Two series of farnesyltransferase (FTase) inhibitors were grouped and their antimalarial activi-ties modeled by means of multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR). ...Two series of farnesyltransferase (FTase) inhibitors were grouped and their antimalarial activi-ties modeled by means of multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR). A reliable model was achieved, with r2 for calibration, external prediction and leave-one-out cross-validation of 0.96, 0.87 and 0.83, respectively. Therefore, biological activities of congeners can be estimated using the QSAR model. The bioactivities of new compounds based on the miscellany of substructures of the two classes of FTase inhibitors were predicted using the MIA-QSAR model and the most promising ones were submitted to ADME (absorption, distribution, metabolism and excretion) and docking evaluation. Despite the smaller interaction energy of the two most promising, predicted compounds in comparison to the two most active compounds of the data set, one of the proposed structures did not violate any Lipinski’s rule of five. Therefore, it is either a potential drug or may drive synthesis of similar, improved compounds.展开更多
Background Primary liver cancer （PLC） is a common malignant tumor. Over the past decade, although farnesyltransferase （FTase） has emerged as a significant target for anticancer therapies and has become a hotspot o...Background Primary liver cancer （PLC） is a common malignant tumor. Over the past decade, although farnesyltransferase （FTase） has emerged as a significant target for anticancer therapies and has become a hotspot of cancer research, its exact mechanism of action remains unknown. The aim of this study was to investigate the expression of FTase in PLC and its role in the development of PLC. Methods Expression of FTase was detected by real-time fluorescent quantitative-polymerase chain reaction （FQ-PCR） in cancer and surrounding normal tissues from 32 patients with PLC. Results Expression of FTase mRNA in PLC was significantly higher than that in normal hepatic tissues （P 〈0.001）. Overexpression of FTase was as high as 87.5%. The positive rate for FTase mRNA in the high tendency to metastatic recurrence group was obviously higher than that in the low tendency to metastatic recurrence group （P=0.02）. The positive rate for FTase mRNA in patients with metastatic recurrence during postoperative follow-up was also significantly higher than that in those without metastatic recurrence （P=-0.01）. Conclusions The level of FTase mRNA expression in cancer tissues is much higher than in normal tissues. FTase may play an important role in the genesis and development of PLC and may be one of the reliable markers for the metastatic activity gained by liver tumor cells. FTase could be used clinically in predicting metastatic recurrence of PLC展开更多
A series of 3-methoxycarbonylpropoxy-7-(imidazol-4-ylpropinamide)-1, 3-dihydrogen- 1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-ones, as farnesyltransferase(Ftase) inhibitors, were synthesized. The preparation of the ke...A series of 3-methoxycarbonylpropoxy-7-(imidazol-4-ylpropinamide)-1, 3-dihydrogen- 1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-ones, as farnesyltransferase(Ftase) inhibitors, were synthesized. The preparation of the key intermediate, 7-amino-3-methoxycabonylpropoxy-1- methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, was improved.展开更多
文摘Two series of farnesyltransferase (FTase) inhibitors were grouped and their antimalarial activi-ties modeled by means of multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR). A reliable model was achieved, with r2 for calibration, external prediction and leave-one-out cross-validation of 0.96, 0.87 and 0.83, respectively. Therefore, biological activities of congeners can be estimated using the QSAR model. The bioactivities of new compounds based on the miscellany of substructures of the two classes of FTase inhibitors were predicted using the MIA-QSAR model and the most promising ones were submitted to ADME (absorption, distribution, metabolism and excretion) and docking evaluation. Despite the smaller interaction energy of the two most promising, predicted compounds in comparison to the two most active compounds of the data set, one of the proposed structures did not violate any Lipinski’s rule of five. Therefore, it is either a potential drug or may drive synthesis of similar, improved compounds.
基金This work was supposed by a grant from the Natural Science Foundation of Shandong Province, China （No. Y2005C45）.
文摘Background Primary liver cancer （PLC） is a common malignant tumor. Over the past decade, although farnesyltransferase （FTase） has emerged as a significant target for anticancer therapies and has become a hotspot of cancer research, its exact mechanism of action remains unknown. The aim of this study was to investigate the expression of FTase in PLC and its role in the development of PLC. Methods Expression of FTase was detected by real-time fluorescent quantitative-polymerase chain reaction （FQ-PCR） in cancer and surrounding normal tissues from 32 patients with PLC. Results Expression of FTase mRNA in PLC was significantly higher than that in normal hepatic tissues （P 〈0.001）. Overexpression of FTase was as high as 87.5%. The positive rate for FTase mRNA in the high tendency to metastatic recurrence group was obviously higher than that in the low tendency to metastatic recurrence group （P=0.02）. The positive rate for FTase mRNA in patients with metastatic recurrence during postoperative follow-up was also significantly higher than that in those without metastatic recurrence （P=-0.01）. Conclusions The level of FTase mRNA expression in cancer tissues is much higher than in normal tissues. FTase may play an important role in the genesis and development of PLC and may be one of the reliable markers for the metastatic activity gained by liver tumor cells. FTase could be used clinically in predicting metastatic recurrence of PLC
文摘A series of 3-methoxycarbonylpropoxy-7-(imidazol-4-ylpropinamide)-1, 3-dihydrogen- 1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-ones, as farnesyltransferase(Ftase) inhibitors, were synthesized. The preparation of the key intermediate, 7-amino-3-methoxycabonylpropoxy-1- methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, was improved.
