Daeho Kwon

Synthesis of diethylamino-curcumin mimics with substituted triazolyl groups and their sensitization effect of TRAIL against brain cancer cells.

A newly designed curcumin mimic library (11a-11k) with 2-ethylamino groups in a chalcone structure and variously substituted triazole groups as side chains was synthesized using the Huisgen 1,3-cycloaddition reaction between various alkynes (a-k) and an intermediate (10), with CuSO4 and sodium ascorbate in a solution mixture of chloroform, ethanol, and water (5:3:1) at room temperature for 5h. In the lactate dehydrogenase (LDH) release assay involving co-treatment with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and/or synthetic curcumin derivatives using TRAIL-resistant human CRT-MG astroglioma cells, the novel curcumin mimic library was found to effectively stimulate the cytotoxicity of TRAIL, causing mild cytotoxicity when administered alone. In particular, 11a and 11j are promising candidates for TRAIL-sensitizers with potential use in combination chemotherapy for brain tumors.

5E- and 5Z-farnesylacetones from Sargassum siliquastrum as novel selective L-type calcium channel blockers.

A specific blocker of L-type Ca(2+) channels may be useful in decreasing arterial tone by reducing the open-state probability of L-type Ca(2+) channels. The aim of the present study was to evaluate the farnesylacetones, which are major active constituents of Sargassum siliquastrum, regarding their vasodilatation efficacies, selectivities toward L-type Ca(2+) channels, and in vivo antihypertensive activities. The application of 5E-(farnesylacetone 311) or 5Z-farnesylacetone (farnesylacetone 312) induced concentration-dependent vasodilatation effects on the basilar artery that was pre-contracted with depolarization and showed an ignorable potential role of endothelial-derived nitric oxide. We also tested farnesylacetone 311 or 312 to determine their pharmacological profiles for the blockade of native L-type Ca(2+) channels in basilar arterial smooth muscle cells (BASMCs) and ventricular myocytes (VMCs), cloned L- (α1C/β2a/α2δ), N- (α1B/β1b/α2δ), and T-type Ca(2+) channels (α1G, α1H, and α1I). Farnesylacetone 311 or 312 showed greater selectivity toward the L-type Ca(2+) channels among the tested voltage-gated Ca(2+) channels. The ranked order of the potency for farnesylacetone 311 was cloned α1C≒L-type (BASMC)≒L-type (VMCs)>α1B>α1H>α1I>α1G and that for farnesylacetone 312 was cloned α1C≒L-type (BASMCs)≒L-type (VMCs)>α1H>α1G>α1B>α1I. The oral administration of the farnesylacetone 311 (80mg/kg) conferred potent, long-lasting antihypertensive activity in spontaneous hypertensive rats, but it did not alter the heart rate.

Synthesis of alkylsulfonyl and substituted benzenesulfonyl curcumin mimics as dual antagonist of L-type Ca2+ channel and endothelin A/B2 receptor

We synthesized a library of curcumin mimics with diverse alkylsulfonyl and substituted benzenesulfonyl modifications through a simple addition reaction of important intermediate, 1-(3-Amino-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-propenone (10), with various sulfonyl chloride reactants and then tested their vasodilatation effect on depolarization (50 mM K(+))- and endothelin-1 (ET-1)-induced basilar artery contraction. Generally, curcumin mimics with aromatic sulfonyl groups showed stronger vasodilation effect than alkyl sulfonylated curcumin mimics. Among the tested compounds, six curcumin mimics (11g, 11h, 11i, 11j, 11l, and 11s) in a depolarization-induced vasoconstriction and seven compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s) in an ET-1-induced vasoconstriction showed strong vasodilation effect. Based on their biological properties, synthetic curcumin mimics can act as dual antagonist scaffold of L-type Ca(2+) channel and endothelin A/B2 receptor in vascular smooth muscle cells. In particular, compounds 11g and 11s are promising novel drug candidates to treat hypertension related to the overexpression of L-type Ca(2+) channels and ET peptides/receptors-mediated cardiovascular diseases.

Toxicological evaluation of dithiocarbamate fungicide mancozeb on the endocrine functions in male rats

In the present study, we evaluated the mancozeb-induced toxicity on the liver, thyroid, and testis via histological and functional hormone assay in male rats. Mancozeb was orally administered at 800 mg/kg body weight/day for 4 weeks. Upon the chronic administration of mancozeb, the body weight slightly decreased, but, liver, thyroid, and testis weights per 100 g body weight were not changed. Histological studies of the testis of male rats treated with mancozeb revealed spermatogenesis inhibition, which was reflected by significant decreases in the numbers of spermatogonia, primary spermatocyte, spermatid, and sperm. Chronic exposure to mancozeb induced gonadal hormone disturbance. Concentrations of estradiol, progesterone, and testosterone in the serum were significantly decreased in mancozeb-treated rats. The volume and histopathology of the thyroid were also distinctly altered. Serum levels of T3 and T4 were markedly decreased in the mancozeb diet group. However, liver toxicity was not observed upon chronic mancozeb exposure.

Diethylamino-curcumin mimic with trizolyl benzene enhances TRAIL-mediated cell death on human glioblastoma cells

BackgroundsGlioblastoma multiforme is one of the most aggressive human malignant brain tumors. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known as the death ligand, which induces preferential apoptosis of transformed cancer cells. In this study, we demonstrated that the newly synthesized diethylamino-curcumin mimic with trizolyl benzene (YM-4) enhances cytotoxicity in combination with TRAIL in human glioblastoma cells.MethodsWe synthesized diethylamino-curcumin mimic with trizolyl benzene (YM-4) and investigated possible apoptotic cell signaling by co-treatment with YM-4 and TRAIL on human glioblastoma cells.ResultsCaspase-8, 9, and 3 and poly (ADP-ribose) polymerase were more efficiently cleaved with cotreatment of YM-4 and TRAIL than treatment with each alone in human glioblastoma cells. Co-treatment with YM-4 and TRAIL significantly increased the expression of Bax and Smac/Diablo and also inhibited the expression of the X-linked inhibitor of apoptosis protein and Survivin in human glioblastoma cells.ConclusionThese results demonstrated that YM-4 can be an anticancer candidate that can be effective on human glioblastoma cells in combination with TRAIL.

O1-6-3Novel curcumin mimics: Potential anticancer drugs against human glioblastoma multiforme

Yongchel Ahn, Cheon-Soo Park, HyukJai Jang, JiHwan Lee, Mikyong Byun, Byung-Gon Park, Woon-Seob Shin, Yoon-Sun Park, Seokjoon Lee, Daeho Kwon Department of Hematology and Oncology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Korea, Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Medical Research Center, Gangneung Asan Hospital, University of Ulsan College of Medicine, Department of Nursing, Korea University College of Nursing, Department of Physiology, Catholic Kwandong University College of Medicine, Department of Pharmacology, Catholic Kwandong University College of Medicine, Department of Microbiology, Catholic Kwandong University College of Medicine