- Design and optimisation of a small-molecule TLR2/4 antagonist for anti-tumour therapy
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In anti-tumour therapy, the toll-like receptor 2/4 (TLR2/4) signalling pathway has been a double-edged sword. TLR2/4 agonists are commonly considered adjuvants for immune stimulation, whereas TLR2/4 antagonists demonstrate more feasibility for anti-tumour therapy under specific chronic inflammatory situations. In individuals with cancer retaliatory proliferation and metastasis after surgery, blocking the TLR2/4 signalling pathway may produce favourable prognosis for patients. Therefore, here, we developed a small-molecule co-inhibitor that targets the TLR2/4 signalling pathway. After high-throughput screening of a compound library containing 14 400 small molecules, followed by hit-to-lead structural optimisation, we finally obtained the compound TX-33, which has effective inhibitory properties against the TLR2/4 signalling pathways. This compound was found to significantly inhibit multiple pro-inflammatory cytokines released by RAW264.7 cells. This was followed by TX-33 demonstrating promising efficacy in subsequent anti-tumour experiments. The current results provide a novel understanding of the role of TLR2/4 in cancer and a novel strategy for anti-tumour therapy.
- Chen, Hekai,Kong, Jun,Li, Tian,Xu, Qun,Yin, Hang,Zhang, Liwei
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supporting information
p. 1771 - 1779
(2021/11/19)
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- Substitution of terminal amide with 1H-1,2,3-triazole: Identification of unexpected class of potent antibacterial agents
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3-Methoxybenzamide (3-MBA) derivatives have been identified as novel class of potent antibacterial agents targeting the bacterial cell division protein FtsZ. As one of isosteres for the amide group, 1,2,3-triazole can mimic the topological and electronic features of the amide, which has gained increasing attention in drug discovery. Based on these considerations, we prepared a series of 1H-1,2,3-triazole-containing 3-MBA analogues via isosteric replacement of the terminal amide with triazole, which had increased antibacterial activity. This study demonstrated the possibility of developing the 1H-1,2,3-triazole group as a terminal amide-mimetic element which was capable of both keeping and modulating amide-related bioactivity. Surprisingly, a different action mode of these new 1H-1,2,3-triazole-containing analogues was observed, which could open new opportunities for the development of antibacterial agents.
- Bi, Fangchao,Ji, Shengli,Venter, Henrietta,Liu, Jingru,Semple, Susan J.,Ma, Shutao
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supporting information
p. 884 - 891
(2018/02/15)
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- Phenolic compounds containing benzyloxy phenyl and preparation method and application of phenolic compounds
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The invention discloses phenolic compounds (I) containing benzyloxy phenyl and a preparation method and application of the phenolic compounds. Pharmacological experiments prove that the phenolic compounds have high inhibiting activity on sphingosine kinase SphK, and part of the compounds has a certain inhibiting effect on inflammatory bowel disease induced by tumor and DSS. The phenolic compounds and the pharmaceutical preparations thereof can be used for preparing drugs for treating a series of cancer and inflammatory diseases such as colon cancer, lung cancer, breast cancer, liver cancer, stomach cancer, inflammatory bowel disease, hepatitis, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis and multiple sclerosis.
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Paragraph 0093; 0094; 0095; 0096; 0097
(2017/09/19)
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- Synthesis and evaluation of small molecules bearing a benzyloxy substituent as novel and potent monoamine oxidase inhibitors
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A new series of small molecules bearing a benzyloxy substituent have been designed, synthesized and evaluated for hMAO inhibitory activity in vitro. Most of the compounds were potent and selective MAO-B inhibitors, and were weak inhibitors of MAO-A. In particular, compounds 9e (IC50 = 0.35 μM) and 10e (IC50 = 0.19 μM) were the most potent MAO-B inhibitors, and exhibited the highest selectivity for MAO-B (9e, SI > 285.7-fold and 10e, SI = 146.8-fold). In addition, the structure-activity relationships for MAO-B inhibition indicated that electron-withdrawing groups in the open small molecules were more suitable for MAO-B inhibition, and substitutions at the benzyloxy of the open small molecules, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking studies have been done to explain the potent MAO-B inhibition of the open small molecules. Furthermore, the representative compounds 9e and 10e showed low neurotoxicity in SH-SY5Y cells in vitro. So the small molecules bearing the benzyloxy substituent could be used to develop promising drug candidates for the therapy of neurodegenerative diseases.
