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Design, synthesis, and in vitro and in vivo anti-angiogenesis study of a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor based on 1,2,3-triazole scaffold
In the past five years, our team had been committed to click chemistry research, exploring the biological activity of 1,2,3-triazole by synthesizing different target inhibitors. In this study, a series of novel indole-2-one derivatives based on 1,2,3-triazole scaffolds were synthesized for the first time, and their inhibitory activity on vascular endothelial growth factor receptor-2 (VEGFR-2) was tested. Most of the compounds had shown promising activity in the VEGFR-2 kinase assay and had low toxicity to human umbilical vein endothelial cells (HUVECs). The compound 13d (IC50 = 26.38 nM) had better kinase activity inhibition ability than sunitinib (IC50 = 83.20 nM) and was less toxic to HUVECs. Moreover, it had an excellent inhibitory effect on HT-29 and MKN-45 cells. On the one hand, by tube formation assay, transwell, and Western blot analysis, compound 13d could inhibit VEGFR-2 protein phosphorylate on HUVECs, thereby inhibiting HUVECs migration and tube formation. In vivo study, the zebrafish model with VEGFR-2 labeling also verified that compound 13d had more anti-angiogenesis ability than sunitinib. On the other hand, molecular docking and molecular dynamics (MD) simulation results showed that compound 13d could stably bind to the active site of VEGFR-2. Based on the above findings, compound 13d could be considered an effective anti-angiogenesis drug and has more development value than sunitinib.
Wang, De-pu,Liu, Kai-li,Li, Xin-yang,Lu, Guo-qing,Xue, Wen-han,Qian, Xin-hua,Mohamed O, Kamara,Meng, Fan-hao
(2020/12/21)

Synthesis of substituted tryptanthrin via aryl halides and amines as antitumor and anti-MRSA agents
The natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione), and its analogues are found to exhibit potent antitumor and anti-MRSA activities. An efficient and convenient method has been developed for the synthesis of tryptanthrin D-ring derivatives through the reaction of substituted tryptanthrins and secondary amines in moderate to good yields. Some of the new compounds exhibited antitumor activities against the human tumor cell lines A549, HCT116 and MDA-MB-231, with mean IC50 values at low micromolar levels. In addition, some of the compounds showed excellent anti-MRSA activities and were more effective than vancomycin, with MIC values of 0.31–1.25 μg/mL for Mu50,RN4220, and Newman strains.
Chen, Huan,Hou, Baolong,Liu, Jianli,Liu, Li,Ma, Xiumei,Wang, Cuiling,Wang, Jilin,Wang, Rui,Wang, Yinyin,Zheng, Xudong
(2019/11/13)

Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis
Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target as the same is found to be over expressed in several types of cancers. In search of effective MARK4 inhibitors, we have synthesized and characterized Isatin-triazole hydrazones (9a-i) and evaluated their inhibitory potential. Of all the compounds, 9g showed better binding affinity and enzyme inhibition potential in sub micromolar range. Human serum albumin (HSA) binding assay suggested an easy transportation of 9g in blood stream due to its binding affinity. In vitro anticancer studies performed on MCF-7, MDA-MB-435s and HepG2 cells using 9g showed inhibition of cell proliferation and cell migration. Further, 9g induces apoptosis in these cancerous cells, with IC50 values of 6.22, 9.94 and 8.14 μM, respectively. Putatively, 9g seems to cause oxidative stress resulting in apoptosis. Functional assay of 9g with a panel of 26 kinases showed MARK4 specific profile. In conclusion, 9g seems to possess an effective inhibitory potential towards MARK4 adding an additional repertoire to anticancer therapeutics.
Aneja, Babita,Khan, Nashrah Sharif,Khan, Parvez,Queen, Aarfa,Hussain, Afzal,Rehman, Md. Tabish,Alajmi, Mohamed F.,El-Seedi, Hesham R.,Ali, Sher,Hassan, Md. Imtaiyaz,Abid, Mohammad
p. 840 - 852
(2019/01/04)

Synthesis and Ameliorative Effect of Isatin–Mesalamine Conjugates on Acetic Acid-induced Colitis in Rats
A series of new isatin–mesalamine conjugates (9a–g) were synthesized via conjugation of isatin (3a) and its derivatives (3b–3d, 4, 5, and 6) with mesalamine (7) by using chloroacetyl chloride as a bifunctional linker. Compounds 3a–3d were prepared by employing Sandmeyer reaction. Compounds 4, 5, and 6 were obtained from isatin (3a) via previously reported methods. The synthesized compounds were characterized by IR, mass, 1H NMR, and 13C NMR spectral techniques. Synthesized compounds (3a–d, 4, 5, 6, and 9a–g) were evaluated for in vitro antioxidant activity by DPPH assay method using ascorbic acid as standard. Hybrids 9b (IC50?=?368.6?±?3.5?μM) and 9f (IC50?=?335.1?±?2.9?μM) showed better antioxidant activity than its parent compounds such as 3a (IC50?=?556.8?±?2.9?μM), 5 (IC50?=?511.9?±?3.6?μM), and 7 (IC50?=?768.9?±?2.7?μM). Acetic acid-induced ulcerative colitis in rat model was chosen to examine the antioxidant potential of the synthesized hybrids (9b and 9f) in the amelioration of ulcerative colitis. Colonic myeloperoxidase and malondialdehyde enzymes were used as biomarkers of anti-ulcerative colitis activity. In the present study, hybrids 9b and 9f reduced the levels of colonic myeloperoxidase and malondialdehyde enzymes significantly (p??0.05) when compared with control (colitic), at a dose (0.03?mM/12.5?mg/kg b.w. p.o.) (50%) less than that of its parent moieties mesalamine (0.16?mM/25?mg/kg) and isatin (0.16?mM/25?mg/kg). Thus, the molecular hybridization was proved to be significant in enhancing the activity of hybrids 9b and 9f by reducing the dose.
Panga, Shyam,Podila, Naveen Kumar,Ciddi, Veeresham
p. 956 - 967
(2019/02/14)

