Dong-Jun Fu

Design, Synthesis and Structure-Activity Relationships of Novel Chalcone-1,2,3-triazole-azole Derivates as Antiproliferative Agents.

A series of novel chalcone-1,2,3-triazole-azole hybrids were designed, synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (SK-N-SH, EC-109 and MGC-803). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, compound I-21 showed the most excellent antiproliferative activity with an IC50 value of 1.52 μM against SK-N-SH cancer cells. Further mechanism studies revealed that compound I-21 induced morphological changes of SK-N-SH cancer cells possibly by inducing apoptosis. Novel chalcone-1,2,3-triazole-azole derivatives in this work might be a series of promising lead compounds to develop anticancer agents for treating neuroblastoma.

Design, synthesis and antiproliferative activity studies of novel dithiocarbamate–chalcone derivates

A series of novel dithiocarbamate-chalcone derivates were designed, synthesized and evaluated for antiproliferative activity against three selected cancer cell lines (EC-109, SK-N-SH and MGC-803). Majority of the synthesized compounds exhibited moderate to potent activity against all the cancer cell lines assayed. Particularly, compounds II2 and II5 exhibited the excellent growth inhibition against SK-N-SH with IC50 values of 2.03μM and 2.46μM, respectively. Further mechanism studies revealed that compound II2 could obviously inhibit the proliferation of SK-N-SH cells by inducing apoptosis and arresting the cell cycle at G0/G1 phase.

Design, synthesis and antiproliferative activity studies of 1,2,3-triazole–chalcones

A series of 1,2,3-triazole–chalcone hybrids were designed, synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (SK-N-SH, HepG-2 and MGC-803). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, compound 12k showed the most excellent antiproliferative activity with an IC50 value of 1.53 μM against SK-N-SH cancer cells. The mechanism studies revealed that compound 12k inhibited the proliferation of SK-N-SH cancer cells by inducing apoptosis and arresting the cell cycle at the G1 phase.

Synthesis of novel antiproliferative 1,2,3-triazole hybrids using the molecular hybridisation approach

A series of nine novel 1,2,3-triazole-chalcone derivatives were designed using the molecular hybridisation approach and synthesised by click chemistry. Most of the synthesised compounds exhibited moderate to good antiproliferative activity against oesophagus, gastric and neuroendocrine cancer cell lines, but a compound containing a p-bromo group in the A ring and a [(4,5-dihydrothiazol-2-yl)thio]methyl group attached at the 4-position of a p-[3-(1,2,3-triazol-1-yl)propyloxy] group in the B ring showed the highest activity with an IC50 value of 8.16 μM against neuroendocrine cancer cells. The structure activity relationships of all nine compounds were discussed.

Design, synthesis and antiproliferative evaluation of 3-aminopropyloxy derivatives of chalcone

A series of 3-aminopropyloxy derivatives of chalcone were synthesised and evaluated for their antiproliferative activity against liver, gastric and neuroendocrine cancer cell lines. Most of the synthesised compounds exhibited moderate to good activity against all three cancer cell lines, but in particular, a 3-(pyrrolidin-1-yl)propyloxy chalcone containing a 3,4,5-trimethoxyphenyl group showed the highest antiproliferative activity with an IC50 value of 2.74 μM against liver cancer cells.

Design and Antiproliferative Evaluation of Novel Sulfanilamide Derivatives as Potential Tubulin Polymerization Inhibitors

A series of sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, MCF-7 and PC-3). The detailed structure-activity relationships for these sulfanilamide-1,2,3-triazole hybrids were investigated. All these sulfanilamide-1,2,3-triazole hybrids exhibited moderate to potent activity against all cell lines. In particular 4-methyl-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (11f) showed the most potent inhibitory effect against PC-3 cells, with an IC50 value of 4.08 μM. Furthermore, the tubulin polymerization inhibitory activity in vitro of compound 11f was 2.41 μM. These sulfanilamide hybrids might serve as bioactive fragments for developing more potent antiproliferative agents.

Design and antiproliferative activity of N-heterocycle-chalcone derivatives

Nine chalcone derivatives containing an N-heterocyclic compound attached by its nitrogen atom to one of the benzene rings were prepared and evaluated for their antiproliferative activity against liver, gastric and neuroendocrine cancer cell lines. Most of the synthesised compounds exhibited moderate to good activity against all three cancer cell lines, but in particular, a chalcone containing a 4-(imidazol-1-yl)phenyl group and a 3,4,5-trimethoxyphenyl group showed the highest antiproliferative activity with an IC50 value of 5.39 μM against liver cancer cells.

Structure-Activity Relationship Studies of β -Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.

A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 up-regulation in gastric cancer cells

A new series of etherification chalcone derivatives were designed and synthesized through Willimison etherification and Claisen-Schmidt condensation. Among them, compound 2-c which was given chemical name of S17, has been successfully screened out as the most potent one on gastric cancer cell line(MGC803) through the investigation for their effects against the growth of five cancer cell lines (EC109, HepG2, MCF7, MGC803, SKNSH). S17 exhibited strong anti-proliferative activity on other two gastric cancer cells (HGC27 and SGC7901), but less cytotoxicity to non-malignant gastric epithelial cells GES1. S17 potently killed gastric cancer cells with causing modulation of Bcl-2 family proteins and activation of caspase 9/3 cascade. S17 also up-regulated DR5 expression and DR5 knockdown partially reversed S17-induced apoptosis, caspase activation and MMP decrease. S17 robustly induced generation of ROS with Keap/Nrf2 pathway activated and the application of ROS scavenger N-acetyl cysteine (NAC) completely blocked these effects by S17 in MGC803 cells. Intraperitoneal administration of S17 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that S17 is a leadbrominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.

Molecular diversity of phenothiazines: design and synthesis of phenothiazine–dithiocarbamate hybrids as potential cell cycle blockers

Novel phenothiazine–dithiocarbamate analogues were designed by molecular hybridization strategy and synthesized and evaluated for their anticancer activity in vitro against three selected cancer cell lines (EC-109, MGC-803, and PC-3). The preliminary structure–activity relationship (SAR) for this phenothiazine–dithiocarbamate hybrids is explored. Among all analogues, 2-oxo-2-(10H-phenothiazin-10-yl)ethyl 4-ethylpiperazine-1-carbodithioate (8a) showed the most potent inhibitory activity with an