A series of cycloalkyl substituted analogues of the natural product sinefungin lacking the amino-acid moiety was designed and synthesized. Two stereoisomers (6-R and 6-S) were separated and their bioactivities examined against EHMT1/2. Of which, compound 14d showed an inhibitory activity against EHMT1/2 (88.9%, IC50=21.8μM for EHMT1 and 77.6%, IC50=39.6μM for EHMT2, respectively) similar to that of sinefungin (100.0%, IC50=28.4μM for EHMT1 and 79.5%, IC50=30.1μM for EHMT2, respectively). Further studies against other methyltransferases such as PRMT1 showed no activity except that 12d displayed about 20% inhibition.