Indazole compounds and preparation method and application thereof
The invention provides indazole compounds and a preparation method and application thereof. A series of completely new small molecule PI3Kdelta inhibitors are designed and synthesized by using indazole as a structural mother nucleus, the PI3Kdelta kinase inhibitory activity test and MV-4-11 cell activity test of the compounds are carried out, and the indazole compounds exhibit better kinase subtype selectivity, and exhibit better in vitro proliferation inhibitory activity against tumor cell lines. The compounds can be used in the preparation of antitumor drugs and in the preparation of activedrugs for inhibiting PI3Kdelta kinase, and a new way is provided for the antitumor drug research. The raw materials are cheap and easy to obtain, the preparation method is simple, and the large-scaleproduction is suitable. The structural formula is as shown in the specification.
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Paragraph 0013-0014

(2019/09/14)

Palladium(II)/N-Heterocyclic Carbene Catalyzed One-Pot Sequential α-Arylation/Alkylation: Access to 3,3-Disubstituted Oxindoles
Rationally designed fluorene-based mono- and bimetallic Pd-PEPPSI complexes were synthesized and demonstrated to be effective for the one-pot sequential α-arylation/alkylation of oxindoles. This streamlined approach offers efficient access to functionalized 3,3-disubstituted oxindoles in excellent yields (up to 89%) under mild reaction conditions.
Reddy Panyam, Pradeep Kumar,Ugale, Bharat,Gandhi, Thirumanavelan
supporting information
p. 7622 - 7632
(2018/06/22)

Design, Synthesis, Characterization, and In Vitro Evaluation of Isatin-Pomalidomide Hybrids for Cytotoxicity against Multiple Myeloma Cell Lines
Inspired by the concept of molecular hybridization, a series of new isatin-pomalidomide hybrids (9a–9g) were designed, synthesized, characterized, and evaluated for in vitro cytotoxic activity against U266B1 and RPMI 8226 multiple myeloma cell lines. Sandmeyer methodology and N-halomethylketo alkylation reaction are the two important reactions involved in the synthesis of isatin-pomalidomide hybrids (9a–9g). All the synthesized compounds (3a–3d, 4, 5, 6, and 9a–9g) were characterized by using IR, mass, 1H-NMR, and 13C-NMR spectral techniques. The efficacy of all the synthesized compounds was tested against the aforementioned cell lines by employing MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) standard protocols while using pomalidomide as a standard. The test concentrations used in the MTT assay were 1, 10, 20, 30, and 40?μM, and the period of incubation was 24?h. All the synthesized compounds were found to have moderate to greater cytotoxic activity against the aforementioned cell lines. Among them, synthesized hybrids 9f (IC50, U266B1?=?5.15?±?0.72?μM, RPMI8226?=?11.66?±?0.79?μM) and 9g (IC50, U266B1?=?2.50?±?0.37?μM, RPMI8226?=?6.70?±?0.55?μM) displayed better cytotoxic activity against both the cell lines used in the present study.
Panga, Shyam,Podila, Naveen Kumar,Ciddi, Veeresham
p. 2919 - 2928
(2018/10/26)

Synthesis and cytotoxic studies of novel 5-phenylisatin derivatives and their anti-migration and anti-angiogenic evaluation
A number of 5-arylisatin derivatives were synthesized in 5–6 steps from readily available starting materials. Their structures were confirmed by 1H NMR and 13C NMR as well as LC/MS. The cytotoxicity of these novel isatins against human leukemia K562 cells were evaluated by MTT assay in vitro. SAR studies indicated that the N-substituted benzyl and C-5 substituted phenyl groups greatly enhance their cytotoxic activity, whereas an intact carbonyl functionality on C-3 present in the parent ring is required to maintain such a potency. Particularly, N-(p-methoxybenzyl)-5-(p-methoxyphenyl)isatin (compound 2m) showed the highest antitumor activity against K562 cell lines (IC50 = 0.03 μM). Moreover, treatment with compound 2m significantly inhibited liver cancer HepG2 cells proliferation and migration, which could also reduce the human umbilical vein endothelial cells (HUVEC) tube formation. In conclusion, compound 2m exhibited very good cancer cells proliferation inhibition by angiogenesis responses in vitro, and 2m might be a promising angiogenesis inhibitor for cancer treatment.
Zhang, Qian,Teng, Yuou,Yuan, Yuan,Ruan, Tingting,Wang, Qi,Gao, Xing,Zhou, Yao,Han, Kailin,Yu, Peng,Lu, Kui
p. 800 - 814
(2018/07/29)

Application of isatin analogues in preparing antineoplastic drugs
The invention belongs to the field of medicinal chemistry, and in particular relates to an application of isatin analogues in preparing antineoplastic drugs. A series of isatin analogues can be synthesized by splicing isatin and [alpha],[beta]-unsaturated ketone via a medicinal chemistry splicing principle. The compounds (the isatin analogues) are relatively good in inhibitory activity on three tumor cells, and an antineoplastic effect can be achieved by inhibiting growth and migration of tumor cells and by blocking cell cycle G2/M period; and based upon in vivo experimental results, it is also indicated that the compounds can inhibit tumor growth.
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Paragraph 0031; 0032

(2018/07/30)

Design, synthesis and QSAR study of novel isatin analogues inspired Michael acceptor as potential anticancer compounds
Molecular hybridization is considered as an effective tactic to develop drugs for the treatment of cancer. A series of novel hybrid compounds of isatin and Michael acceptor were designed and synthesized on the basis of association principle. These hybrid compounds were tested for cytotoxic potential against human cancer cell lines namely, BGC-823, SGC-7901 and NCI-H460 by MTT assay. Most compounds showed good anti-growth activities in all tested human cancer cells. SAR and QSAR analysis may provide vital information for the future development of novel anti-cancer inhibitors. Notably, compound 6a showed potent growth inhibition on BGC-823, SGC-7901 and NCI-H460 with the IC50 values of 3.6 ± 0.6, 5.7 ± 1.2, 3.2 ± 0.7 μM, respectively. Besides, colony formation assays, wound healing assays and flow cytometry analysis indicated 6a exhibited a potent anti-growth and anti-migration ability in a concentration-dependence manner through arrested cells in the G2/M phase of cell cycle. Moreover, 6a significantly repressed tumor growth in a NCI-H460 xenograft mouse model. Overall, our findings suggested isatin analogues inspired Michael acceptor may provide promising lead compounds for the development of cancer chemotherapeutics.
Wang, Jiabing,Yun, Di,Yao, Jiali,Fu, Weitao,Huang, Fangyan,Chen, Liping,Wei, Tao,Yu, Cuijuan,Xu, Haineng,Zhou, Xiaoou,Huang, Yanqing,Wu, Jianzhang,Qiu, Peihong,Li, Wulan
p. 493 - 503
(2018/01/01)

