•A series of novel 4-quinolone-3-carboxamides was prepared and evaluated as antitumor agents.•Compound 8k was found to be the most potent antitumor agent.•Compound 8k could trigger p53/Bax-independent colorectal cancer cell apoptosis via inducing ROS accumulation.A series of novel water-soluble 4-quinolone-3-carboxamides was prepared and evaluated as antiproliferative agents. Preliminary results indicated that most compounds tested in this study showed potent antiproliferative potencies against human tumor cell lines, and compound 8k was found to be the most potent antiproliferative agents with IC50 value of lower than 10 μM against nine human tumor cell lines. These results suggested that (1) the alkylamino side chain substituent was the advisable pharmacophoric group for the enhanced antiproliferative activities; (2) the length of the alkylamino side chain moiety also affected their antiproliferative potencies, and three methylene units were more favorable; (3) introducing arylated alkyl substituent into N1-position of quinolone facilitated antiproliferative activities of this class of compounds. Further investigations on mechanism of action of this class of compound demonstrated that the representative compound 8k could trigger p53/Bax-independent colorectal cancer cell apoptosis via inducing ROS accumulation.A series of novel water-soluble 4-quinolone-3-carboxamides was prepared and evaluated as antitumor agents. The representative compound 8k could trigger p53/Bax-independent colorectal cancer cell apoptosis via inducing ROS accumulation.Download high-res image (157KB)Download full-size image

•A series of novel bivalent β-carbolines was prepared and evaluated as angiogenesis inhibitors.•Compound 4m was found to be the most potent antiangiogenetic agent.•The length of the linker affected antiangiogenetic potency of bivalent β-carbolines.We have synthesized and evaluated a series of novel alkyl diamine linked bivalent β-carbolines as potent angiogenesis inhibitors. The results demonstrated that most bivalent β-carbolines exhibited significant antiproliferative effects against human umbilical vein cell lines EA.HY926. Compound 4m was found to be the most potent antiproliferative agent with IC50 value of 2.16 μM against EA.HY926 cell lines. Mechanism investigations revealed that compound 4m could significantly inhibit EA.HY926 cells migration and tube formation in a dose-dependent manner. Moreover, compound 4m also showed obvious angiogenesis inhibitory effects in CAM assay, and the antiangiogenetic potency was more potent than the reference drug Endostar. The bivalent β-carbolines might be served as candidates for the development of vascular targeting antitumor drugs.

•A series of novel bivalent β-carbolines was prepared and evaluated as angiogenesis inhibitors.•Compound 2s was found to be the most potent antiangiogenetic agent.•The length of the linker affected antiangiogenetic potency of bivalent β-carbolines.A series of novel alkyl diamine linked bivalent β-carbolines was synthesized and evaluated for antiproliferative activity, inhibition of cell migration and tube formation, and anti-angiogenic activity in vivo. The results showed that most bivalent β-carbolines displayed significant antiproliferative effect against human umbilical vein cell lines EA.HY926. Compound 2s was found to be the most potent antiproliferative agent with IC50 value of 1.06 μM against EA.HY926 cell lines. Further investigations on mechanisms of action revealed that compound 2s significantly inhibited EA.HY926 cells migration and tube formation in a dose-dependent manner. Moreover compound 2s exhibited significant angiogenesis inhibitory effects in CAM assay, and the antiangiogenetic potency was comparable with the reference drug Endostar (30 μM).

A series of novel bivalent β-carbolines with a piperazine group spacer between 3-methylene units were synthesized and evaluated as antitumor agents. The results demonstrated that compounds 7e and 7g exhibited the most potent cytotoxic activities against ten tumor cell lines. Structure–activity relationships analysis indicated that (1) the substituents in positions 1 and 9 of the β-carboline ring played a significant role in modulating the antitumor activity; (2) the introduction of alkyl groups into position-9 of the β-carboline nucleus enhanced their cytotoxic potencies and the butyl substituent was the optimal group. Investigation of the preliminary mechanism of action demonstrated that compound 7g showed obvious anti-angiogenic activity in the in vivo CAM assay, and the potency was similar to that of CA4P (200 μM).

