Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma
Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibito...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-08-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383519308706 |
| id |
doaj-17d03d243b804627a1938050be4aa829 |
|---|---|
| record_format |
Article |
| spelling |
doaj-17d03d243b804627a1938050be4aa8292020-11-25T03:41:09ZengElsevierActa Pharmaceutica Sinica B2211-38352020-08-0110814921510Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastomaBiao Wang0Fu Peng1Wei Huang2Jin Zhou3Nan Zhang4Jia Sheng5Phensinee Haruehanroengra6Gu He7Bo Han8Hospital of Chengdu University of Traditional Chinese Medicine, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, ChinaHospital of Chengdu University of Traditional Chinese Medicine, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaHospital of Chengdu University of Traditional Chinese Medicine, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaHospital of Chengdu University of Traditional Chinese Medicine, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, ChinaDepartment of Chemistry and the RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USADepartment of Chemistry and the RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USAState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; Corresponding authors. Tel.: +86 28 85503817; fax: +86 28 85164063.Hospital of Chengdu University of Traditional Chinese Medicine, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Corresponding authors. Tel.: +86 28 85503817; fax: +86 28 85164063.Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibitory activity: selectivity differed by over 40-fold between the least and most potent stereoisomers in time-resolved FRET and KINOMEscan® in vitro assays. Studies in glioblastoma cell lines showed that the most active compound ent-4g induced apoptosis and cell cycle arrest by interfering with MDM2 -P53 interaction and CDK4 activation. Cells treated with ent-4g showed up-regulation of proteins involved in P53 and cell cycle pathways. The compound showed good anti-tumor efficacy against glioblastoma xenografts in mice. These results suggested that rational design, asymmetric synthesis and biological evaluation of novel tetrahydronaphthalene fused spirooxindoles could generate promising MDM2-CDK4 dual inhibitors in glioblastoma therapy.http://www.sciencedirect.com/science/article/pii/S2211383519308706Chiral tetrahydronaphthalene-fused spirooxindolesSynthesisMDM2-CDK4 dual inhibitorsGlioblastomaStructure–activity relationshipApoptosis |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Biao Wang Fu Peng Wei Huang Jin Zhou Nan Zhang Jia Sheng Phensinee Haruehanroengra Gu He Bo Han |
| spellingShingle |
Biao Wang Fu Peng Wei Huang Jin Zhou Nan Zhang Jia Sheng Phensinee Haruehanroengra Gu He Bo Han Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma Acta Pharmaceutica Sinica B Chiral tetrahydronaphthalene-fused spirooxindoles Synthesis MDM2-CDK4 dual inhibitors Glioblastoma Structure–activity relationship Apoptosis |
| author_facet |
Biao Wang Fu Peng Wei Huang Jin Zhou Nan Zhang Jia Sheng Phensinee Haruehanroengra Gu He Bo Han |
| author_sort |
Biao Wang |
| title |
Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma |
| title_short |
Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma |
| title_full |
Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma |
| title_fullStr |
Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma |
| title_full_unstemmed |
Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma |
| title_sort |
rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as mdm2-cdk4 dual inhibitor against glioblastoma |
| publisher |
Elsevier |
| series |
Acta Pharmaceutica Sinica B |
| issn |
2211-3835 |
| publishDate |
2020-08-01 |
| description |
Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibitory activity: selectivity differed by over 40-fold between the least and most potent stereoisomers in time-resolved FRET and KINOMEscan® in vitro assays. Studies in glioblastoma cell lines showed that the most active compound ent-4g induced apoptosis and cell cycle arrest by interfering with MDM2 -P53 interaction and CDK4 activation. Cells treated with ent-4g showed up-regulation of proteins involved in P53 and cell cycle pathways. The compound showed good anti-tumor efficacy against glioblastoma xenografts in mice. These results suggested that rational design, asymmetric synthesis and biological evaluation of novel tetrahydronaphthalene fused spirooxindoles could generate promising MDM2-CDK4 dual inhibitors in glioblastoma therapy. |
| topic |
Chiral tetrahydronaphthalene-fused spirooxindoles Synthesis MDM2-CDK4 dual inhibitors Glioblastoma Structure–activity relationship Apoptosis |
| url |
http://www.sciencedirect.com/science/article/pii/S2211383519308706 |
| work_keys_str_mv |
AT biaowang rationaldrugdesignsynthesisandbiologicalevaluationofnovelchiraltetrahydronaphthalenefusedspirooxindoleasmdm2cdk4dualinhibitoragainstglioblastoma AT fupeng rationaldrugdesignsynthesisandbiologicalevaluationofnovelchiraltetrahydronaphthalenefusedspirooxindoleasmdm2cdk4dualinhibitoragainstglioblastoma AT weihuang rationaldrugdesignsynthesisandbiologicalevaluationofnovelchiraltetrahydronaphthalenefusedspirooxindoleasmdm2cdk4dualinhibitoragainstglioblastoma AT jinzhou rationaldrugdesignsynthesisandbiologicalevaluationofnovelchiraltetrahydronaphthalenefusedspirooxindoleasmdm2cdk4dualinhibitoragainstglioblastoma AT nanzhang rationaldrugdesignsynthesisandbiologicalevaluationofnovelchiraltetrahydronaphthalenefusedspirooxindoleasmdm2cdk4dualinhibitoragainstglioblastoma AT jiasheng rationaldrugdesignsynthesisandbiologicalevaluationofnovelchiraltetrahydronaphthalenefusedspirooxindoleasmdm2cdk4dualinhibitoragainstglioblastoma AT phensineeharuehanroengra rationaldrugdesignsynthesisandbiologicalevaluationofnovelchiraltetrahydronaphthalenefusedspirooxindoleasmdm2cdk4dualinhibitoragainstglioblastoma AT guhe rationaldrugdesignsynthesisandbiologicalevaluationofnovelchiraltetrahydronaphthalenefusedspirooxindoleasmdm2cdk4dualinhibitoragainstglioblastoma AT bohan rationaldrugdesignsynthesisandbiologicalevaluationofnovelchiraltetrahydronaphthalenefusedspirooxindoleasmdm2cdk4dualinhibitoragainstglioblastoma |
| _version_ |
1724531333901844480 |