Synthesis and biological evaluation of suffrutines A, B and their N-fused analogues

A facile synthetic route to the natural products suffrutines A ( 1a ), B ( 1b ) and their N-fused analogues ( 2a and 2b ) has been accomplished starting from pyrrole in 8 steps. Their structures were elucidated by a series of NMR spectra and single crystal X-ray crystallography. The in situ 1 H NMR monitoring experiments showed the interconversion properties of the four isomers of suffrutines and their stability order 1a ( E , E ) > 1b ( Z , E ) > 1d ( Z , Z ) > 1c ( E , Z ) in the solution state under ambient conditions. DFT calculations further confirmed the tautomerization results. The preliminary biological test results showed that 1′-aza-suffrutines B ( 2b ) was the most potent in cytotoxic study (MCF-7, IC 50 = 7.31 μM), while 1′-aza-suffrutines A ( 2a ) was the most active in a 14-day colony formation assay. In addition, 2a was proved to be a cancer cell apoptosis inducer in annexin V-FITC/PI dual staining tests.