Total synthesis of the proposed structures of the DNA methyl transferase inhibitors peyssonenynes, and structural revision of peyssonenyne B.

The purported structures of the peyssonenynes A and B isolated from Peyssonnelia caulifera, and considered to be geometric isomers at the acetoxyenediyne moiety, have been synthesized. The E and Z geometries of the synthetic compounds were secured by the magnitude of the (3)J(H9-C7) values measured using the EXSIDE band-variant of the gradient HSQC pulse sequence and by the chemical shifts of C(6). Comparison of the NMR data of the synthetic and natural products revealed that only those of the Z isomers matched, which correspond to peyssonenyne A. Using HPLC analysis it was found that peyssonenyne B must correspond to the sn-2 positional isomer of the Z sn-1/3 counterpart. The four synthetic sn-1/3 diastereomers are roughly equipotent as DNMT1 inhibitors when evaluated on a radioactive methyl transfer enzymatic assay after immunoprecipitation from K562 human leukemia cells with anti-DNMT1 antibody.