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Relevant academic research and scientific papers

Design, synthesis and biological evaluation of nitro oxide donating N-hydroxycinnamamide derivatives as histone deacetylase inhibitors

Novel nitro oxide (NO)-donating N-hydroxycinnamamide derivatives 12a-j were designed and synthesized by coupling the carboxyl group of N-hydroxycinnamamides with phenylsulfonylfuroxan through various diols or alkylol amines, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed good histone deacetylases (HDACs) inhibition and anti-tumor activities, particularly for 12j, which had great HDACs inhibitory activities (IC50s=0.15-0.26 μm) and antiproliferative effects (IC50s=3.21-7.12 μm) comparable to suberoylanilide hydroxamic acid (SAHA) (IC50s=0.16-1.41 μm for HDACs, IC50s=3.15-7.45 μm for cancer cell inhibition). Furthermore, compound 12j with strong antitumor activities produced high levels of NO (up to 8.0 μm of nitrites/nitrates) in colon cancer cells, and its antiproliferative activity was nearly half-diminished by hemoglobin (10 μm), an NO scavenger. These results suggest that the strong antiproliferative activity of 12j could be attributed to the additive effects of high levels of NO production and inhibition of HDAC in the cancer cells.

Synthesis and biological evaluation of nitric oxide-releasing hybrids from gemcitabine and phenylsulfonyl furoxans as anti-tumor agents

A series of novel hybrids 10a-m were designed and synthesized by coupling phenylsulfonyl furoxans with gemcitabine through various diols or alcohol amine linkers, and their biological activities were evaluated in vitro. Most of the hybrids exhibited good to moderate anti-tumor activities, which are associated with NO release. In particular, hybrid 10e showed excellent anticancer activities which were more potent than or comparable to gemcitabine. However, inhibition of nucleoside transport only significantly decreased the inhibitory rates of gemcitabine against HepG2 cells but not 10e, and the inhibitory rates of 10e were partially reduced by pre-treatment with hemoglobin, demonstrating that the anti-tumor activity of 10e might result from the synergic effect of high levels of NO production and gemcitabine fragment. In addition, compound 10ecould apparently induce cell apoptosis by regulating apoptotic relative proteins. Therefore, our novel findings provide a proof of principle in the design of new furoxan/gemcitabine hybrids for the intervention of human cancers.

Synthesis and in vitro biological evaluation of nitric oxide-releasing derivatives of hydroxylcinnamic acids as anti-tumor agents

Novel furoxan-based nitric oxide-releasing derivatives 6a-p of hydroxylcinnamic acids were synthesized by coupling the carboxyl group of hydroxylcinnamic acids with furoxan through various alkylol amines. Compounds 6a, e-i and m-p displayed more potent anti-tumor activities superior to control 5-fluorouracil (5-FU) in most cancer cells tested. Furthermore, 6f could selectively inhibit tumor cells, but not non-tumor cell proliferation. This inhibition was attributed to high levels of NO released in cancer cells and potentially synergistic effect of NO donor moieties and the bioactivity of hydroxylcinnamic acids.

Novel nitric oxide-releasing derivatives of farnesylthiosalicylic acid: Synthesis and evaluation of antihepatocellular carcinoma activity

Figure Presented. Novel furoxan-based nitric oxide (NO) releasing derivatives (8a-p) of farnesylthiosalicylic acid (FTS) were synthesized. Compound 8l displayed the strongest inhibition on the proliferation of human hepatocellular carcinoma (HCC) cells in vitro, superior to FTS, sorafenib, and furoxan moiety, selectively induced high frequency of HCC cell apoptosis, and produced high levels of NO in HCC cells but not in nontumor liver cells. Furthermore, 8l exhibited low acute toxicity to mice and significantly inhibited the growth of HCC tumors in vivo and the Ras-related signaling in the tumors. Therefore, our novel findings may provide a new framework for the design of new NO-releasing furoxan/FTS hybrids for the intervention of human HCC.