First asymmetric reduction of isatin by marine-derived fungi
In this study, whole cells of marine-derived fungi were used to reduce isatin (1H-indole-2,3-dione) to dioxindole (3-hydroxyindolin-2-one) for 7 days at 32°C. The screening showed that several strains could reduce isatin and produce the enantioenriched dioxindole. The best conversions were obtained by Cladosporium sp. CBMAI 1237 and Westerdykella sp. CBMAI 1679, however, the best enantiomeric excess was obtained only by Aspergillus sydowii CBMAI 935 (66percent ee). In conclusion, marine-derived fungi show potential for asymmetric and chemoselective reduction of isatin (1H-indole-2,3-dione).
Birolli, Willian G.,Ferrreira, Irlon M.,Jimenez, David E. Q.,Silva, Bianca N. M.,Silva, Bárbara V.,Pinto, Angelo C.,Porto, André L. M.
p. 1023 - 1029
(2017/05/01)

Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipole and Abnormal [3 + 2]-Cycloaddition with Maleimide in the Presence of 1,4-Diazabicyclo[2.2.2]octane
A new isatin N,N′-cyclic azomethine imine synthon was devised, and an unexpected abnormal [3 + 2]-cycloaddition with maleimide catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) has been disclosed. A variety of tricyclic spiropyrrolidine oxindoles bearing a dinitrogen heterocycle and succinimide scaffold were obtained in excellent yields (up to 96%) and diastereoselectivities (up to 97:3) under mild conditions.
Wang, Xiao,Yang, Peng,Zhang, Yong,Tang, Chao-Zhe,Tian, Fang,Peng, Lin,Wang, Li-Xin
supporting information
p. 646 - 649
(2017/02/10)

Design, synthesis and biological evaluation of 2-phenylquinoline-4-carboxamide derivatives as a new class of tubulin polymerization inhibitors
A novel series of 2-phenylquinoline-4-carboxamide derivatives was synthesized, characterized and evaluated for its antiproliferative activity against five cancer cell lines, Hela, SK-OV-3, HCT116, A549 and MDA-MB-468, and a normal human fetal lung fibroblastic cell line, MRC-5. Among them, compound 7b displayed potent cytotoxic activity in vitro against SK-OV-3 and HCT116 cell lines with IC50 values of 0.5 and 0.2 μM, respectively. In general, the antiproliferative activity was correlated with the binding property of the colchicine binding site and inhibitory effect on tubulin polymerization. In addition, immunofluorescence and flow cytometry analysis revealed that selected compounds caused disruption of the mitotic spindle assembly and G2/M phase arrest of the cell cycle, which correlated with proliferation inhibitory activity. Molecular docking analysis demonstrated the interaction of 7b at the colchicine binding site of tubulin. These results indicate these compounds are promising inhibitors of tubulin polymerization for the potent treatment of cancer.
Zhu, Li,Luo, Kaixiu,Li, Ke,Jin, Yi,Lin, Jun
p. 5939 - 5951
(2017/10/13)

A Benzisoelenazolone modified pyrrole methyl ester substituted indole ketone compound and use thereof
The invention discloses a benzisoselenazolone-modified pyrrolyl formate-substituted indolone compound and a use thereof. The invention depends on and claims the priority of a Chinese patent application 201110105248.0 submitted on April 26, 2011. Through reference, all contents of the Chinese patent application 201110105248.0 are incorporated into the invention. The benzisoselenazolone-modified pyrrolyl formate-substituted indolone compound is shown in the general formula I. The 2-indolone compound provided by the invention has excellent antitumor activity and can be widely used for preparation of antitumor drugs.
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Paragraph 0109-0111

(2016/10/08)

Practical Synthesis, Antidepressant, and Anticonvulsant Activity of 3-Phenyliminoindolin-2-one Derivatives
Herein, a series of 3-phenyliminoindolin-2-one derivatives were designed, synthesized, and screened for their antidepressant and anticonvulsant activities. The IR spectra of the compounds afforded NH stretching (3340-3346 cm-1) bands and C=O stretching (1731-1746 cm-1). In the 1H-NMR spectra of the compounds, N-H protons of indoline ring were observed at 10.65-10.89 ppm generally as broad bands, and 13C-NMR spectra of the compounds C=O were seen at 161.72-169.27 ppm. Interestingly, compounds 3o, 3p and 3r significantly shortened immobility time in the The forced swimming test (FST) and The tail suspension test (TST) at 50 mg/kg dose levels. In addition, compound 3r exhibited higher levels of efficacy than the reference standard fluoxetine but had no effect on locomotor activity in the open-field test. Compound 3r significantly increased serotonin and norepinephrine and the metabolite 5-hydroxyindoleacetic acid in mouse brain, suggesting that the effects of compound 3r may be mediated through these neurotransmitters. In the seizure screen, 15 compounds showed some degree against PTZ-induced seizure at a dose of 100 mg/kg, and the tested compounds did not show any neurotoxicity at a dose of 300 mg/kg in the rotarod test.
Ma, Jian-Yin,Quan, Ying-Chun,Jin, Hong-Guo,Zhen, Xing-Hua,Zhang, Xue-Wu,Guan, Li-Ping
p. 342 - 351
(2016/03/12)

Synthesis and anti-cancer activity evaluation of 5-(2-carboxyethenyl)-isatin derivatives
A series of novel di- or trisubstituted isatin derivatives were designed and synthesized in 5–6 steps in 25–45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of the fourty-three new isatin derivatives against human T lymphocyte cells Jurkat was evaluated by MTT assay in vitro. SAR study suggested that the combination of 1-benzyl and 5-[trans-2-(methoxycarbonyl)ethen-1-yl] substitution greatly enhanced their cytotoxic activity. Among them, compound 2h was shown to have a significant cytotoxic activity with an IC50 value of 0.03 μM, more than 330-fold higher than that of it's mother molecule isatin. Investigation of the cell morphology changes and annexin-V/PI staining study demonstrated that compound 2h inhibited the proliferation of Jurkat cells by inducing apoptosis. Since compound 2h induced the dissipation of mitochondrial membrane potential and the activation of caspase-3, it was obvious that compound 2h inhibited the proliferation of Jurkat cells through the mitochondrial apoptotic pathway. Other than this, compound 2h exerted inhibition effect to many other tumor cells and only showed weak cytotoxic to human normal cells suggesting that compound 2h possessed a broad range of anticancer spectrum and high safety to normal cells.
Teng, Yu-Ou,Zhao, Hong-Ye,Wang, Jing,Liu, Huan,Gao, Mei-Le,Zhou, Yao,Han, Kai-Lin,Sun, Hua,Yu, Peng,Fan, Zhen-Chuan,Zhang, Yong-Min
p. 145 - 156
(2018/05/02)

