Synthesis and antitumor activity of derivatives of SKF-83566

In this study, five novel SKF-83566 derivatives (8a-8e) were synthesized by covalently linking pomalidomide to SKF-83566, which features a benzazepine skeleton, via flexible linker chains. Their structures were confirmed using ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry. The antiproliferative activity against HeLa (cervical Cancer) and MDA-MB-231 (breast Cancer) cells was evaluated using the MTT assay, with SKF-83566, pomalidomide, and 5-fluorouracil (5-FU) serving as controls. The results indicate that most derivatives demonstrated superior activity compared to the control drug, with compound 8a exhibiting the highest potency: an IC₅₀ of 5.50 ± 0.28 μM against MDA-MB-231 cells and 10.13 ± 0.95 μM against HeLa cells. Further experiments demonstrated that 8a inhibits MDA-MB-231 cell colony formation, adhesion, and migration in a concentration-dependent manner, exhibiting a stronger anti-migration effect than 5-Fu. In the MDA-MB-231 cell chicken embryo chorioallantoic membrane (CAM) xenograft model, 8a also showed superior tumor growth inhibition compared to 5-Fu. Structure-activity relationship analysis shows that pomalidomide can enhance the compound's cytotoxicity and targeting ability, while flexible alkyl chains improve cell permeability and target binding capacity. This study confirms that compound 8a has the potential to become a candidate drug for breast Cancer treatment, providing a foundation for the development of new antitumor therapies.

Antitumor activity; Breast cancer; Pomalidomide; SKF-83566 derivatives.