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.

Synthesis and antibacterial activities of baulamycin A inspired derivatives.

SbnE is an essential enzyme for staphyloferrin B biosynthesis in Staphylococcus aureus. An earlier study showed that natural product baulamycin A has in vitro inhibitory activity against SbnE and antibacterial potency. A SAR study with analogues of baulamycin A was conducted to identify potent inhibitors of SbnE and/or effective antibiotics against MRSA. The results show that selected analogues, including 11, 18, 21, 24a, 24c, 24m and 24n, exhibit single-digit micromolar inhibitory potencies against SbnE (IC50s = 1.81-8.94 µM) and 11, 24m, 24n possess significant activities against both SbnE (IC50s = 4.12-6.12 µM) and bacteria (MICs = 4-32 µg/mL). Biological investigations revealed that these substances possess potent cell wall disruptive activities and that they inhibit siderophore production in MRSA. Among the selected analogues, 7 has excellent antibiotic activities both gram-positive and -negative bacteria (0.5-4 µg/mL). Moreover, these analogues significantly impede biofilm formation in a concentration-dependent manner. Taken together, the results of the investigation provide valuable insight into the nature of novel baulamycin A analogues that have potential efficacy against MRSA owing to their membrane damaging activity and/or inhibitory efficacy against siderophore production.

Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis.

We synthesized 11 novel L-783277 derivatives, in which a structure rigidifying phenyl ring is incorporated into the 14-membered chiral resorcylic acid lactone system. The SAR study with these substances demonstrated that 17 possesses excellent kinase selectivity against a panel of 335 kinases in contrast to L-783277 and inhibits VEGFR3, VEGFR2, and FLT3 with single-digit nanomolar IC50 values. Also, we found that 21, a stereoisomer of 17, has excellent potency (IC50 = 9 nM) against VEGFR3 and selectivity over VEGFR2 and FLT3. 17, a potent dual VEGFR3 and VEGFR2 inhibitor, effectively suppresses both lymphangiogenesis and angiogenesis in a 3D-microfluidic tumor lymphangiogenesis assay and in vivo corneal assay while SAR131675 blocks only lymphangiogenesis. In addition, 17 blocks the endothelial tube formation and suppresses proliferation of PHE tumor vascular model. 17 will be a valuable templatefor developing therapeutically active and selective substances that target both lymphangiogenesis and angiogenesis.