The 3-D conformational shape of N-naphthyl-cyclopenta[d]pyrimidines affects their potency as microtubule targeting agents and their antitumor activity
dc.contributor.author | Xiang, W | |
dc.contributor.author | Quadery, TM | |
dc.contributor.author | Hamel, E | |
dc.contributor.author | Luckett-Chastain, LR | |
dc.contributor.author | Ihnat, MA | |
dc.contributor.author | Mooberry, SL | |
dc.contributor.author | Gangjee, A | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-01-23T21:15:51Z | |
dc.date.available | 2024-01-23T21:15:51Z | |
dc.date.issued | 2021-01-01 | |
dc.identifier.issn | 0968-0896 | |
dc.identifier.issn | 1464-3391 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/33310545 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/192130 | en |
dc.description.abstract | 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. | |
dc.format.medium | Print-Electronic | |
dc.language | eng | |
dc.publisher | Elsevier | |
dc.relation.haspart | 115887 | |
dc.subject | Antitumor activity | |
dc.subject | Cyclopenta[d]pyrimidine | |
dc.subject | Microtubule depolymerizers | |
dc.subject | Microtubule targeting agents | |
dc.subject | Structure-activity relationships | |
dc.subject | Animals | |
dc.subject | Antineoplastic Agents | |
dc.subject | Brain Neoplasms | |
dc.subject | Cell Proliferation | |
dc.subject | Cyclopentanes | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Drug Screening Assays, Antitumor | |
dc.subject | Female | |
dc.subject | Glioma | |
dc.subject | Humans | |
dc.subject | Male | |
dc.subject | Mice | |
dc.subject | Mice, Nude | |
dc.subject | Microtubules | |
dc.subject | Models, Molecular | |
dc.subject | Molecular Conformation | |
dc.subject | Neoplasms, Experimental | |
dc.subject | Pyrimidines | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Tumor Cells, Cultured | |
dc.title | The 3-D conformational shape of N-naphthyl-cyclopenta[d]pyrimidines affects their potency as microtubule targeting agents and their antitumor activity | |
dc.type | Article | |
dc.identifier.pmid | 33310545 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/192130/2/The 3-D conformational shape of N-naphthyl-cyclopenta[d]pyrimidines affects their potency as microtubule targeting agents an.pdf | |
dc.identifier.doi | 10.1016/j.bmc.2020.115887 | |
dc.identifier.doi | https://dx.doi.org/10.7302/22130 | |
dc.identifier.source | Bioorganic and Medicinal Chemistry | |
dc.description.version | Published version | |
dc.date.updated | 2024-01-23T21:15:46Z | |
dc.identifier.orcid | 0000-0003-3648-103X | |
dc.identifier.orcid | 0000-0003-3686-7936 | |
dc.identifier.volume | 29 | |
dc.identifier.startpage | 115887 | |
dc.identifier.name-orcid | Xiang, W | |
dc.identifier.name-orcid | Quadery, TM | |
dc.identifier.name-orcid | Hamel, E; 0000-0003-3648-103X | |
dc.identifier.name-orcid | Luckett-Chastain, LR | |
dc.identifier.name-orcid | Ihnat, MA; 0000-0003-3686-7936 | |
dc.identifier.name-orcid | Mooberry, SL | |
dc.identifier.name-orcid | Gangjee, A | |
dc.working.doi | 10.7302/22130 | en |
dc.owningcollname | Internal Medicine, Department of |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.