Xanthines as a scaffold for molecular diversity

Abstract

SummaryXanthines represent a new, versatile scaffold for combinatorial chemistry. A five-step solid-phase synthesis of xanthine derivatives is described which includes alkylations, a nucleophilic displacement reaction at a heterocycle and a ring closure reaction by condensation of a nitroso function with an activated methylene group. The selected reaction sequence allows the production of a highly diverse small-molecule combinatorial compound library.

Xanthine scaffold: scope and potential in drug development

“…In drug development process, one of the major challenges is deciding the lead molecule which would act as a scaffold to provide avenue for achieving molecular diversity. Xanthine with versatile and structurally rigid scaffold provides highest possibility for molecular diversity in constructing xanthine derivatives for combinatorial chemistry [ 15 , 20 , 21 , 22 , 23 ].…”

Solid-Phase Synthetic Strategies for the Preparation of Purine Derivatives

“…This strategy was initially introduced for 1,3,7,8-tetrasubstituted xanthines . Similar to the previously discussed methods, the key building block (6-chloropyrimidine-2,4­(1 H ,3 H )-dione) required premodification prior to its immobilization.…”

“…This strategy was initially introduced for 1,3,7,8-tetrasubstituted xanthines. 22 Similar to the previously discussed methods, the key building block (6-chloropyrimidine-2,4(1H,3H)-dione) required premodification prior to its immobilization. After solution-phase N 3 -alkylation was performed, the intermediate 33 was appended to the Rink amide resin equipped with the bromoacetyl spacer 32 (Scheme 6).…”

Recent developments in solid-phase organic synthesis

“…The solid-phase approach was validated by the synthesis of eight individual xanthines which were isolated in 10-32% yield after HPLC purification. 107 Providing N-1 was blocked by substitution, the cyclisation of the intermediate 5-nitrosouracil proceeded smoothly. A library theoretically containing 90 xanthines was prepared using this method.…”

“…Classes of compounds which have been shown to undergo N-alkylation using this approach include: peptides; 124,125 sulfonamides; 66,126,127 indoles; 74 benzodiazepines; 95,128 quinazoline-2,4-diones; 102 and xanthines. 107 Miller and Scanlan have devised an operationally simple procedure for site-selective N-methylation of a growing peptide based on the Fukuyama amine synthesis (Scheme 54). 127 A very closely related approach was used by others to prepare N-methyl amino acids, the only difference being that alkylation was achieved using the Mitsunobu reaction.…”