A cinchona alkaloid catalyzed enantioselective sulfa-Michael/aldol cascade reaction of isoindigos: Construction of chiral bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters
A cinchona alkaloid catalyzed diastereoselective and enantioselective sulfa-Michael/aldol cascade reaction between 1,4-dithiane-2,5-diol and isoindigos has been successfully developed to afford the highly congested bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters in high yields (up to 91%), excellent diastereoselectivities (up to >20 : 1 dr), and good enantioselectivities (up to 98% ee). Some synthetic transformations of the reaction products were also studied.
Gui, Yong-Yuan,Yang, Jian,Qi, Liang-Wen,Wang, Xiao,Tian, Fang,Li, Xiao-Nian,Peng, Lin,Wang, Li-Xin
supporting information
p. 6371 - 6379
(2015/06/08)

Design, synthesis and preliminary biological evaluation of indoline-2,3-dione derivatives as novel HDAC inhibitors
Histone deacetylases (HDACs) are zinc-dependent or NAD+ dependent enzymes and play a critical role in the process of tumor development. Herein a series of indoline-2,3-dione derivatives have been designed and synthesized as potential HDACs inhibitors. The preliminary biological evaluation showed that most compounds synthesized have exhibited moderate Hela cell nuclear extract inhibitory activities, among which compound 25a (IC50 = 10.13 nM) has shown the best efficacy. The anti-proliferative activities of some of these compounds were also discussed.
Jin, Kang,Li, Shanshan,Li, Xiaoguang,Zhang, Jian,Xu, Wenfang,Li, Xuechen
p. 4728 - 4736
(2015/08/03)

Design and synthesis of 3-substituted indolin-2-one derivatives with methyl (e)-2-(3-Methoxy) acrylate moiety
In this article, fifteen indolin-2-one derivatives with methyl (E)-2-(3-methoxy)acrylate group were designed and synthesized. The structures of target compounds were confirmed by 1H NMR, IR and HR-MS spectra analysis.
Luo, Xi,Zhang, Yi-Ying,Wang, Yu-Liang
p. 2911 - 2916
(2015/12/11)

Design, synthesis and in vitro cytotoxicity evaluation of 5-(2-carboxyethenyl)isatin derivatives as anticancer agents
Forty four di- or trisubstituted novel isatin derivatives were designed and synthesized in 5-6 steps in 25-45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of these new isatin derivatives against three human tumor cell lines, K562, HepG2 and HT-29, were evaluated by MTT assay in vitro. SAR studies suggested that the combination of 1-benzyl and 5-[trans-2- (methoxycarbonyl)ethen-1-yl] substitution greatly enhance their cytotoxic activity, whereas an intact carbonyl functionality on C-3 as present in the parent ring is required to such a potency. This study leads to the identification of two highly active molecules, compounds 2h (IC50 = 3 nM) and 2k (IC50 = 6 nM), against human leukemia K562 cells.
Han, Kailin,Zhou, Yao,Liu, Fengxi,Guo, Qiannan,Wang, Pengfei,Yang, Yao,Song, Binbin,Liu, Wei,Yao, Qingwei,Teng, Yuou,Yu, Peng
supporting information
p. 591 - 594
(2014/01/23)

A novel strategy to the synthesis of 4-anilinoquinazoline derivatives
A novel approach to prepare 4-anilinoquinazoline derivatives based on the transformation of indoline-2,3-dione to formamidine was developed. The processes with this approach are simple, efficient, and environmentally friendly. The efficiency of this approach was evaluated by synthesizing 17 4-anilinoquinazolines and comparing the obtained yields with those achievable through conventional synthetic methods. It was the first time that compounds 8d, 8e, 8h, and 13b-f were synthesized. The characteristics of the IR and the UV spectra of these compounds and the effects of their substituents on the spectra were observed.
Wang, Zheng,Wang, Cuiling,Sun, Yanni,Zhang, Ning,Liu, Zhulan,Liu, Jianli
p. 906 - 913
(2014/01/23)

Structure-based design, synthesis, andanticonvulsant activity of isatin-1-N-phenylacetamide derivatives
In an effort to develop the potent anticonvulsant agents, a series of novel isatin-1-N-phenylacetamide derivatives was synthesized and screened for their in vivo anticonvulsant activity against maximal electroshock test and evaluated for their neurotoxicity by the rotarod test at the same dose levels. Ten compounds exhibited the anticonvulsant activity. 2-(5-Methyl-2,3-dioxoindolin-1- yl)-N-phenylacetamide (4b) was found to be the most potent compound of the series with an ED50 of 91.3 mg/kg, TD50 of >1,000 mg/kg, a higher protective index (PI = TD50/ED50, >11) was gained than the reference drug phenobarbital and carbamazepine. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore. Springer Science+Business Media 2013.
Xie, Chao,Tang, Li-Ming,Li, Fu-Nan,Guan, Li-Ping,Pan, Cheng-Yan,Wang, Si-Hong
p. 2161 - 2168
(2014/05/06)

Design, synthesis and antiproliferative activity evaluation of new 5-azaisoindigo derivatives
New 5-azaisoindigo derivatives were synthesized with two key intermediates 5-azaoxindole (7) and substituted indole-2,3-dione (10) in this paper. Intermediate 7 was prepared from 3-methylpyridine (1) through 6 steps containing oxidation reaction and so on. Intermediate 10 was obtained by a convenient Sandmeyer's method. The target compounds 5-azaisoindigo derivatives 11a-f were obtained by condensation of these two intermediates 7 and 10 in acidic condition. All target compounds were evaluated for their antiproliferative activity against seven cell lines by SRB assay. Compounds 11e and 11f showed significant antiproliferative activity against K562 cells (IC50: 8.9 μM and 13.6 μM, respectively).
Zhao, Ping,Yan, Yun,Li, Yanzhong,Zhang, Aiying,Zhan, Xiaoping,Liu, Zenglu,Mao, Zhenmin,Chen, Shaoxiong,Wang, Liqun
p. 1923 - 1932
(2014/08/18)

