- Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands – Functional characterization and modeling studies on H3 and H4 receptors
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Histamine acts through four different receptors (H1R-H4R), the H3R and H4R being the most explored in the last years as drug targets. The H3R is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while H4R blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human H3R/H4R ligands as potential drug candidates. In the present study, a set of 12 compounds were synthesized from adequate (dihydro)benzofuran synthons through simple reactions with corresponding piperazines, giving moderate to high yields. Four compounds (1b, 1f, 1g and 1h) showed high hH3R affinity (pKi > 7), compound 1h being the most potent (pKi 8.4), and compound 1f showed the best efficiency (pKi 8.2, LE 0.53, LLE 5.85). BRET-based assays monitoring Gαi activity indicated that the compounds are potent antagonists. Only one compound (2c, pKi 7.1) presented high affinity for hH4R. In contrast to what was observed for hH3R, it showed partial agonist activity. Docking experiments indicated that bulky substituents occupy a hydrophobic pocket in hH3R, while the N-allyl group forms favorable interactions with hydrophobic residues in the TM2, 3 and 7, increasing the selectivity towards hH3R. Additionally, the importance of the indole NH in the interaction with Glu5.46 from hH4R was confirmed by the modeling results, explaining the affinity and agonistic activity of compound 2c. The data reported in this work represent important findings for the rational design of future compounds for hH3R and hH4R.
- Corrêa, Michelle F.,Balico-Silva, André L.,Kiss, Dóra J.,Fernandes, Gustavo A.B.,Maraschin, Jhonatan C.,Parreiras-e-Silva, Lucas T.,Varela, Marina T.,Sim?es, Sarah C.,Bouvier, Michel,Keser?, Gy?rgy M.,Costa-Neto, Claudio M.,Fernandes, Jo?o Paulo S.
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- Novel potent vasodilating agents: Evaluation of the activity and potency of LINS01005 and derivatives in rat aorta
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Cardiovascular diseases (CVDs) present high prevalence rates in the current world. It is estimated that approximately one-third of the global deaths are related to CVDs, and thus there is still a need for novel drugs to treat these disorders. We serendipitously discovered that LINS01005 (5a) is a potent vasodilating agent in rat aorta, and therefore a set of analogues were evaluated for the vasodilating potency in Wistar and SHR rat thoracic aorta precontracted with norepinephrine, with endothelium intact (E+) or denuded (E–) aortic rings. Compounds 5a and 5b were the most potent, showing submicromolar potency for endothelium intact vessels (EC50 853 and 941 nM, respectively) and micromolar values for E– vessels (EC50 2.4 and 7.1 μM, respectively). These compounds were indeed significantly more potent vasodilating agents in SHR-derived aortic rings (p 50 2.4 nM (E+) 9.0 nM (E–)] and 5b [EC50 20 nM (E+) 2.1 μM (E–)]. SAR analysis though PCA and HCA were performed, suggesting that N-phenylpiperazine is essential to the activity, while increasing volume in the substituted aromatic moiety is detrimental to the potency. This is the first report of the vasodilating properties of such compounds, and studies regarding the mechanism of action are in progress in our group.
- Ginoza, Milton,Fernandes, Gustavo A.B.,Corrêa, Michelle F.,Fernandes, Jo?o Paulo S.
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- Profiling of LINS01 compounds at human dopamine D2 and D3 receptors
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Abstract: Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, especially in the limbic areas, making them very attractive to designing drugs with synergistic and/or additive effects. The roles of these systems to treat schizophrenia, drug addiction, Parkinson’s and Alzheimer’s diseases, among others are widely known. The LINS01 compounds were previously reported as histamine H3 receptor (H3R) antagonists and some of them are under evaluation in rodent memory models. Considering their pharmacological potential and similarities to literature dopamine D2 receptor (D2R) and dopamine D3 receptor (D3R) ligands, this work aimed to evaluate these compounds as ligands these receptors by using [3H]spiperone displacement assays. A set of 11 compounds containing the dihydrobenzofuranyl-piperazine core with substituents at 5-position of dihydrobenzofuran ring and at the piperazine nitrogen was examined. The compounds showed low to moderate affinities at both, D2R and D3R. N-Phenyl compounds LINS01005 (1d), LINS01011 (1h), LINS01012 (1i) and LINS01016 (1k) showed the highest affinities in the set to D3R (Ki 0.3–1.5 μM), indicating that N-phenylpiperazine moiety increases the affinity to this receptor subtype with some selectivity, since they showed lower affinities to D2R (Ki 1.3–5.5 μM). With the LINS01 compounds showing moderate binding affinity, new lead structures for optimization with regards to combined H3R and D2R/D3R-ligands are provided. Graphic abstract: Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, and thus LINS01 compounds previously reported as histamine H3 receptor antagonists were evaluated as dopamine D2R and D3R ligands. The compounds showed micromolar affinities to both receptors[Figure not available: see fulltext.].
