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

Human lactate dehydrogenase (LDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, LDHA and LDHB are the predominant ones. In the last few years, LDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. 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 LDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives (-) by reaction between flavylium salts (-) and several nucleophiles (-). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC values lower than 10 µM against LDHA and better activity than our previously reported compound . In order to know the selectivity of the synthesized compounds against LDHA, their LDHB inhibitory activities were also measured. In particular, compounds , , , and have shown the lowest IC values against 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 and behave as noncompetitive inhibitors on LDHA enzyme.