期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 29, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115887
关键词
Microtubule depolymerizers; Microtubule targeting agents; Cyclopenta[d]pyrimidine; Antitumor activity; Structure-activity relationships
资金
- National Institutes of Health, National Cancer Institute [R01 CA142868]
- Duquesne University Adrian Van Kaam Chair in Scholarly Excellence
- Greehey Chair
- Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute [HHSN261200800001E]
A series of methoxy naphthyl substituted cyclopenta [d]pyrimidine compounds were designed and synthesized to study the influence of 3-D conformation on microtubule depolymerizing and antiproliferative activities. The NOESY studies showed that the rotational flexibility and conformational dissimilarity between two compounds, 4 and 5, led to significant differences in biological activities. Compound 5 exhibited potent microtubule depolymerizing effects and strong antitumor activity, making it a potential preclinical candidate for further studies.
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-(6'-methoxynaphthyl-1'-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-(5'-methoxynaphthyl-2'-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 micmtubule depolymerizing and antitumor activity forms the basis for the development of conformation-activity relationships for the cyclopenta [d] pyrimidine class of microtubule targeting agents.
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