The 3-D conformational shape of N-naphthyl-cyclopenta[d]pyrimidines affects their potency as microtubule targeting agents and their antitumor activity.
The 3-D conformational shape of N-naphthyl-cyclopenta[d]pyrimidines affects their potency as microtubule targeting agents and their antitumor activity.
复制标题
DOI：
10.1016/j.bmc.2020.115887
复制
发表时间：
2021-01-01
影响因子：
3.5
通讯作者：
Gangjee A
中科院分区：
文献类型：
--
作者：
Xiang W;Quadery TM;Hamel E;Luckett-Chastain LR;Ihnat MA;Mooberry SL;Gangjee A
设计并合成了一系列甲氧基萘基取代环五[d]嘧啶化合物4-10，研究其三维构象对微管解聚和抗增殖活性的影响。用N，2-二甲基-N-（6′-甲氧基萘基-1′-氨基）-环五[d]嘧啶-4-胺(4)进行的noesi研究表明，环烷环在环五[d]嘧啶支架周围旋转受阻。相比之下，noesi研究表明，N，2-二甲基-N-（5′-甲氧基萘基-2′-氨基）-环五[d]嘧啶-4-胺(5)的萘环围绕环五[d]嘧啶支架自由旋转。4和5之间的旋转柔韧性和构象差异导致了生物活性的显著差异。化合物4是无活性的，而5是该系列中最有效的，具有强大的微管解聚作用和低纳摩尔IC50值，在体外对抗多种癌细胞系。在U251胶质瘤异种移植模型中研究了5在体内抑制肿瘤生长的能力。结果表明，5具有比阳性对照替莫唑胺更好的抗肿瘤作用，并确定5为进一步研究的潜在临床前候选药物。构象对微管解聚和抗肿瘤活性的影响为环五[d]嘧啶类微管靶向剂构象-活性关系的发展奠定了基础。
A series of methoxy naphthyl substituted cyclopenta[d]pyrimidine compounds, 4–10, were designed and synthesized to study the influence of the 3-D conformation on microtubule depolymerizing and antiproliferative activities. NOESY studies with the N,2-dimethyl-N-(6ʹ-methoxynaphthyl-1ʹ-amino)-cyclopenta[d]pyrimidin-4-amine (4) showed hindered rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. In contrast, NOESY studies with N,2-dimethyl-N-(5ʹ-methoxynaphthyl-2ʹ-amino)-cyclopenta[d]pyrimidin-4-amine (5) showed free rotation of the naphthyl ring around the cyclopenta[d]pyrimidine scaffold. The rotational flexibility and conformational dissimilarity between 4 and 5 led to a significant difference in biological activities. Compound 4 is inactive while 5 is the most potent in this series with potent microtubule depolymerizing effects and low nanomolar IC50 values in vitro against a variety of cancer cell lines. The ability of 5 to inhibit tumor growth in vivo was investigated in a U251 glioma xenograft model. The results show that 5 had better antitumor effects than the positive control temozolomide and has identified 5 as a potential preclinical candidate for further studies. The influence of conformation on the microtubule depolymerizing and antitumor activity forms the basis for the development of conformation-activity relationships for the cyclopenta[d]pyrimidine class of microtubule targeting agents.
登录
查看更多内容
影响因子：
11.2
作者：
Risinger AL;Jackson EM;Polin LA;Helms GL;LeBoeuf DA;Joe PA;Hopper-Borge E;Ludueña RF;Kruh GD;Mooberry SL
通讯作者：
Mooberry SL
影响因子：
3.5
作者：
Golani, Lalit K.;Islam, Farhana;Gangjee, Aleem
通讯作者：
Gangjee, Aleem
影响因子：
7.3
作者：
Ganglee, Aleem;Zhao, Ying;Mooberry, Susan L.
通讯作者：
Mooberry, Susan L.
2,5-Diaryl-2,3-二氢-1,3,4-氧化二唑类类似物的设计，合成和生物学评估。
影响因子：
7.3
作者：
Lee L;Robb LM;Lee M;Davis R;Mackay H;Chavda S;Babu B;O'Brien EL;Risinger AL;Mooberry SL;Lee M
通讯作者：
Lee M
影响因子：
7.3
作者：
Gangjee, Aleem;Zhao, Ying;Hamel, Ernest
通讯作者：
Hamel, Ernest