A three-dimensional pharmacophore model was developed from a series of inhibitors of Aurora A kinase to discover new potent anti-cancer agents using the HypoGen module in the Catalyst software. The pharmacophore model...A three-dimensional pharmacophore model was developed from a series of inhibitors of Aurora A kinase to discover new potent anti-cancer agents using the HypoGen module in the Catalyst software. The pharmacophore model was developed based on the structure of 20 currently available inhibitors, which were carefully selected from the literature. The best hypothesis （Hypo 1） was defined by four features： one hydrogen-bond donor and three hy- drophobic points, with the best correlation coefficient of 0.909, the lowest rms deviation of 1.563, and the highest cost difference of 99.075. The Hypo 1 was then validated by a test set consisting of 24 compounds and by a cross-validation of 95% confidence level through randomizing the data using the CatScramble program, which suggested that a predictive pharmacophore model had been successfully obtained.展开更多
Gambogic acid （GA, 1）, the most prominent member of Garcinia natural products, has been reported to be a promising anti-tumor agent. Previous studies have suggested that the planar B ring and the unique 4-oxa-tricyc...Gambogic acid （GA, 1）, the most prominent member of Garcinia natural products, has been reported to be a promising anti-tumor agent. Previous studies have suggested that the planar B ring and the unique 4-oxa-tricyclo- [4.3.1.03.7]dec-2-one caged motif were essential for anti-tumor activity. To further explore the structure-activity relationship （SAR） of caged Garcinia xanthones, two new series of B-ring modified caged GA analogues 13a-13e and 15a-lge were synthesized utilizing a Claisen/Diel-Alder cascade reaction. Subsequently, these compounds were evaluated for their in vitro antitumor activities against A549, MCF-7, SMMC-7721 and BGC-823 cancer cell lines by MTT assay. Among them, 13b-13e exhibited micromolar inhibition against several cancer cell lines, being approximately 2-4 fold less potent in comparison to GA. SAR analysis revealed that the peripheral gem-dimethyl groups are essential for maintaining antitumor activity and substituent group on C1 position of B-ring has a significant effect on potency, while modifications at C-2, C-3 and C-4 positions are relatively tolerated. These findings will enhance our understanding of the SAR of Garcinia xanthones and lead to the development of simplified analogues as potential anti-tumor agents.展开更多
文摘A three-dimensional pharmacophore model was developed from a series of inhibitors of Aurora A kinase to discover new potent anti-cancer agents using the HypoGen module in the Catalyst software. The pharmacophore model was developed based on the structure of 20 currently available inhibitors, which were carefully selected from the literature. The best hypothesis （Hypo 1） was defined by four features： one hydrogen-bond donor and three hy- drophobic points, with the best correlation coefficient of 0.909, the lowest rms deviation of 1.563, and the highest cost difference of 99.075. The Hypo 1 was then validated by a test set consisting of 24 compounds and by a cross-validation of 95% confidence level through randomizing the data using the CatScramble program, which suggested that a predictive pharmacophore model had been successfully obtained.
基金This work was supported by 90713038 and 21072231 of National Natural Science Foundation of China （Key Program）, 2008ZX09401-001, 2009ZX09501-003 and 2010ZX09401-401 of National Major Science and Technology Project of China （Innovation and Development of New Drugs）.
文摘Gambogic acid （GA, 1）, the most prominent member of Garcinia natural products, has been reported to be a promising anti-tumor agent. Previous studies have suggested that the planar B ring and the unique 4-oxa-tricyclo- [4.3.1.03.7]dec-2-one caged motif were essential for anti-tumor activity. To further explore the structure-activity relationship （SAR） of caged Garcinia xanthones, two new series of B-ring modified caged GA analogues 13a-13e and 15a-lge were synthesized utilizing a Claisen/Diel-Alder cascade reaction. Subsequently, these compounds were evaluated for their in vitro antitumor activities against A549, MCF-7, SMMC-7721 and BGC-823 cancer cell lines by MTT assay. Among them, 13b-13e exhibited micromolar inhibition against several cancer cell lines, being approximately 2-4 fold less potent in comparison to GA. SAR analysis revealed that the peripheral gem-dimethyl groups are essential for maintaining antitumor activity and substituent group on C1 position of B-ring has a significant effect on potency, while modifications at C-2, C-3 and C-4 positions are relatively tolerated. These findings will enhance our understanding of the SAR of Garcinia xanthones and lead to the development of simplified analogues as potential anti-tumor agents.
