Synthesis and biological evaluation of tricyclic matrinic derivatives as a class of novel anti-HCV agents

Abstract

Background12N-benzyl matrinic acid analogues had been identified to be a novel scaffold of anti-HCV agents with a specific mechanism, and the representative compound 1 demonstrated a moderate anti-HCV activity. The intensive structure–activity relationship of this kind of compounds is explored so as to obtain anti-HCV candidates with good druglike nature.ResultsTaking compound 1 as the lead, 32 compounds (of which 27 were novel) with diverse structures on the 11-side chain, including methyl matrinate, matrinol, matrinic butane, (Z)-methyl Δβγ-matrinic crotonate derivatives were synthesized and evaluated for their anti-HCV activities. Among all the compounds, matrinol 7a demonstrated potential potency with a greatly improved SI value of 136. Pharmacokinetic studies of 7a showed the potential for oral administration that would allow further in vivo safety studies. The free hydroxyl arm in 7a made it possible to prepare pro-drugs for the potential in the treatment of HCV infection.Conclusions27 novel 12N-substituted matrinol derivatives were prepared. The SAR study indicated that the introduction of electron-donating substitutions on the benzene ring was helpful for the anti-HCV activity, and the unsaturated 11-side chain might not be favorable for the activity. This study provided powerful information on further strategic optimization and development of this kind of compounds into a novel family of anti-HCV agents. Graphical abstractMatrinol derivatives as a class of novel anti-HCV agents

HSPA8/HSC70 in Immune Disorders: A Molecular Rheostat that Adjusts Chaperone-Mediated Autophagy Substrates

“…The overexpression of HSPA8 is associated with various disease phenotypes, and downregulating its activity stands as a rational way to influence the course of chronic and acute diseases, as for instance, in cancer, viral infections and neurodegenerative diseases [69,70,71]. A wide variety of molecules from natural or synthetic or semi-synthetic sources have been described (Table 3; [72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112]). A number of these pharmacological compounds alter the level of HSPA8 mRNA and/or protein, and do not directly bind to HSPA8.…”

Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway

“…Our group has been working on the discovery of innovative candidates agents with novel structure skeletons from Chinese natural products such as matrine (MT) [ 9 , 10 , 11 ]. Since MT is an anti-liver fibrosis monomer [ 12 ], the matrinic acid compound library constructed in our lab [ 9 , 10 , 13 ] was screened by the high-throughput screening model based on COL1A1 promotor as mentioned above, taking epigallocatechin gallate (EGCG) as the positive control [ 14 ]. To our great delight, the hit compound 12- N - p -methyl benzenesulfonyl matrinic acid ( 1 , Figure 1 ) [ 15 ] had been identified to display a reasonable inhibitory effect against COL1A1 at a rate of 18.5% at the concentration of 40 μM.…”