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  • Introduction Thienopyrimidines comprise a thiophene ring fus


    Introduction Thienopyrimidines comprise a thiophene ring fused with the pyrimidine moiety similar to the imidazole moiety in purines [1]. Thienopyrimidines in general have become an interesting structural element in development of pharmaceutical compounds [2,3], and have among others been evaluated as cGMP phosphodiesterase inhibitors [4], anti-viral agents [5], anti-inflammatory agents [6], anti-microbial agents [7], but also as kinase inhibitors and potential anti-cancer agents [8,9]. Protein kinases are enzymes that modify other proteins by phosphorylation which involves transferring a phosphate group from a nucleoside triphosphate (usually ATP) and covalently attaching it to specific Calcium Ionophore I with a free hydroxyl group. Based upon their catalytic specificity, the enzyme classes can be divided into three categories: those specific for Tyr, those specific for Ser/Thr, and those specific for both Tyr and Ser/Thr. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins [10]. Protein kinases constitute one of the largest protein families in human. The human genome contains about 518 protein kinase genes; these constitute about 2% of all human genes. Protein kinases play important roles in signal transduction pathways that regulate numerous cellular functions, including proliferation, differentiation, apoptosis, migration, and angiogenesis. The up-regulation of the signal transduction pathways is well observed in many tumor cells which make inhibitors of protein kinases that target these up-regulated pathways attractive candidates for cancer treatment through targeting the kinase ATP binding site [11,12].
    Synthetic strategy Numerous synthetic strategies have been outlined for the synthesis of thieno[2,3-d]pyrimidine scaffold (A) incorporated in various kinase inhibitors. Substituted ethyl 2-aminothiophene -3-carboxylate (I) has been used in numerous reactions to attain the desired scaffold (A) through different routes. Han et al. [13] reported the reaction of (I) with formamidine acetate in N methylpyrrolidone at 135 °C under argon affording the scaffold (A) (route a). Rashmi et al. [14] reported refluxing compound (I) with formamide (route b) to afford (A). Youla S. et al. [15] accomplished the synthesis of the final compound (A) by refluxing substituted 5-amino-4-cyanothiophenederivatives (II) with formic acid in presence of sulfuric acid (route c). Varvounis et al. [2] reported the synthesis of the final compound (A) by different routes; From carboxamide (III) by heating in formic acid or triethylorthoformate (route d) or from 4-amino 6-chloropyrimidine-5-carbaldehydes (IV) in methanol containing methyl 2-mercaptoacetate and triethylamine (route e) and finally by heating4-chloropyrimidine-5-carbonitriles (V) and alkyl 2-mercaptoacetate in ethanol containing base (route f) (Fig. 1).
    Anticancer activity as kinase inhibitors The biological investigations of thieno[2,3-d]pyrimidines have revealed that substitution of a variety of groups on the scaffold imparts anticancer activity through inhibition of different kinases. The following study is a brief account of different protein kinases reported to be inhibited by thieno[2,3-d]pyrimidine derivatives.
    Conclusion In this review we have compiled and discussed specifically the anticancer potential of thieno[2,3-d]pyrimidine derivatives through inhibition of different kinase enzymes, as well as their synthetic strategies. Many studies have investigated their SAR, and the specific 3D orientation required for their binding at the kinase binding site. This could provide a guide for medicinal chemists for precise and target-specific information for development of thienopyrimidine-based anticancer drugs.
    Introduction The biological activities of some 2′-deoxyribonucleosides and arabinonucleosides have been known for several years [1–3]. Interest in arabinosyl pyrimidines as potential chemotherapeutic agents was stimulated by the observation that ara-C (Fig. 1) was found to have some selective antiviral activity versus DNA viruses such as herpes simplex and vaccinia [4–7]. Ara-C is a synthetic compound chosen for clinical trials in acute leukemias because of its activity in leukemia L1210 and is known as the most effective drug in adult acute leukemia [8–10]; however, it is rapidly inactivated by enzymatic deamination.