3D-QSAR studies of heterocyclic quinones with inhibitory activity on vascular smooth muscle cell proliferation using pharmacophore-based alignment

The abnormal proliferation and migration of vascular smooth muscle cells (SMCs) play an important role in the pathology of coronary artery atherosclerosis and restenosis following angioplasty. It was reported that some heterocyclic quinone derivatives such as 6-arylamino-quinoxaline-5,8-diones and 6-arylamino-1H-benzo[d]imidazole-4,7-diones have inhibitory activity on rat aortic smooth muscle cell (RAoSMC) proliferation. To understand the structural basis for antiproliferative activity to design more potent agents, we generated pharmacophore models of representative molecules with high activity using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD) and aligned a series of compounds to the selected pharmacophore model, then performed three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Good cross-validated correlations were obtained with CoMFA (resulting in q(2) of 0.734 and r(2) of 0.947) and CoMSIA (resulting in q(2) of 0.736 and r(2) of 0.913). The IC(50) values of the heterocyclic quinone derivatives on RAoSMC exhibited a strong correlation with steric and hydrophobic fields of the 3D structure of the molecules, resulting in the reliable prediction of inhibitory activity of the series of compounds.     

Synthesis and antifungal activity of 6-arylamino-phthalazine-5,8-diones and 6,7-bis(arylthio)-phthalazine-5,8-diones

6-Arylamino-phthalazine-5,8-diones and 6,7-bis(arylthio)-phthalazine-5,8-diones were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Among those tested, many compounds showed good antifungal activity. The results suggest that phthalazine-5,8-diones would be potent antifungal agents.     

Synthesis and biological evaluation of benzimidazole-4,7-diones that inhibit vascular smooth muscle cell proliferation

A series of 6-arylamino-5-chloro-benzimidazole-4,7-diones were synthesized and tested for their inhibitory activity on the rat aortic smooth muscle cell (RAoSMC) proliferation. Among them, 6-arylamino-5-chloro-2-methyl-benzimidazole-4,7-diones exhibited potent antiproliferative activity. Benzimidazole-4,7-dione 2c activated SAPK/JNK signaling pathway in the RAoSMCs.     

Synthesis and biological evaluation of 5-arylamino-1H-benzo[d]imidazole-4,7-diones as inhibitor of endothelial cell proliferation

5-Arylamino-1H-benzo[d]imidazole-4,7-diones were synthesized and tested for their inhibitory activities on the proliferation of human umbilical vein endothelial cells (HUVECs) and the smooth muscle cells (SMCs). Among them, several 1H-benzo[d]imidazole-4,7-diones exhibited the selective antiproliferative activity on the HUVECs. Further mechanistic study revealed that the inhibitory effect of one representative 1H-benzo[d]imidazole-4,7-dione 2b on HUVEC proliferation was mediated by the activation of p38 signaling pathway in the HUVECs.     

Synthesis and antifungal activity of 6,7-bis(arylthio)-quinazoline-5,8-diones and furo[2,3-f]quinazolin-5-ols

6,7-Bis(arylthio)-quinazoline-5,8-dione and furo[2,3-f]quinazolin-5-ol derivatives were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species, and Cryptococcus neoformans. Among them tested, many of furo[2,3-f]quinazolin-5-ols and 6,7-bis(arylthio)-quinazoline-5,8-diones showed good antifungal activity. The compounds completely inhibited the growth of all against Candida and Aspergillus species tested at the MIC level of 12.5μg/mL. The results suggest that furo[2,3-f]quinazolin-5-ols and 6,7-bis(arylthio)-quinazoline-5,8-diones would be promising antifungal agents.     

Design, synthesis and evaluation of 2-phenyl-1H-benzo[d]imidazole-4,7-diones as vascular smooth muscle cell proliferation inhibitors

A series of 2-phenyl-1H-benzo[d]imidazole-4,7-diones were synthesized and tested for their inhibitory activity on the PDGF-stimulated proliferation of rat aortic vascular smooth muscle cells. Among the tested compounds, 6-arylthio-5-chloro-2-phenyl-1H-benzo[d]imidazole-4,7-diones exhibited an potent antiproliferative activity.     

