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.

Hydroxymethylthiohydantoin, hydroxymethylthiohydantoin, and hydantoin, containing a pyridine group, were synthesized to study their androgen receptor antagonistic activities. Among them, compounds 6a/6c/7g/19a/19b exhibited excellent androgen receptor antagonistic activity, which was consistent with or even superior to enzalutamide. In addition, compounds 19a and 19b exhibited better antiproliferative activity than enzalutamide in prostate cancer cells. The results show that compound 19a has great potential as a new AR antagonist.

In this study, we constructed a linear antibody–drug conjugate (ADC), 7300-LP1003, by coupling the camptothecin derivative 095 to a linker through an ether bond. In vitro enzyme experiments indicated that LP1003 releases 095 through the action of tissue cathepsin B. Therefore, we introduced lysine pairs with different water-soluble substituents to further modify the linker and synthesized side-chain ADCs 7300-LP3004 and 7300-LP2004, modified by polysarcosine and polyethylene glycol, respectively. In vitro experiments showed that, after incubation at 55 °C in phosphate-buffered saline for 48 h, 7300-LP3004 aggregation was 45.24%, which was significantly lower than that of 7300-LP1003 (77.14%). Cell cytotoxicity assays demonstrated that the side-chain ADCs, 7300-LP3004 and 7300-LP2004, exhibited significantly higher activity (IC50 values of 39.74 nM and 32.17 nM, respectively) compared to the linear ADC and 7300-Deruxtecan (IC50 of 186.5 nM and 124.5 nM, respectively). In the subcutaneous model of SHP-77 NOD scid gamma mice, when the ADC dose was 5 mg/kg, 7300-LP3004 showed the highest tumor inhibition rate with a tumor growth inhibition (TGI) of 106.09%, which was superior to that of the positive control 7300-Deruxtecan, which had a TGI of 103.95%. In conclusion, 7300-LP3004 demonstrated strong antitumor activity and high physicochemical stability, highlighting the need for further research and development of ADC drugs.