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 have 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.

设计并合成了一系列甲氧基萘基取代的环戊[ d ]嘧啶化合物4-10 ，以研究3-D构象对微管解聚和抗增殖活性的影响。 NOESY 对N ,2-二甲基-N- (6ʹ-甲氧基萘基-1ʹ-氨基)-环戊[ d ]嘧啶-4-胺 ( 4 ) 的研究表明，萘环围绕环戊[ d ]嘧啶支架的旋转受到阻碍。相比之下，NOESY 对N ,2-二甲基-N- (5ʹ-甲氧基萘基-2ʹ-氨基)-环戊[ d ]嘧啶-4-胺 ( 5 ) 的研究表明萘环围绕环戊[ d ]嘧啶自由旋转脚手架。 4和5之间的旋转灵活性和构象差异导致了生物活性的显着差异。化合物4没有活性，而5是该系列中最有效的化合物，具有有效的微管解聚作用，并且在体外针对多种癌细胞系具有低纳摩尔 IC ₅₀值。在 U251 神经胶质瘤异种移植模型中研究了5体内抑制肿瘤生长的能力。结果显示， 5比阳性对照替莫唑胺具有更好的抗肿瘤作用，并已确定5作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构成了环戊[ d ]嘧啶类微管靶向剂构象-活性关系发展的基础。