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N-[4-[1-乙基-2-(2,4-二氨基呋[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-L-谷氨酸作为一种抗叶酸剂的合成。

Synthesis of N-[4-[1-ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid as an antifolate.

作者信息

Gangjee Aleem, Zeng Yibin, McGuire John J, Kisliuk Roy L

机构信息

Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.

出版信息

J Med Chem. 2002 Apr 25;45(9):1942-8. doi: 10.1021/jm010575m.

DOI:10.1021/jm010575m
PMID:11960504
Abstract

N-[4-[1-Ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid 3 was designed and synthesized to investigate the effect of homologation of a C9-methyl to an ethyl on dihydrofolate reductase (DHFR) inhibition and on antitumor activity. Compound 3 was obtained via a concise seven step synthesis starting from palladium-catalyzed carbonylation of 4-propionylphenol, followed by a Wittig reaction with 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine (6), catalytic hydrogenation, hydrolysis, and standard peptide coupling with diethyl L-glutamate. The biological results indicated that extending the C9-methyl group to an ethyl on the C8-C9 bridge region (analogue 3) doubled the inhibitory potency against recombinant human (rh) DHFR (IC(50) = 0.21 microM) as compared to the C9-methyl analogue 1 and was 4-fold more potent than the C9-H analogue 2. As compared to 1, compound 3 demonstrated increased growth inhibitory potency against several human tumor cell lines in culture with GI(50) values < 1.0 x 10(-8) M. Compound 3 was also a weak inhibitor of rh thymidylate synthase. Compounds 1 and 3 were efficient substrates of human folylpolyglutamate synthetase (FPGS). Further evaluation of the cytotoxicity of 3 in methotrexate-resistant CCRF-CEM cell sublines and metabolite protection studies implicated DHFR as the primary intracelluar target. Thus, alkylation of the C9 position in the C8-C9 bridge of the classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine is highly conducive to DHFR and tumor inhibitory activity as well as FPGS substrate efficiency.

摘要

设计并合成了N-[4-[1-乙基-2-(2,4-二氨基呋喃并[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-L-谷氨酸3，以研究C9位甲基同系化为乙基对二氢叶酸还原酶（DHFR）抑制作用和抗肿瘤活性的影响。化合物3通过简洁的七步合成法制备，起始于4-丙酰基苯酚的钯催化羰基化反应，随后与2,4-二氨基-5-(氯甲基)呋喃并[2,3-d]嘧啶(6)进行维蒂希反应、催化氢化、水解，以及与L-谷氨酸二乙酯进行标准肽偶联反应。生物学结果表明，在C8-C9桥区域将C9位甲基扩展为乙基（类似物3），与C9位甲基类似物1相比，对重组人（rh）DHFR的抑制效力提高了一倍（IC(50)=0.21 microM），且比C9-H类似物2强4倍。与1相比，化合物3在培养的几种人肿瘤细胞系中表现出更高的生长抑制效力，GI(50)值<1.0×10(-8) M。化合物3也是rh胸苷酸合成酶的弱抑制剂。化合物

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