Six β-diketonate ligands were used to prepare the corresponding antenna europium(III) ternary complexes using 1,10-phenanthroline as an ancillary ligand. All the complexes exhibited high decomposition temperatures. Photophysical properties such as FT-IR spectra, UV-Vis absorption spectra, excitation and emission spectra, relative luminescent intensity ratios, luminescence decay curves and quantum yields based on the complexes were systematically studied and compared with each other. The energy-transfer mechanism was proposed as a ligand-sensitized luminescence process. Bright red light-emitting diodes (LEDs) were then fabricated by coating the complexes onto 395 nm-emitting InGaN chips. The light emission from the InGaN chips could be completely absorbed in the spectra of LEDs. The Commission International de I'Eclairage (CIE) chromaticity coordinates are close to the National Television Standard Committee (NTSC) standard value for the red color. All these findings indicate that these Eu(III) complexes are promising red phosphors for fabrication of near UV-based white LEDs.

A series of novel bivalent β-carbolines with a spacer of three to ten methylene units between the 3-carboxyl oxygens was synthesized and evaluated as antitumor agents. The results demonstrated that most compounds displayed good and selective cytotoxic activities against 769-P and KB cell lines. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated. Compound 22 exhibited potent antitumor activity against Lewis lung cancer in mice with a tumor inhibition rate of 64.2%. Preliminary structure–activity relationship analysis indicated that (1) the length of the spacer affected cytotoxic activities in vitro and six methylene units were more favorable; (2) the introduction of substituents into position-1 of the β-carboline ring might be detrimental to antitumor potency in vivo models.

•A series of N2-alkylated quaternary β-carbolines was synthesized.•SARs of this class of compounds as antitumor agents were well studied.•Appropriate substituents in position-2 and 9 facilitated antitumor activities.•Compound 3m were found to be the most potent antitumor agent.A series of novel N2-alkylated quaternary β-carbolines was synthesized by modification of position-1, 2, 7 and 9 of β-carboline nucleus with various alkyl and arylated alkyl substituents, and their cytotoxic activities in vitro and antitumor potencies in mice were evaluated. Compound 3m was found to be the most potent antitumor agent. SARs analysis revealed that (1) the substituents in position-2 and 9 of β-carboline nucleus played a vital role in modulation of antitumor activity; (2) the benzyl and 3-phenylpropyl substituents in position-2 and 9 of β-carboline ring were the optimal substituents giving rise to significant antitumor agent. These compounds might be a novel promising class of antitumor agents with clinical development potential.A series of novel N2-alkylated quaternary β-carbolines was synthesized and evaluated as antitumor agents. 3m were found to be the most potent compound.

A new europium(III) ternary complex based on a fluorinated β-diketonate ligand and 1,10-phenanthroline as an ancillary ligand has been prepared and evaluated as a candidate for light-emitting diode (LED). The complex exhibits a high decomposition temperature (316 °C). Photophysical properties such as FT-IR spectra, UV–vis absorption spectra, excitation and emission spectra, luminescence decay curve and quantum yield were investigated. The excitation band is well matched with the characteristic emission of 395 nm-emitting InGaN chips. The complex exhibits an efficient energy transfer pathway from the ligands to the central Eu3+ ion via a ligand-sensitized luminescence process. An intense red-emitting LED was fabricated by coating the complex onto a 395 nm-emitting InGaN chip, and its Commission International de I'Eclairage (CIE) chromaticity coordinate (x=0.6389, y=0.3255) is close to the National Television Standard Committee (NTSC) standard value for red color. Meanwhile, the energy transfer from the InGaN chip to the complex is very efficient. All the findings demonstrate the potential application of the Eu(III) complex as red-emitting phosphors for UV-based white LEDs.Highlights► A new europium(III)-β-diketonate complex was synthesized and characterized. ► Thermal stability and photophysical properties were investigated in detail. ► PL mechanism was proposed to involve a ligand-sensitized luminescence process. ► An intense red-emitting LED was fabricated by using the complex. ► CIE chromaticity coordinate is close to NTSC standard value for red color.

