RESUMO
While salarin C (SalaC) is a potent marine cytotoxin, Kashman demonstrated that congeners which had undergone Wasserman rearrangement exhibit little to no cytotoxicity. Given that thiazoles are known to undergo Wasserman rearrangement at a significantly reduced rate, we hypothesized that a thiazole-containing SalaC would exhibit greater stability without significantly altering the macrocyclic conformation. Herein, we describe the synthesis of a simplified, thiazole-containing macrocycle which demonstrates significantly improved stability under identical aerobic conditions.
Assuntos
Antineoplásicos , Tiazóis , Antineoplásicos/farmacologia , Citotoxinas , Macrolídeos , Tiazóis/farmacologiaRESUMO
Carbonic anhydrase IX (CAIX) is a membrane-spanning zinc metalloenzyme that catalyzes the reversible consumption of CO2 and water to form H+ + HCO3-. Many human cancers upregulate CAIX to help control the pH in their hypoxic microenvironments. The consequent overexpression of CAIX on malignant cells and low expression on normal tissues render CAIX a particularly attractive target for small molecule inhibitors, antibody-drug conjugates, and ligand-targeted drugs. In this study, CAIX-targeted fluorescent reporter molecules were initially exploited to investigate CAIX-specific binding to multiple cancer cell lines, where they were shown to display potent and selective binding to CAIX positive cells. A small molecule CAIX-targeted tubulysin B conjugate was then synthesized and examined for its ability to kill CAIX-expressing tumor cells in vitro. Potent therapeutic conjugates were subsequently tested in vivo and demonstrated to eliminate solid human tumor xenografts in murine tumor models without exhibiting overt signs of toxicity. Because most solid tumors contain hypoxic regions where CAIX is overexpressed, development of a method to selectively deliver drugs to these hypoxic regions could aid in the therapy of otherwise difficult to treat tumors.