Synthesis and Biological Activity of 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Inhibitors of de Novo Purine Biosynthesis with Selectivity for Cellular Uptake by High Affinity Folate Receptors and the Proton-Coupled Folate Transporter over the Reduced Folate Carrier

Abstract

We reported the selective transport of classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl-for-benzoyl-substituted side chain and a 3- (3a) and 4-carbon (3b) bridge. Compound 3a was more potent than 3b against tumor cells; While 3b was completely selective for transport by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) over reduced folate carrier (RFC), 3a was not. To determine if decreasing the distance between the bicyclic scaffold and L-glutamate in 3b would preserve transport selectivity and potency against human tumor cells, 3b regioisomers with [1,3] (7 and 8) and [1,2] (4, 5 and 6) substitutions on the thienoyl ring, and with acetylenic insertions in the 4-atom bridge, were synthesized and evaluated. Compounds 7 and 8 were potent nanomolar inhibitors of KB and IGROV1 human tumor cells with complete selectivity for FRα and PCFT over RFC.

Folded conformations due to arene interactions in dissymmetric and symmetric butylidene-linker models based on pyrazolo[3,4-d]pyrimidine, purine and 7-deazapurine

“…The pyrrolo[2,3-d]pyrimidine core is another biologically important system (Wang et al, 2012) and it is structurally related to The molecular structure of (XI), showing -interactions (dashed lines) and the atomic labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.…”

Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

“…30 In other cases, differences were more subtle. For certain analogues ( 3 and 6 ), the modest growth inhibitions previously reported for RFC-expressing PC43–10 cells 25,27 were increased (~5- and ~10-fold, respectively) for their fluorinated counterparts ( 9 and 12 ) (Table 1), although still less than for the FR- and PCFT-expressing CHO sublines. As these inhibitions extended to R2 cells, they must reflect a nonmediated uptake component.…”

“…25,26 Replacements of the side-chain phenyl group with a thiophene resulted in novel compounds 5 and 6 , respectively, 27,28 while replacement of the phenyl moiety of 2 by a pyridine resulted in compound 4 29 (Figure 1). Compounds 4–6 , like 2 and 3 , 25,26 are all selective for PCFT and FR cellular uptake over RFC and inhibited GARFTase, resulting in cytotoxicity and inhibition of tumor cell proliferation.…”

“…Compounds 4–6 , like 2 and 3 , 25,26 are all selective for PCFT and FR cellular uptake over RFC and inhibited GARFTase, resulting in cytotoxicity and inhibition of tumor cell proliferation. 27–29 …”

Molecular Modeling Studies and Synthesis of Novel Methyl 2-(2-(4-Oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)alkanoates with Potential Anti-cancer Activity as Inhibitors for Methionine Synthase

“…7) 6-Substituted pyrrolo-and thieno [2,3-d]pyrimidine derivatives were identified as antifolates with selective membrane transport by proton-coupled folate transporter (PCFT) and folate receptors (FRs) over reduced folate carrier (RFC). 8) A series of pyrido [2,3-d] pyrimidines was successfully synthesized and used by Gangjee et al as selective and potent DHFR inhibitors. 9) In a strategy for discovering specific inhibitors of MetS, some benzo-fused heterocycles have been designed and synthesized that mimic the substructures of 5-methyltetrahydrofolate of MetS.…”