Synthesis of 5,7-disubstituted-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amines as microtubule inhibitors.
Synthesis of 5,7-disubstituted-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amines as microtubule inhibitors.
复制标题
作为微管抑制剂的 5,7-二取代-4-甲基-7H-吡咯并[2,3-d]嘧啶-2-胺的合成。
DOI：
10.1016/j.bmc.2012.12.029
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发表时间：
2013
影响因子：
3.5
通讯作者：
Smith,CharlesD
中科院分区：
文献类型：
--
作者：
Gangjee,Aleem;Kurup,Sonali;Smith,CharlesD
化合物 1-4 先前被报道为具有 Pgp 调节作用的有效抗有丝分裂和抗肿瘤药物。化合物 5-18 的合成是为了优化 1-4 的各种活性。化合物 5-10 探讨了甲氧基取代对 1 中 7-苄基部分的影响，而 11-18 则研究了与 1-3 相比，在 C5 处掺入硫连接基的影响。化合物 5-10 表现出有效的个位数微摩尔肿瘤细胞细胞毒性、Pgp 调节和微管抑制作用。该系列的化合物 7 是最有效的，在标准 NCI 临床前体外筛选中针对多种人类肿瘤细胞系显示出纳摩尔范围内的 GI50 值。与 5-苯乙基类似物 2-4 和标准化合物紫杉醇相比，5-苯硫基化合物 11-14 的抗肿瘤活性和 Pgp 调节作用有所降低。 7-苄基部分上的甲氧基取代提高了 5-苯硫基化合物 16 和 17 的抗肿瘤活性。化合物 16 和 17 对肿瘤细胞具有单数至两位数微摩尔的抑制作用。
Compounds 1–4 were previously reported as potent antimitotic and antitumor agents with Pgp modulatory effects. Compounds 5–18 have been synthesized in an attempt to optimize the various activities of 1–4. Compounds 5–10 explored the influence of methoxy substitutions on the 7-benzyl moiety in 1, while 11–18 investigated the influence of incorporation of a sulfur linker at C5 compared to 1–3. Compounds 5–10 demonstrated potent single-digit micromolar tumor cell cytotoxicity, Pgp modulation and microtubule inhibition. Compound 7 of this series was the most potent and showed GI50values in the nanomolar range against several human tumor cell lines in the standard NCI preclinical in vitro screen. Antitumor activity and Pgp modulatory effects were found to decrease for the 5-phenylthio compounds 11–14 compared to their 5-phenylethyl analogs 2–4 and the standard compound Taxol. Incorporation of methoxy substitutions on the 7-benzyl moiety improved antitumor activity for the 5-phenylthio compounds 16 and 17. Compounds 16 and 17 demonstrated single to two-digit micromolar inhibition of tumor cells.