Rapid Synthesis of New DNMT Inhibitors Derivatives of Procainamide

Abstract

DNA methyltransferases (DNMTs) are responsible for DNA methylation, an epigenetic modification involved in gene regulation. Families of conjugates of procainamide, an inhibitor of DNMT1, were conceived and produced by rapid synthetic pathways. Six compounds resulted in potent inhibitors of the murine catalytic Dnmt3A/3L complex and of human DNMT1, at least 50 times greater than that of the parent compounds. The inhibitors showed selectivity for C5 DNA methyltransferases. The cytotoxicity of the inhibitors was validated on two tumour cell lines (DU145 and HCT116) and correlated with the DNMT inhibitory potency. The inhibition potency of procainamide conjugated to phthalimide through alkyl linkers depended on the length of the linker; the dodecane linker was the best.

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

“…Conjugates of ( 12 ) (a DNA binder) with ( 19 ) (a SAM competitor) have been reported ( 22 ) [45]. As expected, procainamide concentrated the conjugate at CpG-rich regions, while the RG-108 part was well positioned to inhibit the enzyme.…”

“…The hybrids of ( 12 ) with ( 19 ) were designed considering this combined strategy, and ( 22 ) was elucidated with greater inhibition activity compared to the parent compounds [45]. …”

Are epigenetic drugs for diabetes and obesity at our door step?

“…However, procainamide has not been used in diabetes and obesity for the inhibition of DNMT1. Nonetheless, derivatives of procainamide are also under study for more selective inhibition of DNMT1 [65].…”

Epigenetic therapy of hematological malignancies: where are we now?

“…The crystal structure of DNMT1 was recently published and was used to identify nonnucleoside DNMT1 inhibitors, at least one of which appears to have promising activity for epigenetic therapy [Yoo et al 2012]. In addition, some drugs that are approved for other applications have DNMT inhibitory activity, such as the nucleoside analog and antiarrhythmic drug procainamide [Halby et al 2012].…”