A series of novel 1,9-disubstituted β-carbolines was designed, synthesized and evaluated as cytotoxic and DNA intercalating agents. Compounds 7b, 7c, 8b and 8c exhibited the most potent cytotoxic activities with IC50 values of lower than 20 μM against ten human tumor cell lines. The results indicated that (1) the 3-chlorobenzyl and 3-phenylpropyl substituents in position-9 of β-carboline nucleus were the suitable pharmacophoric group giving rise to significant antitumor agents; (2) the length of the alkylamino side chain moiety affected their cytotoxic potencies, and three CH2 units were more favorable. In addition, these compounds were found to exhibit remarkable DNA intercalating effects.A series of 1,9-disubstituted β-carbolines was synthesized and evaluated as potential cytotoxic and DNA intercalating agents.Highlights► 1,9-Disubstituted β-carbolines was synthesized and evaluated as antitumor agents. ► The 3-phenylpropyl substituents in position-9 were the suitable pharmacophoric group. ► The length of the alkylamino side chain moiety affected their cytotoxic potencies. ► These compounds were found to exhibit remarkable DNA intercalating effects.

A series of novel 4-hydroxybenzaldehyde derivatives were synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were investigated. Most of target compounds had more potent inhibitory activities than the parent compound 4-hydroxybenzaldehyde (IC50 = 1.22 mM). Interestingly, compound 3c bearing a dimethoxyl phosphate was found to be the most potent inhibitor with IC50 value of 0.059 mM. The inhibition kinetics analyzed by Lineweaver–Burk plots revealed that compound 3c was a non-competitive inhibitor (KI = 0.0368 mM). In particular, compound 3c showed no side effects at dose of 1600 mg/kg in mice. These results suggested that such compounds might be served as lead compounds for further designing new potential tyrosinase inhibitors.A series of 4-hydroxybenzaldehyde derivatives were synthesized and evaluated as mushroom tyrosinase inhibitors. Compound 3c was found to be the most potent inhibitor .

In a continuing effort to develop novel β-carbolines endowed with better pharmacological profiles, a series of β-carboline derivatives were designed and synthesized based on the previously developed SARs. Cytotoxicities in vitro of these compounds against a panel of human tumor cell lines were also investigated. The results demonstrated that the N2-benzylated β-carbolinium bromides 56–60 represented the most potent compounds with IC50 values lower than 10 μM. The application of 3D-QSAR to these compounds explored the structural basis for their biological activities. CoMFA (q2 = 0.513, r2 = 0.862) and CoMSIA (q2 = 0.503, r2 = 0.831) models were developed for a set of 47 β-carbolines. The results indicated that the antitumor pharmacophore of these molecules were marked at position-1, -2, -3, -7 and -9 of β-carboline ring.The constructive CoMFA and CoMSIA models with highly predictive capacity provided important structural requirement for further design and synthesis of new β-carboline derivatives as potent antitumor agents.

The β-carboline alkaloids have been characterized as a class of potential antitumor agents. To further enhance the cytotoxic potency and improve water solubility of β-carboline, a series of new β-carboline amino acid ester, β-carboline amino acid and N2-benzylated quaternary β-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were evaluated using a panel of human tumor cell lines. The N2-benzylated quaternary β-carboline amino acid ester conjugates represented the most interesting cytotoxic activities. Particularly, compounds 8b and 8g were found to be the most potent compounds with IC50 values lower than 20 μM against all human tumor cell lines investigated. These results confirmed that the N2-benzyl substituent on the β-carboline ring played an important role in the modulation of the cytotoxic potencies.A series of N2-benzylated quaternary β-carboline amino acid ester conjugates was synthesized and evaluated as new antitumor agents. Compounds 8b and 8g were found to be the most potent compounds with IC50 values lower than 20 μM against all tumor cell lines investigated.

