giving XIVa&b.
Also, compounds XVa-e, XVIa&b, XVII, XVIII, XIX, XX, XXI and XXII were synthesized from the reaction of Vb with different aromatic aldehydes , isothiocyanate derivatives, diethyloxalate, diethylmalonate, chloroacetyl chloride, ethyl cyanoacetate, sodium nitrite and oxalyl chloride, sequentially.
Moreover, reacting the acid hydrazide VIII with different aromatic aldehyds and carbon disulfide afforded XXIIIa-e and XXIV, respectively. Reaction of XXIV with different alkylating agents afforded XXVa-d, while reacting XXIV with hydrazine hydrate gave XXVI. Also, compound VIII was subjected to diazotization conditions to yield XXVII. Phthalimido derivative XXVIII was obtained upon reacting VIII with phthalic anhydride.
Additionally, reaction of VIII with Phenyl isothiocyanate afforded XXIX. Cyclization of XXIX either in acidic medium or under basic condition yielded XXX and XXXI, respectively. While, XXXII was obtained from the reaction of VIII and ethyl isothiocyanate. The reaction of VIII with arylidene derivatives gave the unexpected products XXXIIIa-c.
Compound IX was subjected to nucleophilic substitution reactions to afford compounds XXXIVa-d from which XXXVa-d were prepared. Also XXXVIa-c and XXXVIIa-c were prepared from IX. Alkylation of compound IX was occurred to yield XXXVIIIa&b. Substitution of chlorine atom in IX with thiol group in XXXIX, then alkylating the thiol group with different alkylating agents or chloroacetanilide derivatives yielded XXXXa&b and XXXXIa&b, respectively.
The structure elucidation of the new compounds was supported by element analyses, IR, 1H NMR, 13C H NMR in addition to mass spectral data.
Additionally, a brief account on the docking study was explained through the binding conformations in comparison with the experimental results.
The fourth chapter consists of the experimental part of this work which contains the detailed procedures used for the synthesis of the starting compounds Ia-d-III, the intermediates IV,Vb and VI-IX, in addition to the target new pyrazolopyrimidine compounds Va&c, Xa-d-XIIIa-d and XVb-e-XXXXIa&b, in addition to physical properties and detailed data obtained from element and spectral analysis of these compounds. It also includes the in-vitro anticancer activity of thirty-nine compounds of newly synthesized derivatives compared with methotrexate as a standard cytotoxic agent. Compounds XXXIVb, XXXVIIIa, XXXXb and XXXXIa&b showed the highest in-vitro cytotoxic activity. This chapter also demonstrates the correlation between the results of molecular docking study and the anticancer evaluation. There was some sort of consistency between the docking studies prediction and the in-vitro biological cytotoxic evaluation.