Synthesis and cytotoxicity of 6,11-dihydro-pyrido- and 6,11-dihydro-benzo[2,3-b]phenazine-6,11-dione derivatives

6,11-Dihydro-pyrido[2,3-b]phenazine-6,11-diones and 6,11-dihydro-benzo[2,3-b]phenazine-6,11-diones were synthesized from 6,7-dichloro-5,8-quinolinedione and 2,3-dichloro-1,4-naphthoquinone. The study on the cytotoxicity on these products revealed that the pyridophenazinediones, tetracyclic heteroquinone analogues with three nitrogen atoms exhibited a high cytotoxicity on several human tumor cell lines. Compound 9c and 9e showed in vitro antitumor activity comparable or superior to doxorubicin against the human ovarian tumor cells (SK-OV-3) and the human CNS cells (XF 498). The IC(50) value for compound 9e was 0.06 microM against the human CNS cells (XF 498), which was 2.6 times higher than that (0.16 microM) of doxorubicin. In addition, the X-ray crystallographic analysis of two phenazinedione derivatives (9b,c) showed clearly the exact position of the nucleophilic substitution of 6,7-dichloro-5,8-quinolinedione.     

Design, synthesis, and biological evaluation of 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones and related compounds as antifungal and antibacterial agents

A series of (S)-N-(3-chloro-1,4-naphthoquinon-2-yl)-alpha-amino acid ethyl esters 3 and 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones 6-23 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationship of these compounds was studied and the results show that the compounds 3a and 3b exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii whereas compounds 12 and 22 showed in vitro antibacterial activity against Klebsiella pneumoniae and Escherichia coli.     

Synthesis of 1-/2-substituted-[1,2,3]triazolo[4,5-g]phthalazine-4,9-diones and evaluation of their cytotoxicity and topoisomerase II inhibition

Studies on antitumor heterocyclic quinones containing nitrogens revealed that the number and position of nitrogens on the heterocyclic ring have significance on cytotoxicity of quinones. In our continuous effort to find more cytotoxic quinone compounds, we designed triazolophthalazine analogues in order to introduce more nitrogens on the heterocyclic quinones. 1-/2-Substituted-[1,2,3]triazolo[4,5-g]phthalazine-4,9-diones were synthesized by 1,3-dipolar addition of phthalazine-5,8-dione and 4-methoxybenzyl azide by modification of previously reported method. The cytotoxicity of the synthesized compounds was evaluated by a SRB (sulforhodamine B) assay against nine types of human cancer cell lines and inhibition against topoisomerase II (Topo II) of them was assessed by a decatenation assay. Most of the synthesized compounds showed considerably higher cytotoxicity than that of doxorubicin. Also, topoisomerase II inhibitory activity of the tested compounds was higher than that of etoposide and IC(50) values of the compounds were 19.4-64.5 microM.     

Synthesis and evaluation of antitumor activity of novel N-acyllavendamycin analogues and quinoline-5,8-diones

A series of 7-N-acyllavendamycins with zero, one or two substituents at the C-2', C-3', and C-11' were synthesized through short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptamine or tryptophans produced the desired lavendamycins. Screening data on a panel of three ras oncogene-transformed cell lines and the non-transformed parent cell line showed that a significant number of these analogues are potent antitumor agents and appear to be particularly active against K-ras transformed cells. Compared with the corresponding quinolinediones, these novel lavendamycins are much more inhibitory toward the transformed cells indicating that the beta-carboline moiety of the lavendamycin analogues plays an important role in its potency and selective toxicity.     

