Abstract
An olomoucine analogues of 2-[(1-substituted)-2,6-dioxo-2,3,6,7–tetrahydro-1H-purin-8-ylsulfanyl]-N-substituted acetamide 6a-g and 7a-g, 1-substituted-8-[2-(4-substituted phenyl)-2-oxoethylsulphanyl]-3,7-dihydro-1H-purine-2,6-diones 9a-g and 10a-g, 3-(2-substituted benzyl)-6-(4-substituted phenyl)-1H-thiazolo[2,3-f]purine-2,4-dione 11a-g and 12a-g and their isosteres 3-substituted benzyl-5-methyl-7-substituted-1H-pyrido[2,3-d]pyrimidine-2,4-dione 13a-c and 14a-c were designed and synthesized. The target compounds 11a-g and 12a-g were prepared by cyclodehydration of 9a-g and 10a-g in PPA, while 13a-c and 14a-c were synthesized by condensation of 6-amino-3-(2-substituted benzyl)-1H-pyrimidine-2,4-dione 1a or 1b and the appropriate acylacetone in glacial acetic acid. Structures of the new compounds were verified on the basis of their IR, 1H NMR, MS, HRMS and elemental analyses. The newly synthesized compounds were tested for their anticancer activity and most of the tested compounds showed good to excellent inhibition activity against the tested human breast cancer cell line MCF-7 in comparison to doxorubicin as a reference drug.
 KEYWORDS: olomoucine; cyclin-depenent kinase; synthesis; anticancer
Highlights
Cancer is a class of diseases characterized by out-of-control cell growth
Despite the enormous progress made in recent years in the understanding of the mechanisms involved in cancer onset and propagation and apart from classical cytotoxic-based therapies, there has been an active search for new approaches, such as protein kinase inhibition 4
In view of the above-mentioned facts and in continuation of our interest in the synthesis of new heterocyclic compounds comprising in their skeletons the purine-2,6-dione moieties and screening of their biological activities, we report the synthesis and anticancer activity of new purine-diones and their isosters pyridopyrimidine diones
Summary
Cancer is a class of diseases characterized by out-of-control cell growth. Cancers can arise from both genetic and lifestyle factors that lead to abnormal regulation in the growth of particular stem cell populations or by the undifferentiation of mature cell types 1. The pyrimidine and purine ring systems undoubtedly belong to the most ubiquitous heterocycles in nature, as they represent the main structure of many biologically significant compounds, including nucleosides and nucleotides. Several of the latter heterocycles possess a multitude of pronounced biological activities 8. Recently 1,8-disubstituted purine-2,6-diones [AH-216 (II), AH-217 (III); chart 2] were reported to possess potent antitumor activity against breast cancer and leukemia 10 For these reasons, many analogues and derivatives of purine and pyrimidine have been synthesised and developed as pharmacologically active compounds 8. In view of the above-mentioned facts and in continuation of our interest in the synthesis of new heterocyclic compounds comprising in their skeletons the purine-2,6-dione moieties and screening of their biological activities, we report the synthesis and anticancer activity of new purine-diones and their isosters pyridopyrimidine diones
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