RESUMO
Cycloicaritin (CICT), a bioactive flavonoid derived from the genus Epimedium, exhibits a variety of beneficial biological activities, including promising anticancer effects. However, its poor oral bioavailability is attributed to its extremely low aqueous solubility and rapid elimination via phase II conjugative metabolism. To overcome these limitations, we designed and synthesized a series of carbamate-bridged prodrugs, protecting the hydroxyl group at the 3-position of cycloicaritin by binding with the N-terminus of a natural amino acid. The optimal prodrug 4b demonstrated a significant increase in aqueous solubility as compared to CICT, as well as improved stability in phase II metabolism, while allowing for a rapid release of CICT in the blood upon gastrointestinal absorption. The prodrug 4b also facilitated oral absorption through organic anion-transporting polypeptide 2B1-mediated transport and exhibited moderate cytotoxicity. Importantly, the prodrug enhanced the oral bioavailability of CICT and displayed dose-dependent antitumor activity with superior safety. In summary, the prodrug 4b is a novel potential antitumor drug candidate, and the carbamate-bridged amino acid prodrug approach is a promising strategy for the oral delivery of CICT.
Assuntos
Aminoácidos , Antineoplásicos , Carbamatos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pró-Fármacos , Solubilidade , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Humanos , Carbamatos/química , Carbamatos/farmacologia , Carbamatos/síntese química , Carbamatos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Relação Estrutura-Atividade , Aminoácidos/química , Aminoácidos/farmacologia , Aminoácidos/síntese química , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Água/química , Linhagem Celular Tumoral , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/síntese química , Flavonoides/farmacocinética , MasculinoRESUMO
Sex steroid hormones such as estrogen estradiol (E2) and androgen dihydrotestosterone (DHT) are involved in the development of hormone-dependent cancers. Blockade of 17ß-hydroxysteroid dehydrogenase type 7 (17ß-HSD7), a member of the short chain dehydrogenase/reductase superfamily, is thought to decrease E2 levels while increasing those of DHT. Therefore, its unique double action makes this enzyme as an interesting drug target for treatment of breast cancer. The chemical synthesis, molecular characterization, and preliminary biological evaluation as 17ß-HSD7 inhibitors of novel carbamate derivatives 3 and 4 are described. Like previous 17ß-HSD7 inhibitors 1 and 2, compounds 3 and 4 bear a hydrophobic nonyl side chain at the C-17ß position of a 4-aza-5α-androstane nucleus, but compound 3 has an oxygen atom replacing the CH2 in the steroid A-ring C-2 position, while compound 4 has a C17-spiranic E-ring containing a carbamate function. They both inhibited the in vitro transformation of estrone (E1) into E2 by 17ß-HSD7, but the introduction of a (17â¯R)-spirocarbamate is preferable to replacing C-2 methylene with an oxygen atom since compound 4 (IC50 = 63â¯nM) is an inhibitor 14 times more powerful than compound 3 (IC50 = 900â¯nM). Furthermore, when compared to the reference inhibitor 1 (IC50 = 111â¯nM), the use of a C17-spiranic E-ring made it possible to introduce differently the hydrophobic nonyl side chain, without reducing the inhibitory activity.