D- 型氨基酸氧化酶抑制剂的发展

D-型氨基酸氧化酶(D-Amino acid oxidase,DAAO)抑制剂可以阻止D-型氨基酸(主要是D-型丝氨酸)的降解和过氧化氢的生成,在治疗精神分裂症阴性症状和认知障碍与镇痛等方面均表现出较好的疗效。从第一个DAAO抑制剂芳香羧酸类的苯甲酸到经过烯醇互变的α-羟基酮喹类抑制剂喹诺林-2,3-二酮,DAAO抑制剂结构上总共经历了3代变化,抑制剂与酶之间的相互作用模式逐渐加强,其抑制活性升高了数万倍,脂溶性增加,酸性减弱,理化性质逐渐优化。本文就近10年DAAO抑制剂的结构发展与生物活性之间的关系进行综述。     

Design,Synthesis, Molecular Docking,and Biological Evaluation of New Emodin Anthraquinone Derivatives as Potential Antitumor Substances

The emodin anthraquinone derivatives are generally used in traditional Chinese medicine due to their various pharmacological activities. In the present study, a series of emodin anthraquinone derivatives have been designed and synthesized, among which 1,3‐dihydroxy‐6,8‐dimethoxyanthracene‐9,10‐dione is a natural compound that has been synthesized for the very first time, and 1,3‐dimethoxy‐5,8‐dimethylanthracene‐9,10‐dione is a compound that has never been reported earlier. Interestingly, while total seven of these compounds showed neuraminidase inhibitory activity in influenza virus with inhibition rate more than 50 %, specific four compounds exhibited significant inhibition of tumor cell proliferation. The further results demonstrate that 1,3‐dimethoxy‐5,8‐dimethylanthracene‐9,10‐dione showed the best anticancer activity among all the synthesized compounds by inducing highest apoptosis rate to HCT116 cancer cells and arresting their G0/G1 cell cycle phase, through elevation of intracellular level of reactive oxygen species (ROS). Moreover, the binding of 1,3‐dimethoxy‐5,8‐dimethylanthracene‐9,10‐dione with BSA protein has thoroughly been investigated. Altogether, this study suggests the neuraminidase inhibitory activity and antitumor potential of the new emodin anthraquinone derivatives.     

Structures of Naphthoquinones Produced by the Fungus,Fusarium sp., and Their Biological Activity toward Pollen Germination

From an unidentified Fusarium sp., eight substances possessing a 1,4-naphthoquinone skeleton were isolated (F2~F9) and their structures were elucidated from the physical and chemical evidence. The effect of these compounds together with 1,4-naphthoquinone, 5-hydroxy-1,4-naphthoquinone and 5,8-dihydroxy-1,4-naphthoquinone on the pollen germination of Pinus thunbergii Pari was examined. 5,8-Dihydroxy-1,4-naphthoquinone showed marked inhibitory activity.     

N-Acyl and N-sulfonyloxazolidine-2,4-diones are pseudo-irreversible inhibitors of serine proteases

The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors.     

6-Arylamino-7-chloro-quinazoline-5,8-diones as novel cytotoxic and DNA topoisomerase inhibitory agents

A series of 6-arylamino-7-chloro-quinazoline-5,8-diones were prepared and evaluated for their in vitro cytotoxicity in cultured human cancer cell lines A549 (lung cancer), Col2 (colon cancer), and SNU-638 (stomach cancer). The preliminary structure-activity relationship has been described for providing further development of potent antitumor agents. To further investigate the cytotoxic mechanism, the effects of test compounds on DNA topoisomerase I and II activities have been assessed.     

Synthesis and biological evaluation of 5-arylamino-6-chloro-1H-indazole-4,7-diones as inhibitors of protein kinase B/Akt

A series of 5-arylamino-6-chloro-1H-indazole-4,7-diones were synthesized and evaluated for their inhibitory activity on protein kinase B/Akt. The compounds exhibited a potent Akt1 inhibitory activity. Further mechanistic study revealed that they might have dual inhibitory effects on both activity and phosphorylation of Akt1 in PC-3 tumor cell line.     