- Corrêa, Michelle F,Reiner, David,Fernandes, Gustavo A B,Varela, Marina T,Aranha, Cecília M S Q,Stark, Holger,Fernandes, Jo?o Paulo S
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- Small Molecule NF-κB Inhibitors as Immune Potentiators for Enhancement of Vaccine Adjuvants
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Adjuvants are added to vaccines to enhance the immune response and provide increased protection against disease. In the last decade, hundreds of synthetic immune adjuvants have been created, but many induce undesirable levels of proinflammatory cytokines including TNF-α and IL-6. Here we present small molecule NF-κB inhibitors that can be used in combination with an immune adjuvant to both decrease markers associated with poor tolerability and improve the protective response of vaccination. Additionally, we synthesize a library of honokiol derivatives identifying several promising candidates for use in vaccine formulations.
- Moser, Brittany A.,Escalante-Buendia, Yoseline,Steinhardt, Rachel C.,Rosenberger, Matthew G.,Cassaidy, Britteny J.,Naorem, Nihesh,Chon, Alfred C.,Nguyen, Minh H.,Tran, Ngoctran T.,Esser-Kahn, Aaron P.
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- Synthesis of Benzofuran and Indole Derivatives Catalyzed by Palladium on Carbon
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Benzofurans and indoles are key moieties in many natural products and pharmaceuticals. Herein, we describe a cheap and easy-to-execute strategy for the synthesis of benzofurans and indoles, employing Pd/C as the promoter. A variety of substituted allyl-anilines and allyl-phenols were converted into the desired products in good to excellent yields. Recycling of Pd/C was possible up to five cycles, keeping similar levels of reactivity.
- Savvidou, Anatoli,IoannisTzaras, Dimitrios,Koutoulogenis, Giorgos S.,Theodorou, Alexis,Kokotos, Christoforos G.
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supporting information
p. 3890 - 3897
(2019/06/27)
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- Synthesis of honokiol analogues and evaluation of their modulating action on VEGF protein secretion and telomerase-related gene expressions
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A group of 36 biphenyl derivatives structurally related to honokiol were synthesized by means of Suzuki coupling reactions. Their cytotoxicities were evaluated and compared to that of honokiol. Some of the compounds were then evaluated for their ability to downregulate the secretion of the VEGF protein and the expression of the VEGF, hTERT, and c-Myc genes; the two latter involved in the activation of telomerase in tumoral cells. Some of the synthetized derivatives showed promising pharmacological features as they exhibited IC50 values in low micromolar range, good therapeutic margins, and a multiple mode of action on tumor cells based on the inhibition of VEGF and, at the same time, of the expression of genes related to the activation of telomerase.
- Sánchez-Peris, María,Murga, Juan,Falomir, Eva,Carda, Miguel,Marco, Juan Alberto
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p. 577 - 584
(2017/04/06)
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- Green Organocatalytic Synthesis of Dihydrobenzofurans by Oxidation-Cyclization of Allylphenols
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A green and cheap protocol for the synthesis of dihydrobenzofurans via an organocatalytic oxidation of o -allylphenols is presented. The use of 2,2,2-trifluoroacetophenone and H 2 O 2 as the oxidation system, leads to a highly useful synthetic method, where a variety of substituted o -allylphenols were cyclized in high yields..
- Triandafillidi, Ierasia,Sideri, Ioanna K.,Tzaras, Dimitrios Ioannis,Spiliopoulou, Nikoleta,Kokotos, Christoforos G.
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supporting information
p. 4254 - 4260
(2017/09/12)
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- Enantioselective synthesis of benzofurans and benzoxazines via an olefin cross-metathesis-intramolecular oxo-Michael reaction
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Chiral phosphoric acid and Hoveyda-Grubbs II were found to catalyze an olefin cross-metathesis-intramolecular oxo-Michael cascade reaction of the ortho-allylphenols and enones to provide a variety of benzofuran and benzoxazine derivatives in moderate to good yields and enantioselectivity.
