Discovery of N-(2-Amino-4-Fluorophenyl)-4-[bis-(2-Chloroethyl)-Amino]-Benzamide as a Potent HDAC3 Inhibitor

Abstract

In discovery of HDAC inhibitors with improved activity and selectivity, fluorine substitution was performed on our previously derived lead compound. The synthesized molecules N-(2-amino-4-fluorophenyl)-4-[bis-(2-chloroethyl)-amino]-benzamide (FNA) exhibited class I (HDAC1, 2, and 3) selectivity in the in vitro enzymatic assay and especially potent against HDAC3 activity (IC 50 : 95.48 nM). The results of in vitro antiproliferative assay indicated that FNA exhibited solid tumor cell inhibitory activities with IC 50 value of 1.30 µM against HepG2 cells compared with SAHA (17.25 µM). Moreover, the in vivo xenograft model study revealed that FNA could inhibit tumor growth with tumor growth inhibition (TGI) of 48.89% compared with SAHA (TGI of 48.13%). Further HepG2 cell-based apoptosis and cell cycle studies showed that promotion of apoptosis and G2/M phase arrest make contributions to the antitumor activity of FNA. In addition, drug combination results showed that 0.5 µM of FNA could improve the anticancer activity of taxol and camptothecin. The present studies revealed the potential of FNA utilized as a high potent lead compound for further discovery of isoform selective HDAC inhibitors.

Photocatalysis in Aqueous Micellar Media Enables Divergent C–H Arylation andN-Dealkylation of Benzamides

“…The benzamide core is widespread in biologically relevant compounds, including antitumor agents, 1 antidepressants, 2 and recently inhibitors of SARS-CoV-2 replication, 3 which renders the functionalization of this structure a vibrant area of research. 4,5 While different strategies targeting the aromatic ring or the carbonyl group of benzamides are well developed, 6,7 the repertoire of methods for direct transformations at the Nunit remains limited (Scheme 1a, right).…”

“…The benzamide core is widespread in biologically relevant compounds, including antitumor agents, antidepressants, and recently inhibitors of SARS-CoV-2 replication, which renders the functionalization of this structure a vibrant area of research. , While different strategies targeting the aromatic ring or the carbonyl group of benzamides are well developed, , the repertoire of methods for direct transformations at the N -unit remains limited (Scheme a, right). − To overcome this challenge, several indirect approaches have been investigated. They typically involve reductive activation of the aromatic carbon–halide bond at the position ortho to the carbonyl group, followed by intramolecular 1,5-hydrogen-atom transfer (1,5-HAT), giving access to reactive species at a position α to the N -atom (Scheme b). − Although they are highly efficient, these methods necessitate strongly reducing reagents or specific catalysts, thereby restricting the available chemical space to radical reactivityparticularly radical cyclizationand precluding the possibility of more general, divergent strategies.…”

Micellar photocatalysis enables divergent C-H arylation and N dealkylation of benzamides via N-acyliminium cations

“…The benzamide core is widespread in biologically relevant compounds, including anti-tumor agents, [1] antidepressants, [2] or recently inhibitors of SARS-CoV-2 replication, [3] which renders functionalisation of this structure a vibrant area of research. [4,5] While different strategies targeting the aromatic ring or the carbonyl group of benzamides are well developed, [6,7] the repertoire of methods for direct transformations at the N-unit remains limited (Fig.…”

Editorial: Chemo-Radiation-Resistance in Cancer Therapy

“…Nitrogen mustard anticancer drugs were used clinically since 1942, which effectively bind and cross-link to DNA, resulting in prevention of DNA replication and cell proliferation. Yiming Chen et al ( Chen et al, 2020b ) discovered that N-(2-amino-4-fluorophenyl)-4-[bis-(2-chloroethyl)-amino]-benzamide (FNA) was a potent HDAC3 inhibitor by inhibiting tumor growth and promoting apoptosis and G2/M phase arrest, which improved the anticancer activity of paclitaxel and camptothecin.…”