Synthesis and cytotoxicity of 2-methyl-1-substituted-imidazo [4,5-g]quinoline-4,9-dione and 7,8-dihydro-10H-[1,4]oxazino[3',4':2,3]imidazo[4,5-g]quinoline-5,12-dio ne derivatives

2-Methyl-1-substituted-imidazo[4,5-g]quinoline-4,9-diones and 7,8-dihydro-10H-[1,4]oxazino-[3',4':2,3]imidazo[4,5-g]quinoline-5, 12-dione (19) derivatives have been synthesized from 6,7-dichloro-5,8-quinolinedione for developing the new anticancer drugs. Our study on the cytotoxicity of imidazoquinolinedione derivatives has revealed that 7,8-dihydro-10H-[1,4]oxazino-[3',4':2,3]imidazo[4,5-g]quinoline-5, 12-dione (19), a tetracyclic heteroquinone analogue, exhibited high cytotoxicity on human colon tumor cell (HCT 15) in vitro SRB assay. The IC50 value of this compound was 0.026 microg/mL whereas those of doxorubicin and cisplatin were 0.023 microg/mL and 1.482 microg/mL, respectively. Meanwhile compounds 5-7 and 12 in the series of 1-substituted-imidazoquinolinediones showed relatively good activity on human brain tumor cell lines (XF 498).     

Synthesis of 6-chloroisoquinoline-5,8-diones and pyrido[3,4-b]phenazine-5,12-diones and evaluation of their cytotoxicity and DNA topoisomerase II inhibitory activity

The substituted chloroisoquinolinediones and pyrido[3,4-b]phenazinediones were synthesized, and the cytotoxic activity and topoisomerase II inhibitory activity of the prepared compounds were evaluated. Chloroisoquinolinediones have been prepared by the reported method employing 6,7-dichloroisoquinoline-5,8-dione. The cyclization to pyrido[3,4-b]phenazinediones was achieved by adding the aqueous sodium azide solution to the dimethylformamide solution of corresponding chloroisoquinoline-5,8-dione. The cytotoxicity of the synthesized compounds was evaluated by a SRB (Sulforhodamine B) assay against various cancer cell lines such as A549 (human lung cancer cell line), SNU-638 (human stomach cancer cell), Col2 (human colon cancer cell line), HT1080 (human fibrosarcoma cell line), and HL-60 (human leukemia cell line). Almost all the synthesized pyrido[3,4-b]phenazinediones showed greater cytotoxic potential than ellipticine (IC(50)=1.82-5.97 microM). In general, the cytotoxicity of the pyrido[3,4-b]phenazinediones was higher than that of the corresponding chloroisoquinolinediones. The caco-2 cell permeability of selected compounds was 0.62 x 10(-6)-35.3 x 10(-6)cm/s. The difference in cytotoxic activity among tested compounds was correlated with the difference in permeability to some degree. To further investigate the cytotoxic mechanism, the topoisomerase II inhibitory activity of the synthesized compounds was estimated by a plasmid cleavage assay. Most of compounds showed the topoisomerase II inhibitory activity (28-100%) at 200 microM. IC(50) values for the most active compound 6a were 0.082 microM. However, the compounds were inactive for DNA relaxation by topoisomerase I at 200 microM.     

Evaluation of the inhibitory potential of five squaric acid derivatives against pancreatic lipase

A series of 4-alkylamino-2-ethoxycyclobut-3en-1,2-diones has been synthesized, characterized and their inhibitory effect on pancreatic lipase (PL) was evaluated. The compound 1 has shown relatively high potency (IC(50)?=?0.11?mM) compared with the most effective anti-obesity drug, tetrahydrolipstatin (Orlistat) (IC(50) value?=?0.08?mM). The compounds have showed good selectivity toward PL and did not affect the activity of trypsin, another digestive enzyme.     

Synthesis,metabolism and in vitro cytotoxicity studies on novel lavendamycin antitumor agents

A series of lavendamycin analogues with two, three or four substituents at the C-6, C-7 N, C-2′, C-3′ and C-11′ positions were synthesized via short and efficient methods and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The compounds were prepared through Pictet–Spengler condensation of the desired 2-formylquinoline-5,8-diones with the required tryptophans followed by further needed transformations. Metabolism and toxicity studies demonstrated that the best substrates for NQO1 were also the most selectively toxic to NQO1-rich tumor cells compared to NQO1-deficient tumor cells.