Design, synthesis and biological evaluation of N-alkyl or aryl substituted isoindigo derivatives as potential dual cyclin-dependent kinase 2 (CDK2)/glycogen synthase kinase 3β (GSK-3β) phosphorylation inhibitors
A series of N-alkyl or aryl substituted isoindigo derivatives have been synthesized and their anti-proliferative activity was evaluated by Sulforhodamine B (SRB) assay. Some of the target compounds exhibited significant antitumor activity, including compounds 6h and 6k (against K562 cells), 6i (against HeLa cells) and 6j (against A549 cells). N-(p-methoxy-phenyl)-isoindigo (6k) exhibited a high and selective anti-proliferative activity against K562 cells (IC50 7.8 μM) and induced the apoptosis of K562 cells in a dose-dependent manner. Compound 6k arrested the cell cycle at S phase in K562 cells by decreasing the expression of cyclin A and CDK2, which played critical roles in DNA replication and passage through G2 phase. Moreover, compound 6k down-regulated the expression of p-GSK-3β (Ser9), β-catenin and c-myc proteins, up-regulated the expression of GSK-3β, consequently, suppressed Wnt/β-catenin signaling pathway and induced the apoptosis of K562 cells. The binding mode of compound 6k with GSK-3β was simulated using molecular docking tools. All of these studies gave a better understanding to the molecular mechanisms of this class of agents and clues to develop dual CDK2/GSK-3β (Ser9) phosphorylation inhibitors applied in cancer chemotherapy.
Zhao, Ping,Li, Yanzhong,Gao, Guangwei,Wang, Shuai,Yan, Yun,Zhan, Xiaoping,Liu, Zenglu,Mao, Zhenmin,Chen, Shaoxiong,Wang, Liqun
p. 165 - 174
(2014/09/17)

Design, synthesis and evaluation of quinoline-based small molecule inhibitor of stat3
As STAT3 has been validated as an anticancer target, its inhibitors have been shown to possess therapeutic promise for the treatment of human cancers. To identify novel and selective STAT3 inhibitors, a virtual screening based on the STAT3 SH2 domain was performed and a small molecule, 2-phenylquinoline-4- carboxylic acid (5a), with an inhibition constant Ki value of 17.53 iM to STAT3 was discovered. On this basis, the derivatives of 5a including esters, amides and dimers were synthesized. The bioactivity and inhibitory selectivity of the derivatives were assayed using human breast cancer cell lines, MDA-MB-468 and MCF-7. Among the derivatives, 5c and 9b showed the most potent inhibitory activity with a good selectivity, and also inhibited STAT3 protein level of MDA-MB-468 cells. The results demonstrated a successful application of virtual screening for lead discovery. Compound 9b might be an effective STAT3 inhibitor lead for the further development of antitumor agents.
Shi, Zhi-Bing,Zhang, Lei,Bin, Zheng-Yang,Cao, Xiang-Rong,Gong, Zhu-Nan,Li, Jian-Xin
p. 420 - 426
(2013/07/26)

Novel indoline-2,3-dione derivatives as inhibitors of aminopeptidase N (APN)
Aminopeptidase N (APN/CD13), as a zinc-containing ectoenzyme, plays a critical role in the process of tumor angiogenesis, invasion and metastasis. Through the docking-based virtual screening of chemical databases and the further activity assay, we discovered that compound 10c exhibits potent and selective inhibitory ability towards APN. In addition, a series of indoline-2,3-dione derivates have been designed and synthesized as APN inhibitors. The results of preliminary activity evaluation showed that compound 12a (IC50 = 0.074 ± 0.0026 μM) exhibited the best inhibitory activity against APN, which could be used for further anticancer agent research.
Jin, Kang,Zhang, Xiaopan,Ma, Chunhua,Xu, Yingying,Yuan, Yumei,Xu, Wenfang
p. 2663 - 2670
(2013/06/27)

INDENOQUINOLONE COMPOUND, PREPARATION METHOD AND USE THEREOF
An indenoquinolone compounds of Formula (A) is disclosed, wherein the definition of each group is described in the description. These compounds may specifically inhibit topoisomerase I, and they have good activities against many kinds of human tumor cells, such as lung cancer, colon cancer, breast cancer, liver cancer and the like. They can be used in the manufacture of antitumor drugs. The method for preparing the compound of formula (A), and pharmaceutical compositions containing such compounds and the use in the manufacture of antitumor drugs are also disclosed.
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Paragraph 0084

(2013/04/10)

Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2,3-dioxygenase with therapeutic activity in lewis lung cancer (LLC) tumor-bearing mice
Indoleamine 2,3-dioxygenase (IDO-1) is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders, and other diseases that are characterized by pathological tryptophan metabolism. However, only a few structural classes are known to be IDO-1 inhibitors. In this study, a natural compound tryptanthrin was discovered to be a novel potent IDO-1 inhibitor by screening of indole-based structures. Three series of 13 tryptanthrin derivatives were synthesized, and the structure-activity analysis was undertaken. The optimization led to the identification of 5c, which exhibited the inhibitory activity at a nanomolar level. In vitro 5c dramatically augmented the proliferation of T cells. When administered to Lewis lung cancer (LLC) tumor-bearing mice, 5c significantly inhibited IDO-1 activity and suppressed tumor growth. In addition, 5c reduced the numbers of Foxp3 + regulatory T cells (Tregs), which are known to prevent the development of efficient antitumor immune responses.
Yang, Shuangshuang,Li, Xishuai,Hu, Fangfang,Li, Yinlong,Yang, Yunyun,Yan, Junkai,Kuang, Chunxiang,Yang, Qing
supporting information
p. 8321 - 8331
(2013/12/04)

Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety
A series of novel bisquinoline derivatives connected by a 4-oxy-3-fluoroaniline moiety were synthesized and evaluated for their in vitro antitumour activities against a panel of five cancer cell lines (H460, HT-29, MKN-45, U87MG, and SMMC-7721). Most of compounds tested showed a potent activity and high selectivity towards the H460 and MKN-45 cell lines. Among the compounds tested, six (15d, 15e, 15m, 15n, 16a, and 16i) were further examined for their c-Met kinase activity; the compounds showed high efficacy with IC 50 values in the single-digit nM range. An analysis of structure-activity relationships indicated that an unsubstituted or a halogen-substituted phenyl ring on the 2-arylquinoline-4-carboxamide moiety was favourable for antitumour activity.
Li, Sai,Huang, Qiang,Liu, Yajing,Zhang, Xiaolong,Liu, Shuang,He, Chao,Gong, Ping
p. 62 - 73
(2013/07/27)

Synthesis, spectroscopic characterization, in vitro cytotoxic and structure activity relationships of some mononuclear Ru(II) complexes
New mononuclear Ru(II) complexes [Ru(A)2(B)}2+, where A= 2,2'-bipyridine/1,10-phenanthroline and B= 3,4,5-tri-OCH3-DPC, 4-CH3-DPC, 4-N(CH3)2-DPC, 4-NO2-DPC, N-BITSZ, PTSZ and PINH, were prepared and characterized by spectroscopic methods. The in vitro cytotoxic activities of the complexes and their corresponding ligands were investigated against the human cancer TlyMPhocyte cell lines molt 4/c8 and CEM and the murine tumor leukemia cell line L1210, human promyelocytic leukemia cells (HL-60) and Bel-7402 liver cancer cells by MTT assay. The complexes [Ru(A)2(B)}2+ (A= 1,10-phenanthroline, B= 3,4,5-tri-OCH3-DPC) exerts rather more potent activities against all of these cell lines, especially for CEM and L1210. Ru complexes and structure-activity relationships and anticancer mechanisms are also discussed.
Thota, Sreekanth,Vallala, Srujana,Imran, Mohammad,Mekala, Sravani,Anchuri, Shyam Sunder,Karki, Subhas Somalingappa,Yerra, Rajeshwar,Balzarini, Jan,De Clercq, Erik
p. 1031 - 1045
(2013/07/28)

Discovery, Synthesis, and invitro Evaluation of West Nile Virus Protease Inhibitors Based on the 9,10-Dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one Scaffold
West Nile virus (WNV), a member of the Flaviviridae family, is a mosquito-borne pathogen that causes a great number of human infections each year. Neither vaccines nor antiviral therapies are currently available for human use. In this study, a WNV NS2B-NS3 protease inhibitor with a 9,10-dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one scaffold was identified by screening a small library of non-peptidic compounds. This initial hit was optimized by solution-phase synthesis and screening of a focused library of compounds bearing this scaffold. This led to the identification of a novel, uncompetitive inhibitor (1a40, IC50=5.41±0.45μM) of WNV NS2B-NS3 protease. Molecular docking of this chiral compound onto the WNV protease indicates that the Senantiomer of 1a40 appears to interfere with the productive interactions between the NS2B cofactor and the NS3 protease domain; (S)-1a40 is a preferred isomer for inhibition of WNV NS3 protease.
Samanta, Sanjay,Cui, Taian,Lam, Yulin
experimental part
p. 1210 - 1216
(2012/08/08)

Discovery of di-indolinone as a novel scaffold for protein tyrosine phosphatase 1B inhibitors
A series of di-indolinone derivatives was designed and synthesized to optimize our lead compounds basing on molecular docking study as PTP1B inhibitors. Successive enzymatic assay identified the synthetic di-indolinone as novel PTP1B inhibitors with low micromole-ranged inhibitory activity and at least several-fold selectivity over other tested homologous PTPs.
Dai, Hou-Ling,Gao, Li-Xin,Yang, Ying,Li, Jing-Ya,Cheng, Jia-Gao,Li, Jia,Wen, Ren,Peng, Yan-Qing,Zheng, Jian-Bin
p. 7440 - 7443
(2013/02/22)

Synthesis of novel triazol compounds containing isatin as potential antibacterial and antifungal agents by microwave and conventional methods
Microwave irradiation has been used to accelerate the conversion of isatin (1a) and 5-nitroisatin (1b) into their Schiff bases 3-[5′-aryl(alkyl)- 2′,4′-dihydro-1′,2′,4′-triazol-3′-on- 4′-yl]iminoisatin (3a-g) and 3-[5′-aryl(alkyl)-2′,4′- dihydro-1′,2′,4′-triazol-3′-on-4′-yl] imino-5-nitroisatin (4a-g), respectively. Reaction was achieved by microwave-induced technique, which reduced the reaction time drastically and improved the yield when compared to conventional heating. The newly synthesised bases showed moderate antimicrobial activity against the standard bacterial and fungal organisms tested.
Oezil, Musa,Mentese, Emre,Yilmaz, Fatih,Islamoglu, Fatih,Kahveci, Bahittin
scheme or table
p. 268 - 271
(2011/10/05)

The mechanism of Sandmeyer's cyclization reaction by electrospray ionization mass spectrometry
Using electrospray ionization (tandem) mass spectrometry (ESI-MS(/MS)) spectrometric experiments, the Sandmeyer reaction was monitored on-line, and key intermediates were intercepted and characterized for the first time. The mechanistic information provided by on-line ESI-MS(/MS) is in accordance with Sandmeyer's proposal, and was made possible by coupling a microreactor on-line to the ESI ion source, which allowed reactions to be screened from 0.7-2.0 s, identifying and characterizing all intermediates that were formed and consumed during the reaction. Copyright
Silva, Barbara V.,Violante, Flavio A.,Pinto, Angelo C.,Santos, Leonardo S.
experimental part
p. 423 - 428
(2012/01/05)

