Hypoxia-Activated Albumin-Binding Exatecan Prodrug for Cancer Therapy.

As an effective drug delivery strategy for traditional antitumor drugs, the stimulus-responsive albumin-based prodrugs are getting more and more attention. These prodrugs only release drugs in specific tumor microenvironments, which can prevent premature release of the drug in the circulation. Tumor hypoxia is a fundamental feature of the solid tumor microenvironment. As a hypoxia-activated linker, the 5-position branched linker of 1-methyl-2-nitro-5-hydroxymethylimidazole can be a trigger for albumin-based prodrugs. In this study, we report the synthesis and biological evaluation of the hypoxia-activated albumin-binding prodrug Mal-azo-Exatecan. After intravenous administration, the maleimide on the side chain can rapidly bind to endogenous albumin, enabling the prodrugs to accumulate in tumors, where tumor-associated hypoxia microenvironments trigger the selective release of Exatecan. The 5-position branched linker of 1-methyl-2-nitro-5-hydroxymethylimidazole as a cleavable linker has high plasma stability and does not cause Exatecan release from HSA-azo-Exatecan during circulation in vivo, avoiding systemic side effects caused by Exatecan.

Short Protecting Group-free Syntheses of CDE Synthon of Racemic Camptothecin.

A practical and concise total synthesis of tricyclic ketone 7 (CDE ring), a valuable intermediate for the synthesis of racemic camptothecin and analogs, was described (8 chemical steps and 29% overall yield). The synthesis starts with two inexpensive, readily available materials and is operationally simple to perform. It is worth mentioning that the reported protecting group-free synthesis, with advantages of a short route, would be helpful for the future development of industry-scale syntheses of camptothecin-family alkaloids.

Synthesis of Aryl Propionamide Scaffold Containing a Pentafluorosulfanyl Moiety as SARMs.

The pentafluorosulfane (SF5) group, as a more electronegative bioisostere than the trifluoromethyl (CF3) group, has been gaining greater attention and increasingly reported usage in medicinal chemistry. Ostarine is the selective androgen receptor modulators (SARMs) containing a CF3 group in clinical trial III. In this study, 21 ostarine derivatives for replacing the CF3 group with SF5 substituents were synthesized. Some SF5-derivatives showed androgen receptor (AR) agonistic activities in vitro. The results pointed to the potential of using this scaffold to develop new AR agonists.