Design, synthesis and biological evaluation of novel pyrrolo[2,3-d] pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier
Design, synthesis and biological evaluation of novel pyrrolo[2,3-d] pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier
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DOI：
10.1016/j.bmc.2020.115544
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发表时间：
2020-06-15
影响因子：
3.5
通讯作者：
Gangjee, Aleem
中科院分区：
文献类型：
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作者：
Golani, Lalit K.;Islam, Farhana;Gangjee, Aleem
基于 2 的肿瘤靶向 6-取代吡咯并[2,3-d]嘧啶苯甲酰基化合物通过用杂原子 N (4)、O (5) 或 S (6) 或用 N-取代甲酰基 (7)、三氟乙酰基 (8) 或乙酰基 (9) 取代邻位 (C11) 碳，在 4 碳桥处进行等排修饰。用硫替代 (6) 提供了最有效的 KB 肿瘤细胞抑制剂，与母体 2 类似，效果好 6 倍。此外，与普遍存在的还原叶酸载体 (RFC) 相比，6 通过叶酸受体 (FR) α 和 -β 保留了肿瘤转运选择性。 6 的 FR α 介导的细胞抑制通常相当于 2，而 FR β 介导的活性比 2 提高了 16 倍。N (4) 和 O (5) 取代提供了与 2 相似的肿瘤细胞抑制作用，并且对 FR α 和 β 的选择性高于 RFC。 N-取代的类似物7-9还保留了对FRα和-β相对于RFC的转运选择性。对于表达 FR α 的 CHO 细胞，效力顺序为 8 > 7 > 9。而 8 和 9 显示与表达 FR β 的 CHO 细胞相似的结果，而 7 的活性比 2 相似，活性高 16 倍。通过核苷救援实验，所有化合物均抑制从头嘌呤生物合成，可能是在甘氨酰胺核糖核苷酸甲酰基转移酶催化的步骤中。因此，2桥中CH2的杂原子取代提供了具有增强的肿瘤细胞抑制作用的类似物，其可以提供优于2的优势，以及优于临床使用的抗叶酸剂（包括甲氨蝶呤和培美曲塞）的肿瘤转运选择性。
Tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine benzoyl compounds based on 2 were isosterically modified at the 4-carbon bridge by replacing the vicinal (C11) carbon by heteroatoms N (4), O (5) or S (6), or with an N-substituted formyl (7), trifluoroacetyl (8) or acetyl (9). Replacement with sulfur (6) afforded the most potent KB tumor cell inhibitor, similar to 6-fold better than the parent 2. In addition, 6 retained tumor transport selectivity via folate receptor (FR) alpha and-beta over the ubiquitous reduced folate carrier (RFC). FR alpha-mediated cell inhibition for 6 was generally equivalent to 2, while the FR beta-mediated activity was improved by 16-fold over 2. N (4) and O (5) substitutions afforded similar tumor cell inhibitions as 2, with selectivity for FR alpha and-beta over RFC. The N-substituted analogs 7-9 also preserved transport selectivity for FR alpha and-beta over RFC. For FR alpha expressing CHO cells, potencies were in the order of 8 > 7 > 9. Whereas 8 and 9 showed similar results with FR beta-expressing CHO cells, 7 was similar to 16-fold more active than 2. By nucleoside rescue experiments, all the compounds inhibited de novo purine biosynthesis, likely at the step catalyzed by glycinamide ribonucleotide formyltransferase. Thus, heteroatom replacements of the CH2 in the bridge of 2 afford analogs with increased tumor cell inhibition that could provide advantages over 2, as well as tumor transport selectivity over clinically used antifolates including methotrexate and pemetrexed.