- Inhibition of P-glycoprotein-mediated Multidrug Resistance (MDR) by N,N-bis(cyclohexanol)amine aryl esters: Further restriction of molecular flexibility maintains high potency and efficacy
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Conformational modulation of the aryl portion of a set of N,N-bis(cyclohexanol)amine aryl esters (1a-d) that are potent Pgp-dependent MDR inhibitors has been performed. Toward this end the trans-3-(3,4,5- trimethoxyphenyl)acrylic acid present in set 1 was
- Martelli, Cecilia,Dei, Silvia,Lambert, Catherine,Manetti, Dina,Orlandi, Francesca,Romanelli, Maria Novella,Scapecchi, Serena,Salerno, Milena,Teodori, Elisabetta
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Read Online
- Structure based modification of chalcone analogue activates Nrf2 in the human retinal pigment epithelial cell line ARPE-19
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Oxidative stress-induced degeneration of retinal pigment epithelial (RPE) cells is known to be a key contributor to the development of age-related macular degeneration (AMD). Activation of the nuclear factor-(erythroid-derived 2)-related factor-2 (Nrf2)-mediated cellular defense system is believed to be a valid therapeutic approach. In the present study, we designed and synthesized a novel chalcone analogue, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), as a Nrf2 activator. The potency of Tak was measured in RPE cells by the induction of the Nrf2-dependent antioxidant genes HO-1, NQO-1, GCLc, and GCLm, which were regulated through the Erk pathway. We also showed that Tak could protect RPE cells against oxidative stress-induced cell death and mitochondrial dysfunction. Furthermore, by modifying the α, β unsaturated carbonyl entity in Tak, we showed that the induction of antioxidant genes was abolished, indicating that this unique feature in Tak was responsible for the Nrf2 activation. These results suggest that Tak is a potential candidate for clinical application against AMD.
- Cao, Ruijun,Cui, Yuting,Feng, Zhihui,Huang, Na,Li, Yuan,Liu, Jiankang,Meng, Lingjie,Xiong, Yue
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- Activity-based protein profiling reveals GSTO1 as the covalent target of piperlongumine and a promising target for combination therapy for cancer
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Through systematic target identification for piperlongumine, a cancer-selective killing molecule, we identified GSTO1 as its major covalent target for cancer cell death induction. We also reveal that GSTO1 inhibition is a promising combination strategy with other anti-cancer agents by drug combination screening in which piperlongumine exhibits broad-spectrum synergistic effects with a large proportion of the tested anti-cancer agents, especially with PI3K/Akt/mTOR pathway inhibitors.
- Li, Li,Zhao, Yue,Cao, Ran,Li, Lin,Cai, Gaihong,Li, Jiaojiao,Qi, Xiangbing,Chen, She,Zhang, Zhiyuan
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supporting information
p. 4407 - 4410
(2019/04/26)
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- Modular synthesis and biological investigation of 5-hydroxymethyl dibenzyl butyrolactones and related lignans
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Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway.
- Davidson, Samuel J.,Pilkington, Lisa I.,Dempsey-Hibbert, Nina C.,El-Mohtadi, Mohamed,Tang, Shiying,Wainwright, Thomas,Whitehead, Kathryn A.,Barker, David
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- Design and synthesis of cenocladamide analogues and their evaluation against breast cancer cell lines
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This work describes the total synthesis of the alkaloid cenocladamide and a concise library of nine structural analogues aiming at their evaluation against the breast cancer cell line MDA-MB-231. The most promising compound (3; IC50 = 6.6 μM) was also evaluated in a panel of seven breast cancer cell lines and two non-tumorigenic cell lines. We further conducted an initial investigation on the mechanism of action of analogue 3, which lacks the endocyclic double bond when compared to cenocladamide. The present study presents the discovery of a cenocladamide analogue with interesting cytotoxic activity, which could be useful for further optimization towards new chemotherapeutic agents for breast cancer treatment.
- Santos, Carla C. F.,Paradela, Luciana S.,Novaes, Luiz F. T.,Dias, Sandra M. G.,Pastre, Julio C.
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p. 755 - 766
(2017/04/27)
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- NOVEL COMPOUNDS USEFUL AS S100-INHIBITORS
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A compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising the compound. The compound is an inhibitor of interactions between S100A9 and interaction partners such as RAGE, TLR4 and EMMPRIN and as such is useful in the treatment of disorders such as cancer, autoimmune disorders, inflammatory disorders and neurodegenerative disorders.
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Page/Page column 73; 74
(2015/12/08)
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- Synthesis of indole-derived allocolchicine congeners through Pd-catalyzed intramolecular C-H arylation reaction
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The synthesis of several new heterocyclic structural analogs of the natural antimitotic agent allocolchicine is reported. As a key step an intramolecular Pd-catalyzed C-H arylation reaction was used to close the seven-membered ring fused with two electron
- Sitnikov, Nikolay S.,Kokisheva, Antonina S.,Fukin, Georgy K.,Neud?rfl, J?rg-Martin,Sutorius, Hannah,Prokop, Aram,Fokin, Valery V.,Schmalz, Hans-Günther,Fedorov, Alexey Yu.
