Design, synthesis and evaluation of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones as histone deacetylase inhibitors and antitumor agents.

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized several series of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones (4a-h, 8a-d, 10a-d). Biological evaluation showed that these hydroxamic acids were generally cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). It was found that the N-hydroxypropenamides (10a-d) were the most potent, both in term of HDAC inhibition and cytotoxicity. Several compounds, e.g. 4e, 8b-c, and 10a-c, displayed up to 4-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range. Docking experiments on HDAC2 isozyme revealed some important features contributing to the inhibitory activity of synthesized compounds, especially for propenamide analogues. Importantly, the free binding energy computed was found to have high quantitative correlation (R2 ∼ 95%) with experimental results.

Design, synthesis and biological evaluation of novel hydroxamic acids bearing artemisinin skeleton.

A series of novel hydroxamic acids bearing artemisinin skeleton was designed and synthesized. Some compounds in this series exhibited moderate inhibition against the whole cell HDAC enzymes. Especially, compound 6g displayed potent cytotoxicity against three human cancer cell lines, including HepG2 (liver cancer), MCF-7 (breast cancer) and HL-60 (leukemia cancer), with IC50 values of 2.50, 2.62 and 1.28µg/mL, respectively. Docking studies performed with two potent compounds 6a and 6g using Autodock Vina showed that both compounds bound to HDAC2 with relatively high binding affinities from -7.1 to 7.0kcal/mol compared to SAHA (-7.4kcal/mol). It was found in this research that most of the target compounds seemed to be more cytotoxic toward blood cancer cells (HL-60) than liver (HepG2), and breast (MCF-7) cancer cells.

Coumarin-derived Hydroxamic Acids as Histone Deacetylase Inhibitors: A Review of Anti-cancer Activities.

Since coumarin and hydroxamic acid compounds are well-known in medicinal chemistry, a variety of their derivatives have been highlighted due to their potential uses for plentiful treatments. Different compounds of their derivatives acting through diverse activities, such as anti-tumor, anti-cancer, anti-inflammation, and histone deacetylase inhibition, have been comprehensively investigated by many researchers over the years. This present review provides the latest literature and knowledge on hydroxamic acids derived from coumarin. Overall, some recent advancements in biological activities of hybrid derivatives of hydroxamic acids containing coumarin moieties in medicinal chemistry are discussed.

Novel Conjugated Quinazolinone-Based Hydroxamic Acids: Design, Synthesis and Biological Evaluation.

BACKGROUND: The target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development. Histone deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat. AIMS: This study aims at developing novel HDAC inhibitors bearing conjugated quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. METHODS: A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin- 4(3H)-ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain more insight into the structureactivity relationships. RESULTS: It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds 15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with IC50 value of 1.86 µM, and HDAC inhibition with IC50 value of 6.36 µM. Docking experiments on HDAC2 isozyme showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward SKLu-1than MCF-7 and HepG-2. CONCLUSION: The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.

Nucleoside-based phospholipids and their liposomes formed in water.

Phospholipids and liposomes have been the subjects of considerable attention because of their importance in biological systems. We have efficiently synthesized novel nucleoside-based phospholipids in six-step sequences starting from their corresponding nucleosides. These nucleoside-based phospholipids self-assemble into liposome-like structures in aqueous solutions. We have analyzed the structures of these liposomes by dynamic light scattering, transmission electron microscopy, and confocal microscopy.