Chien-Ming Huang

Synthesis, Preferentially Hypoxic Apoptosis and Anti-Angiogenic Activity of 3-Amino-1,2,4-Benzotriazine-1,4-Dioxide Bearing Alkyl Linkers with a 3-Amino-1,2,4-Benzotriazine-1-Oxide Moiety.

3-(Aminoalkylamino)-1,2,4-benzotriazine-1,4-dioxide-extended derivatives were synthesized by the structural modification of 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) that incorporated homologue-alkyl linkers, without or with an extended 3-amino-1,2,4-benzotriazine-1-oxide moiety at the 3-position of the TPZ. According to sequential evaluation of preferentially normoxic and hypoxic cytotoxicities against MCF-7, NCI-H460 and HCT-116, most of the synthesized compounds exhibited hypoxic cytotoxicity greater than or comparable to that of TPZ. Among them, compounds 9a and 9b more powerfully inhibited the proliferation of MCF-7, NCI-H460 and HCT-116 in hypoxia than did TPZ. The representative of 3-(aminoalkylamino)-1,2,4-benzotriazine-1,4-dioxide-extended derivatives, 9a exhibited greater hypoxic cytotoxicity than TPZ, mediated by cell cycle arrest. The induction of DNA damage, the activation of caspase 3/7 and cleaved poly(ADP-ribose) polymerase-related apoptosis, which were detected in HCT-116 cells in both normoxia and hypoxia. In vitro anti-angiogenic assay of co-cultured HUVECs and fibroblasts that were exposed to the selected 7b, 8g, 9a and 9b exhibited 80-90% inhibition of tube formation at 20 μM, whereas TPZ exhibited approximately 50% inhibition of tube formation at 20 μM. At 2 μM, 9a and 9b significantly reduced the areas, lengths, paths and joints of tube formation by 70-80% and 45-50%, respectively. These results reveal that most of synthesized TPZ derivatives in this study exhibited more potent anti-angiogenesis than TPZ.

Synthesis of N-(Chlorophenyl)-2-hydroxynicotinanilides as Potential Anti-inflammatory Agents

Leflunomide 1 and its non-enzymically active metabolite, malononitrilamide (MNA, 2) are clinical use for treating rheumatoid arthritis (RA). Study indicated that the active pharmacophore, a β-keto amide with the enolic hydroxyl group, was fully responsible for the immunosuppressive effects of malononitrilamide 2 leading a salicylamide derivative 3 developed. Previously, we have conducted isosterically structural modification mainly based on salicylamide derivative 3, which β-hydroxy-enamide-containing portion remains untouched, to successfully synthesize a series of N-(4-substituted phenyl)-2-hydroxynicotinanilides. After pharmacological screenings, compounds bearing electron-withdrawing groups such as 4-Cl, 4-Br, and 4-NO2 significantly showed potent anti-inflammatory activity. Currently, a series of compounds 5-14, which are the chloro variants on phenyl moiety, mainly based on N-(substituted phenyl)-2-hydroxynicotin-anilide 4-14 were further synthesized in high yields. After systematic pharmacological screenings of compounds 4-14 and controls, compound 14 exhibited potent in-vivo anti-inflammatory activity comparable to that of compound 5 and Leflunomide 1, whereas the other compounds have comparable activity to compound 4 and malononitrilamide 2 by both in vitro suppressing nitric oxide (NO) production under the LPS-elicited macrophage Raw 264.7 cell and the in-vivo carrageenaninduced paw edema assay, except for compounds 8 and 11.

