Identification of Novel ROS Inducers: Quinone Derivatives Tethered to Long Hydrocarbon Chains

We performed the first synthesis of the 17-carbon chain-tethered quinone moiety <b>22</b> (SAN5201) of irisferin A, a natural product exhibiting anticancer activity, and its derivatives. We found that <b>22</b> is a potent ROS inducer and cytotoxic agent. Compound <b>25</b> (SAN7401), the hydroquinone form of <b>22</b>, induced a significant release of intracellular ROS and apoptosis (EC₅₀ = 1.3–2.6 μM) in cancer cell lines, including A549 and HCT-116. Compared with the activity of a well-known ROS inducer, piperlongumine, <b>22</b> and <b>25</b> showed stronger cytotoxicity and higher selectivity over noncancerous cells. Another hydroquinone tethering 12-carbon chain, <b>26</b> (SAN4601), generated reduced levels of ROS but showed more potent cytotoxicity (EC₅₀ = 0.8–1.6 μM) in cancer cells, although it lacked selectivity over noncancerous cells, implying that the naturally occurring 17-carbon chain is also crucial for ROS production and a selective anticancer effect. Both <b>25</b> and <b>26</b> displayed strong, equipotent activities against vemurafenib-resistant SK-Mel2 melanoma cells and p53-deficient H1299 lung cancer cells as well, demonstrating their broad therapeutic potential as anticancer agents

Structural Revision of Baulamycin A and Structure–Activity Relationships of Baulamycin A Derivatives

Total synthesis of the proposed structure of baulamycin A was performed. The spectral properties of the synthetic compound differ from those reported for the natural product. On the basis of comprehensive NMR study, we proposed two other possible structures for natural baulamycin A. Total syntheses of these two substances were performed, which enabled assignment of the correct structure of baulamycin A. Key features of the convergent and fully stereocontrolled route include Evans Aldol and Brown allylation reactions to construct the left fragment, a prolinol amide-derived alkylation/desymmetrization to install the methyl-substituted centers in the right fragment, and finally, a Carreira alkynylation to join both fragments. In addition, we have determined the inhibitory activities of novel baulamycin A derivatives against the enzyme SbnE. This SAR study provides useful insight into the design of novel SbnE inhibitors that overcome the drug resistance of pathogens, which cause life-threatening infections

Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L‑783277

We synthesized <b>1</b> (San78-130), a reversible version of L-783277, as a selective and potent ALK1 inhibitor. Our study showed that <b>1</b> possesses great kinase selectivity against a panel of 342 kinases and more potent activity against ALK1 than L-783277. Among the six ALK isotypes (ALK1–6), ALK1 is most significantly inhibited by compound <b>1</b>. Compound <b>1</b> suppresses the BMP9-induced Smad1/5 pathway by mainly inhibiting ALK1 in C2C12 cells. Our molecular dynamics simulations suggest that H-bonding interaction between the C-4′ hydroxyl group of <b>1</b> and Arg334 of ALK1 substantially contributes to the ALK1 inhibition. To the best of our knowledge, <b>1</b> is the first selective ALK1 inhibitor. Furthermore, compound <b>1</b> promoted angiogenesis in both endothelial tube formation and microfluidic chip based 3D angiogenesis assays, suggesting that <b>1</b> could be a lead compound for therapeutic angiogenesis agents. Our study may provide an insight into designing selective and potent inhibitors against ALK1