Diastereoselective Heterocyclization of Geminal Bromo-fluoro Arylcyclopropanes by Nitrosonium Tetrafluoroborate: Access to 4-fluorinated Isoxazolines and Isoxazoles

A series of 5-aryl-4-bromo-4-fluoroisoxazolines was synthesized via nitrosation of 2-aryl-1-bromo-1-fluorocyclopropanes with NOBF4. It was shown that the E-isomers of the cyclopropanes react highly regio- and diastereoselectively leading exclusively to the E-isomers of the isoxazolines. The obtained 5-aryl-4-bromo-4-fluoroisoxazolines were transformed selectively into the corresponding 5-aryl-4-fluoro- or 5-aryl-4-bromoisoxazoles in good yields in the reaction with Lewis acids

Access to 5-fluoroisoxazoles via the Nitrosation of Geminal Bromo-fluoro Arylcyclopropanes

A new method for the synthesis of 3-aryl-5-fluoroisoxazoles via the reaction of nitrosonium chlorosulfate with 2-aryl-1-bromo-1-fluorocyclopropanes containing acceptor substituents in the aromatic ring has been developed. The reaction proceeds highly regioselectively thus providing 3-aryl-5-fluoroisoxazoles in good yields. The structure of isoxazoles was corroborated by the DU8+ hybrid DFT/parametric computational approach

Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate

Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc

Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate

Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc