| dcterms.abstract | Cancer is one of the top two leading causes of death in the United States, responsible for one in six deaths worldwide. Although paclitaxel and docetaxel are still being heavily used in clinic for treatment of various cancers, the multi-drug resistance (MDR) problems are becoming more and more serious. Therefore, it is still important to develop next-generation taxoid anticancer agents with superior pharmacological properties and improved potency against various classes of tumors, in particular drug-resistant cancers and cancer stem cells. Highly potent taxoids are also very important as the warheads of tumor-targeting drug conjugates. Building upon our extensive SAR studies on taxoids, a new series of taxoids, bearing a m-OCF3/ OCF2H group at the C2-benzoate position, were designed and synthesized using the ?-lactam synthon method. SB-T-121205 and SB-T-101141 exhibited the best efficacy against drug-sensitive and drug-resistant breast cancer cell lines. By inhibiting the transgelin 2 and PI3K/Akt pathway, SB-T-121205 promoted apoptosis, changed EMT properties and suppressed the migration and invasion of MCF-7/PTX cells. However, in contrast to the dramatically increased p27 gene expression caused by SB-T-121205, SB-T-101141 downregulated cell cycle inhibitor p27 expression to render the faster cell cycle progression as well as the possible cell autophagy. In addition, both SB-T-1214 and SB-CST-10202 demonstrated distinct inhibitory effects on photolabeling of ?-tubulin from different eukaryotic sources. To increase the efficacy and specificity of drugs, the development of drug delivery system is equally important. Using vitamin as the tumor-targeting module, taxoid-based SMDCs including BLT-1, BLT-S, BLT-S-05 and FLT1-05 were designed and synthesized for bioassays. A novel fluorescence probe of DHA-SBT-1214 by attaching a fluorescein tether at the C7 position of the taxoid moiety was designed and synthesized to study the internalization mechanism of NE-DHA-SBT-1214 that currently underway toward IND filing. | |
