2024/01/23 by Xiang, W, Quadery, TM, Hamel, E +4
#Animals #Antineoplastic Agents #Antitumor #Antitumor activity #Brain Neoplasms #Cell Proliferation #Cultured #Cyclopenta[d]pyrimidine #Cyclopentanes #Dose-Response Relationship #Drug #Drug Screening Assays #Experimental #Female #Glioma #Humans #Male #Mice #Microtubule depolymerizers #Microtubule targeting agents #Microtubules #Models #Molecular #Molecular Conformation #Neoplasms #Nude #Pyrimidines #Structure-Activity Relationship #Structure-activity relationships #Tumor Cells
paper · doi:10.7302/22130
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.