- Lan, Jin-Shuai,Zhang, Tong,Liu, Yun,Zhang, Yong,Hou, Jian-wei,Xie, Sai-Sai,Yang, Jing,Ding, Yue,Cai, Zhen-zhen
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p. 471 - 478
(2017/03/08)
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- Benzyloxynitrostyrene analogues – A novel class of selective and highly potent inhibitors of monoamine oxidase B
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This study examines a series of novel 3-benzyloxy-β-nitrostyrene analogues as a novel class of inhibitors of the monoamine oxidase (MAO) enzymes. MAO inhibitors are considered useful for the treatment of depression and Parkinson's disease, and have recently attracted attention as potential therapeutic agents for a range of disorders including Alzheimer's disease, prostate cancer and certain cardiomyopathies. This study shows that the 3-benzyloxy-β-nitrostyrene analogues are potent inhibitors of the MAO-B isoform with IC50values in the nanomolar range (39–565 nM). Significantly, effectiveness towards MAO-B inhibition seems to be governed by the introduction of a 4″-fluoro-substituent on the benzyloxy ring, with compound 2b exhibiting the highest degree of MAO-B inhibition potency (IC50= 0.039 μM) and selectivity (SI = 166) among the compounds investigated. Since some of the 3-benzyloxy-β-nitrostyrene analogues possess potencies that are comparable to that of the reversible inhibitor, safinamide (IC50= 0.080 μM), it may be concluded that this class may be promising leads for the development of reversible and selective MAO-B inhibitors, that may be useful for the management of Parkinson's disease.
- Van der Walt, Mietha M.,Terre'Blanche, Gisella,Petzer, Jacobus P.,Petzer, Anél
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p. 1193 - 1199
(2016/11/23)
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- Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice
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Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N′-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure-activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human.
- Xi, Meiyang,Ge, Jun,Wang, Xiaojian,Sun, Chenbin,Liu, Tianqi,Fang, Liang,Xiao, Qiong,Yin, Dali
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p. 3218 - 3230
(2016/07/06)
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- Cyclic compounds and uses thereof
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Compounds of general formula (1) R1—X1—W—X2—Z1—Z2—R2 or salts thereof, exhibiting preventive and therapeutic effects against HIV infectious diseases wherein R1is an optionally substituted five- or six-membered ring group; X1is a free valency or the like; W is a divalent group represented by, e. g., general formula (2) (wherein A and B are each an optionally substituted five- to seven-membered ring; E1and E4are each optionally substituted carbon or the like; E2and E3are each oxygen or the like; and a and b are each a single bond or a double bond); X2is a divalent group constituting a straight chain moiety; Z1is a divalent cyclic group or the like; Z2is a free valency or the like; and R2is optionally substituted amino or the like.
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- CYCLIC COMPOUNDS AND USES THEREOF
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Compounds of general formula (1) or salts thereof, exhibiting preventive and therapeutic effects against HIV infectious diseases wherein R1 is an optionally substituted five- or six-membered ring group; X1 is a free valency or the like; W is a divalent group represented by, e. g., general formula (2) (wherein A and B are each an optionally substituted five-to seven-membered ring; E1 and E4 are each optionally substituted carbon or the like; E2 and E3 are each oxygen or the like; and a and b are each a single bond or a double bond); X2 is a divalent group constituting a straight chain moiety; Z1 is a divalent cyclic group or the like; Z2 is a free valency or the like; and R2 is optionally substituted amino or the like.
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