Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyrimidine as a potent microtubule targeting agent
dc.contributor.author | Xiang, W | |
dc.contributor.author | Choudhary, S | |
dc.contributor.author | Hamel, E | |
dc.contributor.author | Mooberry, SL | |
dc.contributor.author | Gangjee, A | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-01-23T21:20:39Z | |
dc.date.available | 2024-01-23T21:20:39Z | |
dc.date.issued | 2018-05-15 | |
dc.identifier.issn | 0968-0896 | |
dc.identifier.issn | 1464-3391 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/29655610 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/192136 | en |
dc.description.abstract | We report a series of tubulin targeting agents, some of which demonstrate potent antiproliferative activities. These analogs were designed to optimize the antiproliferative activity of 1 by varying the heteroatom substituent at the 4′-position, the basicity of the 4-position amino moiety, and conformational restriction. The potential metabolites of the active compounds were also synthesized. Some compounds demonstrated single digit nanomolar IC50 values for antiproliferative effects in MDA-MB-435 melanoma cells. Particularly, the S-methyl analog 3 was more potent than 1 in MDA-MB-435 cells (IC50 = 4.6 nM). Incubation of 3 with human liver microsomes showed that the primary metabolite of the S-methyl moiety of 3 was the methyl sulfinyl group, as in analog 5. This metabolite was equipotent with the lead compound 1 in MDA-MB-435 cells (IC50 = 7.9 nM). Molecular modeling and electrostatic surface area were determined to explain the activities of the analogs. Most of the potent compounds overcome multiple mechanisms of drug resistance and compound 3 emerged as the lead compound for further SAR and preclinical development. | |
dc.format.medium | Print-Electronic | |
dc.language | eng | |
dc.publisher | Elsevier | |
dc.subject | Cyclopenta[d]pyrimidine | |
dc.subject | Metabolism | |
dc.subject | Microtubule targeting agent | |
dc.subject | Antineoplastic Agents | |
dc.subject | Binding Sites | |
dc.subject | Cell Line, Tumor | |
dc.subject | Drug Design | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Humans | |
dc.subject | Microsomes, Liver | |
dc.subject | Models, Molecular | |
dc.subject | Molecular Conformation | |
dc.subject | Molecular Docking Simulation | |
dc.subject | Protein Binding | |
dc.subject | Pyrimidines | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Tubulin | |
dc.subject | Tubulin Modulators | |
dc.title | Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyrimidine as a potent microtubule targeting agent | |
dc.type | Article | |
dc.identifier.pmid | 29655610 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/192136/2/Structure based drug design and in vitro metabolism study Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyri.pdf | |
dc.identifier.doi | 10.1016/j.bmc.2018.04.010 | |
dc.identifier.doi | https://dx.doi.org/10.7302/22136 | |
dc.identifier.source | Bioorganic and Medicinal Chemistry | |
dc.description.version | Published version | |
dc.date.updated | 2024-01-23T21:20:36Z | |
dc.identifier.volume | 26 | |
dc.identifier.issue | 9 | |
dc.identifier.startpage | 2437 | |
dc.identifier.endpage | 2451 | |
dc.identifier.name-orcid | Xiang, W | |
dc.identifier.name-orcid | Choudhary, S | |
dc.identifier.name-orcid | Hamel, E | |
dc.identifier.name-orcid | Mooberry, SL | |
dc.identifier.name-orcid | Gangjee, A | |
dc.working.doi | 10.7302/22136 | en |
dc.owningcollname | Internal Medicine, Department of |
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