ABSTRACT
pH-sensitive drug carriers that are sensitive to the acidic (pH = ~6.5) microenvironments of tumor tissues have been primarily used as effective drug/gene/siRNA/microRNA carriers for releasing their payloads to tumor cells/tissues. Resistance to various drugs has become a big hurdle in systemic chemotherapy in cancer. Therefore delivery of chemotherapeutic agents and siRNA's targeting anti apoptotic genes possess advantages to overcome the efflux pump mediated and anti apoptosis-related drug resistance. Here, we report the development of nanocarrier system prepared from kojic acid backbone-based cationic amphiphile containing endosomal pH-sensitive imidazole ring. This pH-sensitive liposomal nanocarrier effectively delivers anti-cancer drug (Paclitaxel; PTX) and siRNA (Bcl-2), and significantly inhibits cell proliferation and reduces tumor growth. Tumor inhibition response attributes to the synergistic effect of PTX potency and MDR reversing ability of Bcl-2 siRNA in the tumor supporting that kojic acid based liposomal pH-sensitive nanocarrier as efficient vehicle for systemic co-delivery of drugs and siRNA.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Drug Delivery Systems , Melanoma, Experimental/therapy , Paclitaxel/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Skin Neoplasms/therapy , Animals , Antineoplastic Agents, Phytogenic/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Drug Compounding , Gene Expression Regulation, Neoplastic/drug effects , Hydrogen-Ion Concentration , Imidazoles/chemistry , Liposomes/chemistry , Liposomes/pharmacokinetics , Melanoma, Experimental/genetics , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Mice , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Paclitaxel/chemistry , Phosphatidylethanolamines/chemistry , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyrones/chemistry , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Tumor Burden/drug effectsABSTRACT
A stereoselective synthesis of decahydrofuro[3,2-d]isochromene derivatives has been achieved by the condensation of 2-cyclohexenylbutane-1,4-diol with aldehydes in the presence of a stochiometric amount of BF3·OEt2 in dichloromethane at -78 °C. Similarly, the condensation of 2-cyclopentenylbutan-1,4-diol with aldehydes provides the corresponding octahydro-2H-cyclopenta[c]furo[2,3-d]pyran derivatives in good yields with high diastereoselectivity. It is an elegant strategy for the quick construction of tricyclic architectures with four contiguous stereogenic centers in a single step. These tricyclic frameworks are the integral part of numerous natural products.
ABSTRACT
A wide array of aldehydes undergo smooth cross-coupling with 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-1-methylindolin-2-one in the presence of 10 mol% BF3·OEt2 at 0 °C in dichloromethane to afford the corresponding 2,3,5,6-tetrahydro-1'H-spiro[pyran-4,4'-quinoline]-2',3'-dione derivatives in good yields with excellent diastereoselectivity. This is the first report on the synthesis of tetrahydro-1'H-spiro[pyran-4,4'-quinoline]-2',3'-dione scaffolds through a cascade of Prins/pinacol reactions.