Design, synthesis and in vitro antibacterial and antifungal activities of some novel spiro[azetidine-2,30-indole]-2,4(10H)-dione
The present study deals with the synthesis of novel spiro[azetidine-2,30- indole]-20,4(10H)-dione derivative from the reactions of 3-(phenylimino)-1,3- dihydro-2Hindol- 2-one derivatives with chloracetyl chloride in the presence of triethylamine (TEA). All the compounds were characterized using IR, 1H-NMR, MS, and elemental analysis. They were screened for their antibacterial and antifungal activities. The bacterial strains used were Grampositive Staphylococcus aureus (MTCC-96) and Gramnegative Escherichia coli (MTCC-521) and Pseudomonas aeruginosa (MTCC-647). The antifungal screening was done on Candida albicans (MTCC-183) and Asperigillus niger (MTCC-343) fungal strains. Results revealed that, compounds (7a), (7b), (7c), (7d), and (7e) showed very good activity with MIC value of 6.25-12.5 lg/ml against three evaluated bacterial strains and the remaining compounds showed good to moderate activity comparable to standard drugs as antibacterial agents. Compounds (7c) and (7h) displayed equipotent antifungal activity in comparison to standard drugs. Amoxicillin, gentamycin, and streptomycin were used as standard drugs for antibacterial activity while fluconazole and itraconazole were used as standard drugs for antifungal activity. Structure-activity relationship study of the compounds showed that the presence of electron withdrawing group substitution at 50 and 70 positions of indoline ring and on ortho or para position of phenyl ring increases both antibacterial and antifungal activity of the compound. Henceforth, our findings will have a good impact on chemists and biochemists for further investigations in search of spiro-fused antimicrobial agents. Springer Science+Business Media, LLC 2011.
Shah, Ravi J.,Modi, Neha R.,Patel, Manish J.,Patel, Laxmanbhai J.,Chauhan, Bhupendrasinh F.,Patel, Madhabhai M.
experimental part
p. 587 - 594
(2012/04/04)

Synthesis and biological evaluation of novel indolin-2-one derivatives as protein tyrosine phosphatase 1b inhibitors
3-Substituted indolin-2-one derivatives had been designed and synthesized as a novel class ofprotein tyrosine phosphatase 1B (PTP1B) inhibitors. These compounds had been evaluated for their inhibitory activities against PTP1B in vitro with IC50 values in a low micromolar range.Compound 36, the lowest, bore an IC50 value of 3.48 μM. Preliminary structure-activity relationship was summarized.
Dai, Hou-Ling,Shen, Qiang,Zheng, Jian-Bin,Lib, Jing-Ya,Wen, Ren,Li, Jia
scheme or table
p. 526 - 530
(2012/04/23)

Synthesis and biological evaluation of 3-[4-(amino/methylsulfonyl)phenyl] methylene-indolin-2-one derivatives as novel COX-1/2 and 5-LOX inhibitors
Fourteen new 3-[4-(amino/methylsulfonyl)phenyl]methylene-indolin-2-one derivatives were synthesized. Six compounds displayed potent inhibitory activities against COX-1/2 and 5-LOX with IC50 in the range of 0.10-9.87 μM. Particularly, 10f exhibited well balanced inhibitory action on these enzymes (IC50 = 0.10-0.56 μM). More importantly, 10f and several other compounds had comparable or stronger anti-inflammatory and analgesic activities, but better gastric tolerability in vivo, as compared with darbufelone mesilate and tenidap sodium. Therefore, our findings may aid in the design of new and safe anti-inflammatory reagents for the intervention of painful inflammatory diseases, such as rheumatoid arthritis at clinic.
Lai, Yisheng,Ma, Lin,Huang, Wenxing,Yu, Xing,Zhang, Yihua,Ji, Hui,Tian, Jide
scheme or table
p. 7349 - 7353
(2011/01/12)

Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists
A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT6 antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT6 receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (Ki = 12.3 nM) for 5-HT6 receptor with good selectivity over other serotonin and dopamine (D1-D4) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC50 = 0.61 μM).
Seong, Churl Min,Park, Woo Kyu,Park, Chul Min,Kong, Jae Yang,Park, No Sang
p. 738 - 743
(2008/12/23)

An improved synthesis of isonitrosoacetanilides
A novel two-step synthesis of isonitrosoacetanilides [2-(hydroxyimino)-N- phenylacetamides] has been developed, involving the initial acylation of aniline derivatives with 2,2-diacetoxyacetyl chloride, followed by reaction with hydroxylamine hydrochloride. The method works equally well with a variety of different aniline derivatives, including those with poor aqueous solubility and those containing electron rich ortho-substituents, neither of which react well under traditional conditions.
Rewcastle, Gordon W.,Sutherland, Hamish S.,Weir, Claudette A.,Blackburn, Adrian G.,Denny, William A.
p. 8719 - 8721
(2007/10/03)

Synthesis, anticancer and antibacterial activity of some novel mononuclear Ru(II) complexes
In search of potential anticancer drug candidates in ruthenium complexes, a series of mononuclear ruthenium complexes of the type [Ru(phen) 2(nmit)]Cl2 (Ru1), [Ru(bpy)2(nmit)]Cl 2 (Ru2), [Ru(phen)2(icpl)]Cl2 (Ru3), Ru(bpy)2(icpl)]Cl2 (Ru4) (phen51,10-phenanthroline; bpy=2,2′-bipyridine; nmit=N-methyl-isatin-3-thiosemicarbazone, icpl=isatin-3-(4-Cl-phenyl)thiosemicarbazone) and [Ru(phen)2(aze)] Cl2 (Ru5), [Ru(bpy)2(aze)]Cl2 (Ru6) (aze=acetazolamide) and [Ru(phen)2(R-tsc)](ClO4) 2 (R=methyl (Ru7), ethyl (Ru8), cyclohexyl (Ru9), 4-Cl-phenyl (10), 4-Br-phenyl (Ru11), and 4-EtO-phenyl (Ru12), tsc=thiosemicarbazone) were prepared and characterized by elemental analysis, FTIR, 1H-NMR and FAB-MS. Effect of these complexes on the growth of a transplantable murine tumor cell line (Ehrlich Ascites Carcinoma) and their antibacterial activity were studied. In cancer study the effect of hematological profile of the tumor hosts have also been studied. In the cancer study, the complexes Ru1-Ru4, Ru10 and Ru11 have remarkably decreased the tumor volume and viable ascitic cell count as indicated by trypan blue dye exclusion test (p0.05). Treatment with the ruthenium complexes prolonged the lifespan of Ehrlich Ascites Carcinoma (EAC) bearing mice. Tumor inhibition by the ruthenium chelates was followed by improvements in hemoglobin, RBC and WBC values. All the complexes showed antibacterial activity, except Ru5 and Ru6. Thus, the results suggest that these ruthenium complexes have significant antitumor property and antibacterial activity. The results also reflect that the drug does not adversely affect the hematological profiles as compared to that of cisplatin on the host.
Mazumder, Upal Kanti,Gupta, Malaya,Karki, Subhas Somalingappa,Bhattacharya, Shiladitya,Rathinasamy, Suresh,Thangavel, Sivakumar
p. 178 - 185
(2007/10/03)