In a continuing effort to develop novel β-carbolines endowed with better pharmacological profile, a series of water-soluble β-carbolines bearing a flexible amino side chain was designed and synthesized, and the cytotoxic activities in vitro of these compounds were evaluated. The N9-arylated alkyl substituted β-carbolines represented the most interesting cytotoxic agents, and compounds 4c and 4d were found to be the most potent compounds with IC50 values lower than 10 μM against ten human tumor cell lines. The results confirmed that the N9-arylated alkyl substituents of β-carboline played a very important role in the modulation of the cytotoxic potencies. In addition, the interaction with DNA of these compounds was also investigated, these compounds were found to exhibit significant DNA binding affinity.A series of water-soluble β-carbolines bearing a flexible amino side chain was synthesized and evaluated. Compounds 4c and 4d were found to be the most potent compounds with IC50 values lower than 10 μM against ten tumor cell lines.

A series of water-soluble β-carbolines, bearing a flexible amino side chain, was prepared and evaluated in vitro against a panel of human tumor cell lines. The N9-arylated alkyl substituted β-carbolines represented the most interesting cytotoxic activities, and compound 7b was found to be the most potent antitumor agent with IC50 values lower than 10 μM against eight human tumor cell lines. The results confirmed that the N9-arylated alkyl substituents of β-carboline nucleus played an important role in the modulation of the cytotoxic potencies. In addition, these compounds were found to exhibit significant DNA-binding affinity.A series of water-soluble β-carbolines, bearing a flexible amino side chain, has been prepared and evaluated in vitro against a panel of human cell lines. Compound 7b were found to be the most potent compound with IC50 values lower than 10 μM against eight human tumor cell lines.

A series of alkylidenethiosemicarbazide compounds were synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that most of the synthesized compounds exhibited significant inhibitory activities. Especially, compound 1f was found to be the most potent inhibitor with IC50 value of 0.086 μM, suggesting that further development of such compounds may be of interest.A series of alkylidenethiosemicarbazide compounds were synthesized and their inhibitory activities against the diphenolase activity of mushroom tyrosinase were investigated. Compound 1f was found to be the best potent compound with IC50 value of 0.086 μM.

A series of novel 5-benzylidene barbiturate and thiobarbiturate derivatives were synthesized and evaluated as tyrosinase inhibitors and antibacterial agents. The results demonstrated that some compounds had more potent inhibitory activities than the parent compound 4-hydroxybenzaldehyde (IC50 = 1.22 mM). Particularly, compounds 1a and 2a were found to be the most potent inhibitors with IC50 value of 13.98 μM and 14.49 μM, respectively. The inhibition mechanism study revealed that these compounds were irreversible inhibitors. The circular dichroism spectra indicated that these compounds induced conformational changes of mushroom tyrosinase upon binding. In addition, these compounds exhibited selectively antibacterial activity against Staphylococcus aureus. All these results suggested that further development of such compounds may be of interest. A series of novel 5-benzylidene barbiturate and thiobarbiturate derivatives were synthesized and evaluated as tyrosinase inhibitors. Compounds 1a and 2a were found to be the most potent inhibitors.

To elucidate further our SARs' study on the chemistry and cytotoxic activity and probe the structural requirement for the potent antitumor activity of β-carbolines, a series of novel 1,9-disubstituted and 1,3,9-trisubstituted β-carboline derivatives were designed and synthesized from the starting material l-tryptophan and 3,4,5-trimethoxybenezaldehyde. Cytotoxic activities of these compounds in vitro were investigated, and the SARs associated with position-1, 3 and 9 substituents in β-carbolines have also been discussed. It has been observed that these compounds only displayed moderate to weak cytotoxic activities. Interestingly, most of the investigated compounds displayed selectively cytotoxic activities to human BCG-823 cell lines with IC50 value lower than 100 μM. In addition, the short alkyl substituents in position-9 increased the cytotoxic activities with the tendency of n-butyl > ethyl > methyl. These data confirmed that (1) an alkyl substituent at position-9 of β-carboline nucleus plays an important role in determining their antitumor activities; (2) different β-carbolines bearing various substituents in β-carboline nucleus interacted selectively with specific targets leading to the difference of biochemical and pharmacological effects.A series of novel 3,4,5-trimethoxyphenyl substituted β-carboline derivatives were designed and synthesized from the starting material l-tryptophan and 3,4,5-trimethoxybenezaldehyde. Cytotoxic activities of these compounds in vitro were investigated. Most of the investigated compounds displayed selectively cytotoxic activities to human BCG-823 cell lines.

