Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits β-glycinamide ribonucleotide formyltransferase

Lei Wang, Sita Kugel Desmoulin, Christina Cherian, Lisa Polin, Kathryn White, Juiwanna Kushner, Andreas Fulterer, Min Hwang Chang, Shermaine Mitchell-Ryan, Mark Stout, Michael F Romero, Zhanjun Hou, Larry H. Matherly, Aleem Gangjee

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine antifolates with a thienoyl side chain (compounds 1-3, respectively) were synthesized for comparison with compound 4, the previous lead compound of this series. Conversion of hydroxyl acetylen-thiophene carboxylic esters to thiophenyl-α-bromomethylketones and condensation with 2,4-diamino-6- hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidine compounds of type 18 and 19. Coupling with l-glutamate diethyl ester, followed by saponification, afforded 1-3. Compound 3 selectively inhibited the proliferation of cells expressing folate receptors (FRs) α or β, or the proton-coupled folate transporter (PCFT), including KB and IGROV1 human tumor cells, much more potently than 4. Compound 3 was more inhibitory than 4 toward β-glycinamide ribonucleotide formyltransferase (GARFTase). Both 3 and 4 depleted cellular ATP pools. In SCID mice with IGROV1 tumors, 3 was more efficacious than 4. Collectively, our results show potent antitumor activity for 3 in vitro and in vivo, associated with its selective membrane transport by FRs and PCFT over RFC and inhibition of GARFTase, clearly establishing the 3-atom bridge as superior to the 1-, 2-, and 4-atom bridge lengths for the activity of this series.

Original languageEnglish (US)
Pages (from-to)7150-7164
Number of pages15
JournalJournal of Medicinal Chemistry
Volume54
Issue number20
DOIs
StatePublished - Oct 27 2011

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Proton-Coupled Folate Transporter
Hydroxymethyl and Formyl Transferases
Reduced Folate Carrier Protein
Folic Acid Antagonists
Folic Acid
Esters
Thiophenes
SCID Mice
Hydroxyl Radical
Glutamic Acid
Neoplasms
Adenosine Triphosphate
Cell Proliferation
Membranes
glycinamide ribonucleotide
Pyrrolo(2,3-d)pyrimidine

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits β-glycinamide ribonucleotide formyltransferase. / Wang, Lei; Desmoulin, Sita Kugel; Cherian, Christina; Polin, Lisa; White, Kathryn; Kushner, Juiwanna; Fulterer, Andreas; Chang, Min Hwang; Mitchell-Ryan, Shermaine; Stout, Mark; Romero, Michael F; Hou, Zhanjun; Matherly, Larry H.; Gangjee, Aleem.

In: Journal of Medicinal Chemistry, Vol. 54, No. 20, 27.10.2011, p. 7150-7164.

Research output: Contribution to journalArticle

Wang, Lei ; Desmoulin, Sita Kugel ; Cherian, Christina ; Polin, Lisa ; White, Kathryn ; Kushner, Juiwanna ; Fulterer, Andreas ; Chang, Min Hwang ; Mitchell-Ryan, Shermaine ; Stout, Mark ; Romero, Michael F ; Hou, Zhanjun ; Matherly, Larry H. ; Gangjee, Aleem. / Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits β-glycinamide ribonucleotide formyltransferase. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 20. pp. 7150-7164.
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T1 - Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits β-glycinamide ribonucleotide formyltransferase

AU - Wang, Lei

AU - Desmoulin, Sita Kugel

AU - Cherian, Christina

AU - Polin, Lisa

AU - White, Kathryn

AU - Kushner, Juiwanna

AU - Fulterer, Andreas

AU - Chang, Min Hwang

AU - Mitchell-Ryan, Shermaine

AU - Stout, Mark

AU - Romero, Michael F

AU - Hou, Zhanjun

AU - Matherly, Larry H.

AU - Gangjee, Aleem

PY - 2011/10/27

Y1 - 2011/10/27

N2 - 2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine antifolates with a thienoyl side chain (compounds 1-3, respectively) were synthesized for comparison with compound 4, the previous lead compound of this series. Conversion of hydroxyl acetylen-thiophene carboxylic esters to thiophenyl-α-bromomethylketones and condensation with 2,4-diamino-6- hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidine compounds of type 18 and 19. Coupling with l-glutamate diethyl ester, followed by saponification, afforded 1-3. Compound 3 selectively inhibited the proliferation of cells expressing folate receptors (FRs) α or β, or the proton-coupled folate transporter (PCFT), including KB and IGROV1 human tumor cells, much more potently than 4. Compound 3 was more inhibitory than 4 toward β-glycinamide ribonucleotide formyltransferase (GARFTase). Both 3 and 4 depleted cellular ATP pools. In SCID mice with IGROV1 tumors, 3 was more efficacious than 4. Collectively, our results show potent antitumor activity for 3 in vitro and in vivo, associated with its selective membrane transport by FRs and PCFT over RFC and inhibition of GARFTase, clearly establishing the 3-atom bridge as superior to the 1-, 2-, and 4-atom bridge lengths for the activity of this series.

AB - 2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine antifolates with a thienoyl side chain (compounds 1-3, respectively) were synthesized for comparison with compound 4, the previous lead compound of this series. Conversion of hydroxyl acetylen-thiophene carboxylic esters to thiophenyl-α-bromomethylketones and condensation with 2,4-diamino-6- hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidine compounds of type 18 and 19. Coupling with l-glutamate diethyl ester, followed by saponification, afforded 1-3. Compound 3 selectively inhibited the proliferation of cells expressing folate receptors (FRs) α or β, or the proton-coupled folate transporter (PCFT), including KB and IGROV1 human tumor cells, much more potently than 4. Compound 3 was more inhibitory than 4 toward β-glycinamide ribonucleotide formyltransferase (GARFTase). Both 3 and 4 depleted cellular ATP pools. In SCID mice with IGROV1 tumors, 3 was more efficacious than 4. Collectively, our results show potent antitumor activity for 3 in vitro and in vivo, associated with its selective membrane transport by FRs and PCFT over RFC and inhibition of GARFTase, clearly establishing the 3-atom bridge as superior to the 1-, 2-, and 4-atom bridge lengths for the activity of this series.

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