Inflammation modulators
Compounds, compositions and methods that are useful in the treatment of inflammatory, immunoregulatory, metabolic and cell proliferative conditions or diseases are provided herein. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in inflammation, metabolism and cell proliferation. The subject compounds contain quinoline or quinazoline rings.
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(2008/06/13)

Synthesis, characterization and pharmacological screening of some isatinoid compounds
Schiff bases and hydrazones of substituted isatins have been prepared by reacting isatin and the appropriate aromatic primary amine l hydrazines and characterized by spectral and elementary analysis. The compounds have been screened for analgesic, antiinflammatory and antipyretic activity. 3[(4-Bromo phenylidene)-1-amino] isatin is the only compound to exhibit all the activities. 3[(4-Bromo phenylidene)-1-amino] isatin and 3[(4- Bromo phenylidene)-1-amino]-5-methyl isatin possesses analgesic activity equipotent to paracetamol. 3(4-Phenylhydrazino) isatin and 3(thiosemicarbazino) isatin exhibit marked reduction of acetic acid induced inflammation. 3[(4-Methyl phenylidene)-1-amino] isatin at 200 mg/kg exhibits pronounced antipyretic activity comparable to paracetamol.
Sridhar,Ramesh
p. 668 - 672
(2007/10/03)

N-[(substituted five-membered di- or triaza diunsaturated ring)carbonyl] guanidine derivatives for the treatment of ischemia
NHE-1 inhibitors, methods of using such NHE-1 inhibitors and pharmaceutical compositions containing such NHE-1 inhibitors. The NHE-1 inhibitors are useful for the reduction of tissue damage resulting from tissue ischemia.
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(2008/06/13)

Synthesis of carbamoylformhydroxymoyl chlorides and study of their reactivities
Carbamoylformhydroxymoyl chlorides were synthesized by the reactions of carbamoylformamide oximes with sodium nitrite in the presence of hydrochloric acid, and their reactivities were examined.
Yarovenko,Kosarev,Zavarzin,Krayushkin
p. 1504 - 1509
(2007/10/03)

Quinoline derivatives
The invention relates to compounds of general formula (I) wherein R is selected from ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and allyl; R4 is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations; R5 is selected from methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, CF3, and OCHxFy; wherein x=0-2, y=1-3 with the proviso that x+y=3; R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; and any tautomer hereof. The invention also relates to pharmaceutical compositions containing a compound of the general formula (I) together with a pharmaceutically acceptable carrier. Included are also processes for the preparation of the compounds of formula (I), as well as methods of treating mammals suffering from diseases resulting from autoimmunity and pathological inflammation by administering a compound having the formula (I) to said mammal.
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(2008/06/13)

Quinoline derivatives
The invention is related to compounds of general formula (I) wherein R is methyl, ethyl, n-propyl, iso-propyl, n-butyl or allyl; R' is methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, or OCHxFy, wherein x=0-2, y=1-3 with the proviso that x+y=3, R'' is hydrogen, fluoro or chloro; with the proviso that R'' is fluoro or chloro only when R' is fluoro or chloro; R4 is hydrogen or pharmaceutically acceptable inorganic or organic cations; R5 is ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, trifluoromethyl, OCHxFy, or OCH2CHxFy wherein x=0-2, y=1-3 with the proviso that x+y=3; R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; and any tautomer thereof. The invention also relates to pharmaceutical compositions containing a compound of the general formula (I) together with a pharmaceutically acceptable carrier. Included are also processes for the preparation of the compounds of formula (I), as well as methods for the treatment of mammals suffering from diseases resulting from autoimmunity and pathological inflammation by administering of a compound having the formula (I) to said mammal.
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(2008/06/13)

Microwave assisted preparation of isatins and synthesis of (±)- convolutamydine-A
Microwave assisted preparation of a number of isatin derivatives is reported. A simple synthesis of (±)-convolutamydine-A, a potent compound against leukemia cells, is presented.
Jnaneshwara,Bedekar,Deshpande
p. 3627 - 3633
(2007/10/03)

Process for producing 2-(carboxyphenyl)-4-quinolinecarboxylic acid compounds
Quinolin-2-yl benzoic acid compounds which are useful as intermediates of quinoline compounds having angiotensin II antagonist activity prepared by decarboxylating 2-(carboxyphenyl)-4-quinolinecarboxylic acid compounds in which a carboxyl group bonded to a phenyl group may be esterified, while a carboxyl group bonded to a quinoline ring is not esterified, and both rings may have one or more substituents inert to the decarboxylation reaction.
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(2008/06/13)

Process for producing quinolin-2-yl benzoic acid compounds
A quinolin-2-yl benzoic acid compound useful as intermediates of angiotensin II antagonists which are effective for treating hypertension can be produced by decarboxylating a 2-carboxyphenyl-4-quinolinecarboxylic acid compound in which two carboxyl groups are not substituted and a benzene ring and a quinoline ring may have substituents inert to said decarboxylation reaction.
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(2008/06/13)

Biological activities and quantitative structure-activity relationships of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones as aldose reductase inhibitors
A series of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones were prepared and tested for aldose reductase inhibitory activity. The 6'- halogenated derivatives were found to be highly potent in vitro inhibitors of male rabbit lens aldose reductase and in vivo inhibitors of polyol accumulation in the sciatic nerves of galactosemic rats. Of these, (4R)-6'- chloro-3'-methylspiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-trione (67) showed the most potent in vitro and in vivo activities. An oral dose of 3 g/kg of compound 67 caused neither death nor behavioral abnormality in the preliminary acute toxicity study using mice and rats. Compound 67 was selected as a candidate for further evaluation. The quantitative structure- activity relationships in this series are also discussed.
Yamagishi,Yamada,Ozaki,Asao,Shimizu,Suzuki,Matsumoto,Matsuoka,Matsumoto
p. 2085 - 2094
(2007/10/02)