Anti-inflammatory Activity and Structure-activity Relationships of 2-Hydroxy-N-(alkylphenyl)nicotinamides

Leflunomide 1 and its non-enzymically active metabolite, malononitrilamide (MNA, 2) are clinical use for treating rheumatoid arthritis (RA). Study indicated that the active pharmacophore, a β-keto amide with the enolic hydroxyl group, was fully responsible for the immunosuppressive effects of malononitrilamide 2 leading a salicylamide derivative 3 developed. Previously, we have conducted isosterically structural modification mainly based on salicylamide derivative 3, which β-hydroxy-enamide-containing portion remains untouched, to successfully synthesize a series of 2-hydroxy-N-(4-substituted phenyl)nicotinamides. After pharmacological screenings, compounds bearing electron-withdrawing groups such as 4-Cl, 4-Br, and 4-NO2 significantly showed potent anti-inflammatory activity. 1 Currently, a series of compounds 5-13, which are alkyl substitution on phenylmoiety, mainly based on 2-hydroxy-N-(phenyl)nicotinamide 4 were further synthesized in high yields. After systematic pharmacological screenings of compounds 5-13, all compounds exhibited less potent anti-inflammatory activity comparable to leflunomide 1 and malononitrilamide 2 by both in vitro suppressing nitric oxide (NO) production under the LPS-elicited macrophage Raw 264.7 cell and the in-vivo carrageenan-induced paw edema assay.

Synthesis of Mannich Base Derivatives of Oroxylin a Endowed with Anti-inflammatory Activity

Synthesis of baicalein, oroxylin A and wogonin, major active constituents of Scutellaria baicalensis GEORGI, was successfully developed in a previous report. In this investigation of novel oroxylin A derivatives as potential anti-infl ammatory agents, a series of Mannich base derivatives at C-8 in A-ring of oroxylin A were designed and synthesized. All the oroxylin A derivatives exhibited signifi cant anti-infl ammatory activity against λ-carrageenan-induced rat hind paw edema (CIPE). The results showed that the target compounds, oroxylin A (4a) and derivatives 4b-i (oroxylin A bearings a 8-substituent as piperidin-1-ylmethyl, morpholin-4-ylmethyl, 4-methyl-piperazin-1-ylmethyl, 4-pyridin-2-yl-piperazin- 1-ylmethyl, 4-pyrimidin-2-yl-piperazin-1-ylmethyl, 4-(2-chloro-phenyl)-piperazin-1-ylmethyl, 4-(4-nitro-phenyl)- piperazin-1-ylmethyl, 4-(4-fluoro-phenyl)-piperazin-1-ylmethyl, respectively) exerted a remarkably anti-inflammatory effect with a signifi cant reduction in swelling. Among them, compounds 4b (8-morpholin-4-ylmethyl oroxylin A), 4c (8-piperidinyl-4-ylmethyl oroxylin A), and 4f (8-[N-(N-2-pyrimidinyl)-piperazin-1-yl]methyl oroxylin A) proved to be the most potent with over 100% inhibition at 20 mg/kg dose in the fi rst hour and potency lasted 5 hours in comparison to that of ibuprofen (as a positive control).

A New 6-Substituted Coumarin Derivative

Coumarin derivatives have been reported to be potent drugs of anti-hormonal cancers because of their estrogen-like structures. In this article, a new acrylic-substituted courmarin derivative 7 was first described by using a mild acidic condition and temperature in the synthesis.

An Expedient One-pot Synthesis of Polyfunctionalized 4-Aryl-4H-benzo[b]pyrans as Potential Cytotoxic Agents

A practically facile microwave-enhanced synthesis of polyfunctionalized benzopyrans is described. The respective aromatic aldehyde and trimethoxyphenol with malononitrile in the presence of phase transfer agent (10 mol%, tetramethylammonium bromide or benzyltriethylammonium chloride) in water by microwave irradiation-assisted Knoevenagel and Pinner condensations provided novel polyfunctionalized 4-aryl-4H-benzopyrans, substituted 2-amino-4-aryl-4H-5,6,7-trimethoxy-chromene-3-carbonitriles (1-12), in high yields. The title benzopyrans had been primarily examined the cytotoxicity for MCF-7 (breast cancer cell), NCI-H460 (lung cancer cell) and SF268 cells (glioblastoma cell) by sulforhodamine B (SRB) assay.