Discovery of Tumor-Targeted 6-Methyl Substituted Pemetrexed and Related Antifolates with Selective Loss of RFC Transport.
Discovery of Tumor-Targeted 6-Methyl Substituted Pemetrexed and Related Antifolates with Selective Loss of RFC Transport.
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发现肿瘤靶向6-甲基取代的培美曲塞和选择性丧失RFC转运的相关抗叶酸剂。
DOI：
10.1021/acsmedchemlett.3c00326
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发表时间：
2023-12-14
影响因子：
4.2
通讯作者：
Gangjee, Aleem
中科院分区：
文献类型：
--
作者：
Kaku, Krishna;Ravindra, Manasa P.;Tong, Nian;Choudhary, Shruti;Li, Xinxin;Yu, Jianming;Karim, Mohammad;Brzezinski, Madelyn;O'Connor, Carrie;Hou, Zhanjun;Matherly, Larry H.;Gangjee, Aleem
培美曲塞和相关的5-取代吡咯并[2，3-d]嘧啶抗叶酸剂是广泛表达的还原型叶酸载体（RFC）、质子偶联叶酸转运蛋白（PCFT）和叶酸受体（FR）的底物，具有更强的肿瘤选择性。一个长期的目标是发现肿瘤靶向治疗剂，这些治疗剂利用癌细胞的一碳代谢脆弱性，并且选择性地通过FR和PCFT而不是RFC进行运输。我们发现，5-取代的2-氨基-4-氧代-吡咯并[2，3-d]嘧啶抗叶酸剂1-4（包括培美曲塞）的双环骨架中吡咯环6位的甲基消除了RFC的转运，对FR或PCFT的影响不大。从分子建模，RFC运输的损失涉及由于6-甲基部分在支架结合位点的空间排斥。6-甲基取代保留了对人肿瘤细胞（KB，IGROV 3）的抗增殖活性，对IOSE 7576正常卵巢细胞具有选择性，并抑制从头嘌呤生物合成。因此，向5-取代的吡咯并[2，3-d]嘧啶抗叶酸剂中加入6-甲基部分提供了肿瘤转运选择性，同时保留了抗肿瘤功效。
Pemetrexed and related 5-substituted pyrrolo[2,3-d]pyrimidine antifolates are substrates for the ubiquitously expressed reduced folate carrier (RFC), and the proton-coupled folate transporter (PCFT) and folate receptors (FRs) which are more tumor-selective. A long-standing goal has been to discover tumor-targeted therapeutics that draw from one-carbon metabolic vulnerabilities of cancer cells and are selective for transport by FRs and PCFT over RFC. We discovered that a methyl group at the 6-position of the pyrrole ring in the bicyclic scaffold of 5-substituted 2-amino-4-oxo-pyrrolo[2,3-d]pyrimidine antifolates 1–4 (including pemetrexed) abolished transport by RFC with modest impacts on FRs or PCFT. From molecular modeling, loss of RFC transport involves steric repulsion in the scaffold binding site due to the 6-methyl moiety. 6-Methyl substitution preserved antiproliferative activities toward human tumor cells (KB, IGROV3) with selectivity over IOSE 7576 normal ovary cells and inhibition of de novo purine biosynthesis. Thus, adding a 6-methyl moiety to 5-substituted pyrrolo[2,3-d]pyrimidine antifolates affords tumor transport selectivity while preserving antitumor efficacy.
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影响因子：
50.5
作者：
Giovannetti, E.;Zucali, P. A.;Peters, G. J.
通讯作者：
Peters, G. J.
DOI：
10.1007/978-1-4419-8417-3_2
发表时间：
2011-01-01
期刊：
TARGETED DRUG STRATEGIES FOR CANCER AND INFLAMMATION
影响因子：
--
作者：
Kamen, Barton A.
通讯作者：
Kamen, Barton A.
影响因子：
5.5
作者：
Qiu, Andong;Min, Sang Hee;Goldman, I. David
通讯作者：
Goldman, I. David
肿瘤以新型的6个取代的吡罗洛[2,3-d]嘧啶氨酸抗性酸酯抗凝聚酸盐，通过叶酸受体α和质子偶联的叶酸转运蛋白和protoin purine purine核苷酸生物合成的细胞摄取和杂原桥取代。
影响因子：
7.3
作者：
Golani, Lalit K.;Wallace-Povirk, Adrianne;Deis, Siobhan M.;Wong, Jennifer;Ke, Jiyuan;Gu, Xin;Raghavan, Sudhir;Wilson, Mike R.;Li, Xinxin;Poling, Lisa;de Waal, Parker W.;White, Kathryn;KushnerP, Juiwanna;O'Connor, Carrie;Hou, Zhanjun;Xu, H. Eric;Melcher, Karsten;Dann, Charles E., III;Matherly, Larry H.;Gangjee, Aleem
通讯作者：
Gangjee, Aleem
影响因子：
7.3
作者：
Mitchell-Ryan S;Wang Y;Raghavan S;Ravindra MP;Hales E;Orr S;Cherian C;Hou Z;Matherly LH;Gangjee A
通讯作者：
Gangjee A