Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure
Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal Article |
| Published: |
American Chemical Society
2018
|
| Online Access: | http://hdl.handle.net/20.500.11937/73343 |
| _version_ | 1848762989492043776 |
|---|---|
| author | Dohle, W. Jourdan, Fred Menchon, G. Prota, A. Foster, P. Mannion, P. Hamel, E. Thomas, M. Kasprzyk, P. Ferrandis, E. Steinmetz, M. Leese, M. Potter, B. |
| author_facet | Dohle, W. Jourdan, Fred Menchon, G. Prota, A. Foster, P. Mannion, P. Hamel, E. Thomas, M. Kasprzyk, P. Ferrandis, E. Steinmetz, M. Leese, M. Potter, B. |
| author_sort | Dohle, W. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure-activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the aß-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in aß-tubulin. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template. |
| first_indexed | 2025-11-14T10:56:20Z |
| format | Journal Article |
| id | curtin-20.500.11937-73343 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:56:20Z |
| publishDate | 2018 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-733432019-02-26T07:18:28Z Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure Dohle, W. Jourdan, Fred Menchon, G. Prota, A. Foster, P. Mannion, P. Hamel, E. Thomas, M. Kasprzyk, P. Ferrandis, E. Steinmetz, M. Leese, M. Potter, B. Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure-activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the aß-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in aß-tubulin. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template. 2018 Journal Article http://hdl.handle.net/20.500.11937/73343 10.1021/acs.jmedchem.7b01474 American Chemical Society restricted |
| spellingShingle | Dohle, W. Jourdan, Fred Menchon, G. Prota, A. Foster, P. Mannion, P. Hamel, E. Thomas, M. Kasprzyk, P. Ferrandis, E. Steinmetz, M. Leese, M. Potter, B. Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure |
| title | Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure |
| title_full | Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure |
| title_fullStr | Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure |
| title_full_unstemmed | Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure |
| title_short | Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure |
| title_sort | quinazolinone-based anticancer agents: synthesis, antiproliferative sar, antitubulin activity, and tubulin co-crystal structure |
| url | http://hdl.handle.net/20.500.11937/73343 |