Synthesis and h LDH Inhibitory Activity of Analogues to Natural Products with 2,8-Dioxabicyclo[3.3.1]nonane Scaffold.

Human lactate dehydrogenase ( h LDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, h LDHA and h LDHB are the predominant ones. In the last few years, h LDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. h LDHA inhibition has been clinically validated as a safe therapeutic method and clinical trials using biotechnological approaches are currently being evaluated. Despite the well-known advantages of pharmacological treatments based on small-molecule drugs, few compounds are currently in preclinical stage. We have recently reported the detection of some 2,8-dioxabicyclo[3.3.1]nonane core derivatives as new h LDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives ( 42 - 70 ) by reaction between flavylium salts ( 27 - 35 ) and several nucleophiles ( 36 - 41 ). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC 50 values lower than 10 µM against h LDHA and better activity than our previously reported compound 2 . In order to know the selectivity of the synthesized compounds against h LDHA, their h LDHB inhibitory activities were also measured. In particular, compounds 58 , 62a , 65b , and 68a have shown the lowest IC 50 values against h LDHA (3.6-12.0 µM) and the highest selectivity rate (>25). Structure-activity relationships have been deduced. Kinetic studies using a Lineweaver-Burk double-reciprocal plot have indicated that both enantiomers of 68a and 68b behave as noncompetitive inhibitors on h LDHA enzyme.