A series of 4-functionalized phenyl-O-β-d-glycosides were designed, synthesized and evaluated as a new class of mushroom tyrosinase inhibitors. The results demonstrated that compounds 6a–13a bearing a thiosemicarbazide moiety exhibited potent activities with IC50 values range from 0.31 to 52.8 μM. Particularly, compound 9a containing acetylated glucose moiety was found to be the most active molecule with an IC50 value of 0.31 μM. SARs analysis suggested that (1) the thiosemicarbazide moiety remarkably contributed to the increase of inhibitory effects on tyrosinase; (2) the configuration and bond type of sugar moiety also played a very important role in determining their inhibitory activities. The inhibition kinetics and inhibition mechanism study revealed that compound 9a was reversible and competitive type inhibitor, whereas compound 13a was reversible and competitive–uncompetitive mixed-II type inhibitor.A series of 4-functionalized phenyl-O-β-d-glycosides were designed, synthesized and evaluated as tyrosinase inhibitors. Compound 9a was found to be the most potent inhibitor.

A series of 5-benzylidene(thio)barbiturate-β-d-glycosides were designed, synthesized and evaluated as a new class of mushroom tyrosinase inhibitors. The results demonstrated that most of compounds had more potent inhibitory activities than arbutin (IC50 8.4 mmol/L). Compound 12b was found to be the most potent inhibitor with IC50 value of 0.05 mmol/L. SARs analysis suggested that (1) 5-benzylidenethiobarbiturate substructures were efficacious for the inhibitory activity; (2) the lipophilic property of acetylated sugar moiety facilitated the inhibitory potency; (3) the hydroxyl group of 3′-configuration contributed to the increase of inhibitory effects. In addition, the inhibition mechanism study revealed that 5-benzylidene(thio)barbiturate-β-d-glycosides were irreversible inhibitors.A series of 5-benzylidene(thio)barbiturate-β-d-glycosides were designed, synthesized and evaluated as tyrosinase inhibitors. Compound 12b was found to be the most potent inhibitor.

A series of new β-carboline derivatives, bearing a benzylidine substituent at position-1, has been prepared and evaluated in vitro against a panel of human cell lines. The N2-benzylated β-carbolinium bromates represented the most interesting cytotoxic activities. In particular, compounds 19 were found to be the most potent compounds with IC50 values lower than 5 μM against 10 strains human tumor cell lines. These results confirmed that the N2-benzyl substituent on the β-carboline ring played an important role in the modulation of the cytotoxic activities and suggested that further development of such compounds may be interest.A series of new β-carboline derivatives, bearing a benzylidine substituent at position-1, has been prepared and evaluated in vitro against a panel of human cell lines. The N2-benzylated β-carbolinium bromates represented the most interesting cytotoxic activities. Compounds 19 were found to be the most potent compounds with IC50 values lower than 5 μM against 10 strains human tumor cell lines.

Six β-diketonate ligands were used to prepare the corresponding antenna europium(III) ternary complexes using 1,10-phenanthroline as an ancillary ligand. All the complexes exhibited high decomposition temperatures. Photophysical properties such as FT-IR spectra, UV-Vis absorption spectra, excitation and emission spectra, relative luminescent intensity ratios, luminescence decay curves and quantum yields based on the complexes were systematically studied and compared with each other. The energy-transfer mechanism was proposed as a ligand-sensitized luminescence process. Bright red light-emitting diodes (LEDs) were then fabricated by coating the complexes onto 395 nm-emitting InGaN chips. The light emission from the InGaN chips could be completely absorbed in the spectra of LEDs. The Commission International de I'Eclairage (CIE) chromaticity coordinates are close to the National Television Standard Committee (NTSC) standard value for the red color. All these findings indicate that these Eu(III) complexes are promising red phosphors for fabrication of near UV-based white LEDs.