RESUMO
Natural products discovered by using agnostic approaches, unlike rationally designed leads or those obtained through high-throughput screening, offer the ability to reveal new biological pathways and, hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine-cephalostatin family of natural products displays robust and potent antitumor activities, with sub-nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we used comparative cellular and molecular biological methods to uncover the ritterazine-cephalostatin cytotoxic mode of action (MOA) in human tumor cells. Our findings indicated that, whereas ritterostatin GN 1N , a cephalostatin-ritterazine hybrid, binds to multiple HSP70s, its cellular trafficking confines activity to the endoplasmic reticulum (ER)-based HSP70 isoform, GRP78. This targeting results in activation of the unfolding protein response (UPR) and subsequent apoptotic cell death.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Fenazinas/química , Pirazinas/farmacologia , Esteroides/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Sistemas de Liberação de Medicamentos , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Humanos , Sondas Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirazinas/químicaRESUMO
Cephalostatins, ritterazines and their hybrid bis-steroidal pyrazine analogs such as 25-epi-rittereostatin GN1N show unusually high potency against a wide range of cancer cell lines. Herein, we report the synthesis and bioactivity of 23-deoxy-25-epi ritterostatin GN1N, which lacks the 23-hydroxyl group of 25-epi rittereostatin GN1N. The less oxygenated bis-steroidal pyrazine was â¼50- to 1000-fold less potent than 25-epi ritterostatin GN1N, highlighting the importance of the 23-hydroxyl group for the antiproliferative activity of the cephalostatin/ritterazine class of drugs.
Assuntos
Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Esteroides/síntese química , Esteroides/farmacologia , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Oxirredução , Compostos de Espiro/química , Esteroides/químicaRESUMO
An efficient synthesis of the 23-deoxy-25-epi north unit of cephalostatin 1 has been achieved in 17 steps via reductive and oxidative functionalizations of hecogenin acetate with an overall yield of 3.8%. This synthesis features transetherification-mediated E-ring opening, D-ring oxidation, hemiketalization-mediated E-ring closure, and stereoselective 5/5-spiroketalization.