- Zhang, Jun-Wei,Cai, Quan,Gu, Qing,Shi, Xiao-Xin,You, Shu-Li
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supporting information
p. 7750 - 7752
(2013/09/02)
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- Design, synthesis, and anti-proliferative evaluation of [1,1′-biphenyl]-4-ols as inhibitor of HUVEC migration and tube formation
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Allylated biphenol neolignans contain a variety of chemopreventive entities that have been used as anti-tumor drug leads. Herein, 37 allylated biphenols were evaluated for anti-proliferative activity by the MTT assay and inhibitory effect on the migration and tube formation of HUVECs featuring anti-angiogenic properties. 3-(2-Methylbut-3-en-2-yl)-3′,5′-bis(trifluoromethyl)-[1, 1′-biphenyl]-4-ol (5c) exerted an inhibitory effect on HUVECs compared to honokiol (IC50 = 47.0 vs. 52.6 μM) and showed significant blocking effects on the proliferation of C26, Hela, K562, A549, and HepG2 (IC 50 = 15.0, 25.0, 21.2, 29.5, and 13.0 μM, respectively), superior to those of honokiol (IC50 = 65.1, 62.0, 42.0, 75.0, and 55.4 μM, respectively). Importantly, compound 5c inhibited the migration and capillary-like tube formation of HUVECs in vitro.
- Ran, Yan,Ma, Liang,Wang, Xuewei,Chen, Jinying,Wang, Guangcheng,Peng, Aihua,Chen, Lijuan
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p. 8091 - 8104
(2012/10/07)
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- Structural modification of honokiol, a biphenyl occurring in magnolia officinalis: The evaluation of honokiol analogues as inhibitors of angiogenesis and for their cytotoxicity and structure-activity relationship
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Honokiol, widely known as an antitumor agent, has been used as an antiangiogenesis drug lead. In this paper, 47 honokiol analogues and derivatives were investigated for their antiangiogenic activity by application of the transgenic zebrafish screening model, antiproliferative and cytotoxic activity against HUVECs, and three tumor cell lines by MTT assay. 3′,5-Diallyl-2, 4′-dihydroxy-[1,1′-biphen-yl]-3,5′-dicarbaldehyde (8c) was found to suppress the newly grown segmental vessels from the dorsal aorta of zebrafish and prevent inappropriate vascularization as well as exhibit more potent inhibitory effects on the proliferation of HUVECs, A549, HepG2, and LL/2 cells (IC50 = 15.1, 30.2, 10.7, and 21.7 μM, respectively) than honokiol (IC50 = 52.6, 35.0, 16.5, and 65.4 μM, respectively). Analogue 8c also effectively inhibited the migration and capillary-like tube formation of HUVECs in vitro. The antiangiogenic effect and antiproliferative activity of these structurally modified honokiol analogues and derivatives have led to the establishment of a structure-activity relationship.
- Ma, Liang,Chen, Jinying,Wang, Xuewei,Liang, Xiaolin,Luo, Youfu,Zhu, Wei,Wang, Tianen,Peng, Ming,Li, Shucai,Jie, Shi,Peng, Aihua,Wei, Yuquan,Chen, Lijuan
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p. 6469 - 6481
(2011/12/01)
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- Efficient Claisen rearrangement of allyl para-substituted phenyl ethers using microreactors
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A green way to synthesize allyl phenols has been developed. Quantitative yield of 2-allyl-4-methoxyphenol was obtained via a fast Claisen rearrangement in a microreactor system without solvent and work-up.
- Kong, Lingjie,Lin, Qi,Lv, Xiaoming,Yang, Yongtai,Jia, Yu,Zhou, Yaming
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supporting information; experimental part
p. 1108 - 1111
(2010/04/23)
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- A domino amidation route to indolines and indoles: Rapid syntheses of anhydrolycorinone, hippadine, oxoassoanine, and pratosine
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(Chemical Equation Presented) When subjected to palladium-catalyzed amidation conditions, 2-triflyloxy phenethyl carbonates undergo, in addition to the expected aryl cross-coupling, an additional amidation with net displacement of the carbonate. The result is a one-step synthesis of indolines which may be oxidized to indoles. The utility of the procedure is illustrated by the two- or three-step syntheses of anhydrolycorinone, hippadine, oxoassoanine, and pratosine.
- Ganton, Michael D.,Kerr, Michael A.
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p. 4777 - 4779
(2007/10/03)
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- Aryloxazolidinediones: Identification of potent orally active PPAR dual α/γ agonists
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A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual α/γ agonists. Based on the results of efficacy studies in the db/db mice
- Desai, Ranjit C.,Gratale, Dominick F.,Han, Wei,Koyama, Hiroo,Metzger, Edward,Lombardo, Victoria K.,MacNaul, Karen L.,Doebber, Thomas W.,Berger, Joel P.,Leung, Kwan,Franklin, Ronald,Moller, David E.,Heck, James V.,Sahoo, Soumya P.
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p. 3541 - 3544
(2007/10/03)
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