Synthesis of substituted pyrazolopyrimidines

and a series of analogs containing the pyrazolopyrimidine core were synthesized.

Synthesis and biological evaluation of …

To improve the overall yield of the cyclization strategy it was necessary to synthesize the E-oxime 3 with high diastereoselectivity. The stereoselectivity of oxime formation can be difficult to control for aromatic aldehydes, with results often depending on catalyst and temperature. However, in this case, changes to the reaction conditions gave little improvement in diastereoselectivity of this reaction. It had previously been proposed that E-oxime diastereoselectivity could be improved by increasing the steric hindrance of the O-substituent on the hydroxylamine. To investigate this rationale, a number of oxime derivatives were generated using substituted hydroxylamines (Table ).

The synthesis of a variety of previously ..

To improve the overall yield of the cyclization strategy it was necessary to synthesize the E-oxime 3 with high diastereoselectivity. The stereoselectivity of oxime formation can be difficult to control for aromatic aldehydes, with results often depending on catalyst and temperature. However, in this case, changes to the reaction conditions gave little improvement in diastereoselectivity of this reaction. It had previously been proposed that E-oxime diastereoselectivity could be improved by increasing the steric hindrance of the O-substituent on the hydroxylamine. To investigate this rationale, a number of oxime derivatives were generated using substituted hydroxylamines (Table ).

,′-(4,4′-Sulfonylbis(4,1-phenylene))bis(2-cyanoacetamid) 2 was utilized as a key intermediate for the synthesis of novel dihydropyridines 3, 4, 8, dihydroisoquinolines 57, dithiolan 10, dithian 11, acrylamide 12, benzochromenes 17 and 18 and chromenopyridones 19 and 20. Compound 2 was the starting material in the synthesis of the acrylamide derivative 14, the pyrazole derivative 15 and the pyrazolopyrimidine derivative 16. All the synthesized compounds were evaluated for their anticancer activity against human breast cancer cell line (MCF7). Compound 19 showed the best cytotoxic activity with IC50 value 19.36 µ. In addition, molecular docking study of the synthesized compounds on the active sites of farnesyltransferase and arginine methyltransferase was performed in order to give a suggestion about the mechanism of action of their cytotoxic activity.


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During a recent project investigating the function of chaperonin ATPases in cancer, we required the rapid synthesis of a library of ATP-mimics based on the [3,4-d]pyrazolopyrimidine scaffold. To achieve this, we developed a novel one-pot synthesis that is readily applicable to producing analogues using commercially available starting materials and does not require metal-based catalysts or hydrazines.

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In Kemp and Woodward’s seminal publication on the use of hydroxylamine-O-sulfonic acid for the synthesis of benzisoxazole, biphasic reaction conditions were employed to facilitate the cyclization reaction. Presumably, aqueous conditions stabilize the highly charged sulfonate leaving group, promoting the cyclization process. A solution of intermediate 9 in acetonitrile was therefore diluted with dichloromethane and aqueous 1 M sodium hydroxide solution. Clean cyclization proceeded to give the desired pyrazolopyrimidine 6 in 59% yield from 2, and no nitrile byproduct 5 was observed. Finally, we were able to combine all three steps of this synthesis into a one-pot procedure by carrying out the nucleophilic substitution reaction of 1 with aniline in acetonitrile. Hydroxylamine-O-sulfonic acid was then added followed by dilution with dichloromethane and aqueous 1 M sodium hydroxide solution to give a biphasic mixture, which resulted in the formation of the desired pyrazolopyrimidine 6 in 51% yield from 1 (Scheme ).

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During a recent project investigating the function of chaperonin ATPases in cancer, we required the rapid synthesis of a library of ATP-mimics based on the [3,4-d]pyrazolopyrimidine scaffold. To achieve this, we developed a novel one-pot synthesis that is readily applicable to producing analogues using commercially available starting materials and does not require metal-based catalysts or hydrazines.