2018
DOI: 10.1021/acs.jmedchem.8b00408
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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

Abstract: Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine analogues 7–12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) α and β or the proton-coupled folate transporter (PCFT) and for antitumor efficacy. Compounds 8, 9, 11, and 12 showed increased in vitro antiproliferative activities (~11-fold) over the nonfluorinated analogues 2, 3, 5, and 6 toward engineered Chinese hamster ovary and HeLa cells expressing FRs or PCFT. Compounds 8, 9, 11, and 12 also inhibite… Show more

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Cited by 23 publications
(47 citation statements)
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“…Moreover, PCFT transport is further enhanced by a replacement of the side-chain phenyl ring by a 2′,3′- and 2′,4′-thiophene, as in AGF94 and AGF154, respectively ( Figure 2 B) [ 41 , 147 , 148 ]. Side-chain 3′-fluorinated thienoyl analogs of this series (AGF278, AGF283; Figure 2 B) were also synthesized and show high levels of FRα- and PCFT-targeted activity [ 149 ].…”
Section: Targeting Eoc Via Targeted Antifolates: C1 Metabolism As a Unique Vulnerability For Eocmentioning
confidence: 99%
See 2 more Smart Citations
“…Moreover, PCFT transport is further enhanced by a replacement of the side-chain phenyl ring by a 2′,3′- and 2′,4′-thiophene, as in AGF94 and AGF154, respectively ( Figure 2 B) [ 41 , 147 , 148 ]. Side-chain 3′-fluorinated thienoyl analogs of this series (AGF278, AGF283; Figure 2 B) were also synthesized and show high levels of FRα- and PCFT-targeted activity [ 149 ].…”
Section: Targeting Eoc Via Targeted Antifolates: C1 Metabolism As a Unique Vulnerability For Eocmentioning
confidence: 99%
“…Panel ( A ): structures are shown for the dual SHMT1 and SHMT2 inhibitors SHIN1 and SHIN2 [ 150 , 151 ], the MTHFD2 inhibitor DS18561882 [ 152 ], as well as pemetrexed [ 137 ] and CT900 (BGC945, ONX0801) [ 26 ] (both principally thymidylate synthase inhibitors). Panel ( B ): structures are shown for pyrrolo[2,3- d ]pyrimidine GARFTase inhibitors, AGF17 [ 145 ], AGF23 [ 145 ], AGF94 [ 147 ], AGF154 [ 148 ], AGF278 [ 149 ], and AGF283 [ 149 ], as well as the pyrrolo[3,2- d ]pyrimidine antifolate AGF347 [ 153 ], which acts as a multitargeted inhibitor of SHMT2 in the mitochondria and of SHMT1, GARFTase, and ATIC in the cytosol.…”
Section: Targeting Eoc Via Targeted Antifolates: C1 Metabolism As a Unique Vulnerability For Eocmentioning
confidence: 99%
See 1 more Smart Citation
“…To identify the individual (RFC versus PCFT) transport fluxes, assays were performed in the presence of 10 μM of the RFC [N α -(4-amino-4-deoxypteroyl)-N δ -hemiphthaloyl-L-ornithine (PT523)] 37 or PCFT (AGF94) 28 inhibitors. PT523 selectively inhibits RFC transport 38 and AGF94 selectively inhibits PCFT transport 13 , 32 , 33 . Results for R1-11/Tet-on-RFC/PCFT cells are shown in Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Membrane Transport Assays. Plasma membrane transport measurements were performed at 37°C as previously described (Ravindra et al, 2018). Buffers used were MES [2-(N-morpholino) ethanesulfonic acid]-buffered saline at pH 5.5 (20 mM MES, 140 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , and 5 mM glucose) and HEPES [4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid]-buffered saline at pH 6.8 and pH 7.2 (20 mM HEPES, 140 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , and 5 mM glucose).…”
Section: Methodsmentioning
confidence: 99%