A Novel Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitor Derivative, N25, Exhibiting Improved Antitumor Activity in both Human U251 and H460 Cells

Abstract

. This invention is a hydroxamic acid compound with a structural formula of RNHCO(CH 2 )6CONHOH (wherein R=2, 5dimethoxyaniline), a pharmaceutically acceptable salt which is soluble. In the present study, we investigated the effects of N25 with regard to drug distribution and molecular docking, and anti-proliferation, apoptosis, cell cycling, and LD 50 . First, we designed a molecular approach for modeling selected SAHA derivatives based on available structural information regarding human HDAC8 in complex with SAHA (PDB code 1T69). N25 was found to be stabilized by direct interaction with the HDAC8. Anti-proliferative activity was observed in human glioma U251, U87, T98G cells and human lung cancer H460, A549, H1299 cells at moderate concentrations (0.5-30μM). Compared with SAHA, N25 displayed an increased antitumor activity in U251 and H460 cells. We further analyzed cell death mechanisms activated by N25 in U251 and H460 cells. N25 significantly increased acetylation of Histone 3 and inhibited HDAC4. On RT-PCR analysis, N25 increased the mRNA levels of p21, however, decreased the levels of p53. These resulted in promotion of apoptosis, inducing G0/G1 arrest in U251 cells and G2/M arrest in H460 cells in a time-dependent and dosedependent manner. In addition, N25 was able to distribute to brain tissue through the blood-brain barrier of mice (LD 50 : 240.840mg/kg). In conclusion, our findings demonstrate that N25 will provide an invaluable tool to investigate the molecular mechanism with potential chemotherapeutic value in several malignancies, especially human glioma.

Ethanol but not Aqueous Extracts of Tubers of Sauromatum Giganteum(Engl.) Cusimano and Hett Inhibit Cancer Cell Proliferation

“…The solubility and acute toxicity of extract were determined, the max solubility of ethanol extract and aqueous extract was 15 mg/mL and 20 mg/mL, respectively. The aim of the "Acute toxicity study in vivo" is that determining the median lethal dose (LD50) (Zhang et al, 2014) or the largest drug concentration and providing the basis for dosage regimen in the follow-up research (Sakthivel et al, 2012). The result showed that no deaths or adverse effects were detected during the 24 hour observation period in mice treated with up to the max administration dose of ethanol extract (1200 mg/kg.bw=15mg/ mL×0.8mL/20g·bw×twice/day×50) or aqueous extract (1600 mg/kg.bw=20mg/mL×0.8mL/20g·bw×twice/ day×50).…”

HDAC Inhibitors: A New Radiosensitizer for Non-small-cell Lung Cancer

“…N25 and vorinostat decreased the expression of the p53 gene in H460 cells (54). Vorinostat increased the level of wild-type p53 protein in H520 and H460 cells (55).…”

Synthesis, Biological Evaluation, and Computer‐Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors

“…CN 103159646). Compared with SAHA, N25 displayed an increased antineoplastic activity that significantly upregulated acetylation of histone H3 and inhibited HDAC4 in U251 cells, and N25 leads to initiation of apoptosis, inducing G0/G1 stage arrest, increasing p21WAF1/CIP1 expression and reducing p53 levels in U251 cells (8). Our current data proved that N3F can increase Beclin-1 and Caspase-3, 9 and inhibit Bcl-2 and demonstrated that Caspase inhibition resulted in significantly upregulation of Beclin-1 expression in U251 cells.…”

“…In our preliminary studies, the suberoylanilide hydroxamic acid of HDACis has shown potential effect in the treatment of glioma . Compounds inhibited HDAC activity that might decrease the expression of certain genes, resulting in antiproliferative and antitumor effects.…”