| The naturally occurring retinoids and their synthetic analogs all-trans retinoic acid (ATRA) play a key role in cell differentiation, proliferation, and apoptosis, and their use/pot-ential in oncology, dermatology and a variety of diseases are well documented. However, the lack of self-trans retinoic acid in patients, given exogenous retinoic acid to treat oncology and dermatology, easily be metabolized by the cytochrome P450, recurrence in the short term resistance. In order to overcome the limitation of exogenous ATRA therapy, it is very pivotal to search the retinoic acid metabolism blocking agents (RAMBAs).Based on the results of computer aided drug design and pharmacological tests, the compounds possess CYP26A1 inhibiting effects were determined.13 new amide derivatives were designed and synthesized, and their structures were confirmed by 1H-NMR and LC-MS.By trial and error, the target compounds were obtained through one of designed route as following:substituted methyl-2-amino-3-phenylpropanoate hydrochloride was got from starting material 2-amino-3-phenylpropanoic acid, and then the key intermediates 5-tert-but-yl-2-methyl-furan-3-carbonyl chloride and 5-phenyl-2-methyl-furan-3-carbonyl chloride were given by Paal-Knorr reaction, hydrolysis reaction and substitution reaction. After reduction and de-protection, the target compounds were synthesized successfully.As a result of the screening of the pharmacological experiments in NB4 cells,13 of the target compounds were found to have strong growth inhibitory activities and induce differen-tiation after combinated administration with ATRA.The mentioned above may make theoretical and practical bases for future work on the project searching for more potential leading compounds. |
PDF Full Text Request