Abstract 1620: Synthesis and preclinical evaluation of novel 6-substituted pyrrolo[2,3-d]pyrimidines as targeted antifolates

Autor: Adrianne Wallace, Shermaine Mitchell-Ryan, Aleem Gangjee, Steven Orr, Larry H. Matherly, Lalit K. Golani, Lisa Polin, Christina Cherian
Rok vydání: 2014
Předmět:
Zdroj: Cancer Research. 74:1620-1620
ISSN: 1538-7445
0008-5472
Popis: Reduced folates are essential cofactors for biosynthesis of purines and pyrimidines. Since humans do not synthesize folate, it is necessary to obtain these cofactors from dietary sources. In mammals, three specialized systems exist that mediate membrane transport of folates and antifolates across biological membranes. These include the reduced folate carrier (RFC), the primary route for the uptake of folates and antifolates in mammalian cells, folate receptors (FRs) α and β, and the proton-coupled folate transporter (PCFT). Whereas RFC is ubiquitously expressed, FRs and PCFT show a more narrow pattern of tissue expression. Toxicity of clinically used antifolates occurs in part, to their lack of selectivity for tumor cells over normal cells due to RFC transport. Antifolates with tumor-specific FR and/or PCFT drug uptake would circumvent major toxicities of currently used antifolates. Our analog AG17F had shown selective FR and PCFT transport over RFC with excellent cell inhibitory activity in KB tumor cell line (IC50 = 1.7 nM). On the basis of AG17F, AG140F with sulfur in place of carbon at C10, AG182F with oxygen in place of carbon at C10 and AG183F with nitrogen in place of carbon at C10 were designed and synthesized. This isosteric replacement of carbon with heteroatoms in the bridge provides compounds with different chain lengths, angles, conformations and extra hydrogen bond donors and/or acceptors compared to the parent carbon chain analogues. AG17F had shown inhibitory activity toward the growth of a CHO cell line (hRFC) expressing human RFC (IC50 = 304 nM), the three heteroatom analogues AG140F, AG182F and AG183F were inactive in the CHO cell line expressing RFC transport at concentrations up to 1000 nM, but were highly active in inhibiting CHO cell lines (RT16) expressing human FRα (IC50s of 0.62, 1.10, and 2.3 nM respectively) and inhibiting PCFT-expressing CHO cells (R2/PCFT4) (IC50s of 267, 57.3, and 87.4 nM respectively). AG140F, AG182F, and AG183F were potently inhibitory toward KB tumor cells (IC50s of 2, 0.32 and 0.34 nM respectively) and IGROV1 tumor cells (IC50s of 0.51, 0.58 and 0.48 nM respectively). AG140F, AG182F, and AG183F showed binding affinities to FRα in RT16 cells exceeding that for AG17F, and comparable to folic acid. With R2/PCFT4 cells, all compounds showed high affinities with binding (reflected in Ki values) in the order of AG17F>AG182F∼AG183F>AG140F. In KB cells, adenosine and 5-aminoimidazole-4-carboxamide protected from growth inhibition suggesting de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase) and the likely targets. By in situ assays in KB cells, GARFTase inhibition was confirmed at concentrations similar to those which inhibit cell proliferation. AG183F was further evaluated for against early stage human IGROV tumor xenograft in female SCID mice models and was found to be remarkably efficacious (T/C = 12%) without any acute or long term toxicities. Citation Format: Lalit Kumar Golani, Aleem Gangjee, Christina Cherian, Steven Orr, Shermaine Mitchell-Ryan, Lisa Polin, Adrianne Wallace, Larry H. Matherly. Synthesis and preclinical evaluation of novel 6-substituted pyrrolo[2,3-d]pyrimidines as targeted antifolates. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1620. doi:10.1158/1538-7445.AM2014-1620
Databáze: OpenAIRE
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