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p. 6481 - 6492
(2016/02/18)
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- The design, synthesis and in vitro immunosuppressive evaluation of novel isobenzofuran derivatives
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The synthesis and biological evaluation of a series of novel isobenzofuran-based compounds are described. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and IMPDH type II inhibitor activity in vitro, as well as their structure-activity relationships were assessed. Several compounds demonstrated highly efficacious immunosuppressive properties, especially compounds 2d, 2e, 2h and 2j, which were superior to MPA, while compounds 2k, 2m, 2n, 4c and 5d exhibited an equipotent inhibitory activity compared to MPA. Generally, it was obviously demonstrated that α,β-unsaturated amides proved more potent than the diamide and urea series. The present study provides a guide for further research on development of safe and effective immunosuppressive agents.
- Yang, Na,Wang, Qing-He,Wang, Wen-Qian,Wang, Jian,Li, Feng,Tan, Shen-Peng,Cheng, Mao-Sheng
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scheme or table
p. 53 - 56
(2012/02/16)
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- Controlled and chemoselective reduction of secondary amides
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This communication describes a metal-free methodology involving an efficient and controlled reduction of secondary amides to imines, aldehydes, and amines in good to excellent yields under ambient pressure and temperature. The process includes a chemoselective activation of a secondary amide with triflic anhydride in the presence of 2-fluoropyridine. The electrophilic activated amide can then be reduced to the corresponding iminium using triethylsilane, a cheap, rather inert, and commercially available reagent. Imines can be isolated after a basic workup or readily transformed to the aldehydes following an acidic workup. The amine moiety can be accessed via a sequential reductive amination by the addition of silane and Hantzsch ester hydride in a one-pot reaction. Moreover, this reduction tolerates various functional groups that are usually reactive under reductive conditions and is very selective to secondary amides.
- Pelletier, Guillaume,Bechara, William S.,Charette, Andre B.
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supporting information; experimental part
p. 12817 - 12819
(2010/11/05)
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- An investigation into the electrophilic cyclisation of N-acyl-pyrrolidinium ions: A facile synthesis of Pyrrolo-tetrahydroisoquinolones and Pyrrolo-benzazepinones
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The triflic acid-mediated cyclisation of N-arylmethyl- and N-arylethyl-acylpyrrolidinium ions gave moderate to good yields of pyrrolo-tetrahydroisoquinolones and pyrrolo-benzazepinones respectively. Electron-donating R substituents enhanced the rate of reaction and gave higher yields than electron-withdrawing substituents. Substituents on the methyl or ethyl chain in general enhanced the reaction, unless sterically encumbered. The equivalent acylpiperidinium ions cyclised much slower and in lower yield.
- King, Frank D.,Aliev, Abil E.,Caddick, Stephen,Copley, Royston C. B.
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experimental part
p. 3561 - 3571
(2010/01/06)
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- Novel heterobivalent tacrine derivatives as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase
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Two series of novel heterobivalent tacrine derivatives were synthesized. A trimethoxy substituted benzene was linked to the tacrine moiety by a hydrazide-based linker. The compounds were evaluated as cholinesterase inhibitors, and trimethoxybenzoic acid derivatives with 11- or 12-atom spacers were the most potent inhibitors of human acetylcholinesterase. The inhibitors showed a surprising selectivity toward human butyrylcholinesterase, where several trimethoxyphenylpropionic acid derivatives had IC50 values less than 250 pM.
- Elsinghorst, Paul W.,González Tanarro, Camino M.,Gütschow, Michael
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p. 7540 - 7544
(2007/10/03)
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- Facile construction of the colchicine skeleton by a rhodium-catalyzed cyclization/cycloaddition cascade
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The major alkaloid of the meadow saffron is colchicine, which displays remarkable antimitotic activity and has long been used in the treatment of acute gout and is currently being tested against a broad variety of other diseases. In a remarkable Rh-cataly
- Graening, Timm,Friedrichsen, Willy,Lex, Johann,Schmalz, Hans-Guenther
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p. 1524 - 1526
(2007/10/03)
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- Tricyclic compounds
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Novel tricyclic compounds of formula I as defined in the specification, a process for their preparation and their use for the preparation of optically active or racemic colchicine and thiocolchicine derivatives.
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- A KEY INTERMEDIATE FOR THE SYNTHESIS OF ANTITUMOR LIGNAN PROTOTYPES
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Procedures are described for the convenient generation of an iodinated carboxylic acid possessing considerable utility as a precursor to several biologically active lignans.
- Belletire, J. L.,Fremont, S. L.,Fry, D. F.
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p. 699 - 710
(2007/10/02)
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- Biosynthesis. Part 26. Synthetic Studies of Structural Modification of Late Biosynthetic Precursors for Colchicine
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The latter part of the natural pathway to colchicine is known to involve conversion of phenethyltetrahydroisoquinoline (2) by phenol oxidation into a dienone (O-methylandrocymbine) (4), the dienone subsequently undergoing ring-expansion to generate the tr
- Battersby, Alan R.,McDonald, Edward,Stachulski, Andrew V.
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p. 3053 - 3064
(2007/10/02)
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