162957-24-6Relevant articles and documents
New tetrahydroisoquinoline derivatives overcome pgp activity in brain-blood barrier and glioblastoma multiforme in vitro
Salaroglio, Iris Chiara,Gazzano, Elena,Kopecka, Joanna,Chegaev, Konstantin,Costamagna, Costanzo,Fruttero, Roberta,Guglielmo, Stefano,Riganti, Chiara
, (2018/06/15)
P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs used against glioblastoma multiforme (GB). Indeed, Pgp is highly expressed in GB stem cells and in the brain-blood barrier (BBB), the peculiar endothelium surrounding the brain. Inhib
The selective oxidation of substituted aromatic hydrocarbons and the observation of uncoupling via redox cycling during naphthalene oxidation by the CYP101B1 system
Hall, Emma A.,Sarkar, Md Raihan,Bell, Stephen G.
, p. 1537 - 1548 (2017/06/05)
The cytochrome P450 monooxygenase enzyme CYP101B1, from Novosphingobium aromaticivorans DSM12444, efficiently and selectively oxidised a range of naphthalene and biphenyl derivatives. Methyl substituted naphthalenes were better substrates than ethylnaphthalenes and naphthalene itself. The highest product formation activity for a singly substituted alkylnaphthalene was obtained with 2-methylnaphthalene. The oxidation of alkylnaphthalenes was regioselective for the benzylic methyl or methine C-H bonds. The products from 1- and 2-ethylnaphthalene oxidation were highly enantioselective with a single stereoisomer being generated in significant excess. The disubstituted substrate, 2,7-dimethylnaphthalene, had a higher product formation activity than either 1- and 2-methylnaphthalene. Methyl substituted biphenyls were also better substrates than biphenyl and had similar biocatalytic parameters to 1-methylnaphthalene. CYP101B1 catalysed oxidation of 2- and 3-methylbiphenyl was selective for attack at the methyl C-H bonds. The exception was the turnover of 4-methylbiphenyl which generated 4′-(4-methylphenyl)phenol as the major product (70%) with 4-biphenylmethanol making up the remainder. The drug molecule diclofenac was also regioselectively oxidised to 4′-hydroxydiclofenac by CYP101B1. The activity of the CYP101B1 system with naphthalene was more complex and the rate of NADH oxidation increased over time but very little product, 1-naphthol, was generated. Addition of samples of 1-naphthol and 2-naphthol and low concentrations of 1,4-naphthoquinone induced rapid NADH oxidation activity in the in vitro turnovers in both the presence and absence of the cytochrome P450 enzyme. Hydrogen peroxide was generated in these reactions in absence of the P450 enzymes demonstrating that the ferredoxin and ferredoxin reductase in combination with quinones from naphthol oxidation and oxygen can undergo redox cycling giving rise to a form of uncoupling of the reducing equivalents.
A Potent and Selective P-gp Modulator for Altering Multidrug Resistance Due to Pump Overexpression
Guglielmo, Stefano,Contino, Marialessandra,Lazzarato, Loretta,Perrone, Maria Grazia,Blangetti, Marco,Fruttero, Roberta,Colabufo, Nicola Antonio
supporting information, p. 374 - 376 (2016/03/01)
P-glycoprotein (P-gp) is a membrane protein responsible for the active transport of several endogenous and exogenous substances. It constitutes a defense mechanism and, at the same time, it severely compromises the success rate of antitumor chemotherapy. In this study a small library of alkyl/oxyalkyl derivatives of MC70 [4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol], a well-known P-gp inhibitor, was synthesized through straightforward functionalization of the phenolic group present in the structure of MC70. All compounds were characterized for their effect on P-gp, proving capable of blocking P-gp-mediated calcein-AM efflux with micromolar potency, following their ability to act as high-affinity substrates of this transporter. Excitingly, compound 4 [6,7-dimethoxy-2-((4′-butoxybiphen-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline] exhibited low nanomolar potency (5.2 nm) and had a peculiar activity profile, acting both as a positive allosteric modulator and as a substrate of the transporter. A new and more efficient synthesis of MC70 is also described. Simple chemical modification of MC70, a well-known but rather nonselective P-glycoprotein (P-gp) inhibitor, led to a very potent and selective P-gp ligand (EC50=5.2 nm). The derivative displayed an intriguing double-faced mechanism of action, acting as both substrate and modulator. The synthesis of MC70 was also greatly improved, using a straightforward and protecting-group-free Suzuki-Miyaura coupling of halophenol.
Peptide nanofibers decorated with Pd nanoparticles to enhance the catalytic activity for C-C coupling reactions in aerobic conditions
Maity, Indrajit,Rasale, Dnyaneshwar B.,Das, Apurba K.
, p. 2984 - 2988 (2014/01/06)
We report the synergistic effects of peptide nanofibers decorated with Pd nanoparticles to enhance the catalytic activity for C-C coupling reactions in mild and aerobic conditions.
A general approach to N-heterocyclic carbenes with a fused tetracyclic core: Ligands for suzuki-miyaura cross-coupling reaction
Sutar, Revannath L.,Kumar, Vinod,Shingare, Rahul D.,Thorat, Shridhar,Gonnade, Rajesh,Reddy, D. Srinivasa
supporting information, p. 4482 - 4486 (2014/08/05)
The synthesis of an N-heterocyclic carbene (NHC) based on a tetracyclic scaffold by using simple, general, and scalable chemistry is disclosed. The developed route is suitable for introducing multiple substitutions on the tetracyclic scaffold. The utility of the present NHC as a ligand in the Suzuki-Miyaura cross-coupling reaction is demonstrated with a low catalyst loading. Copyright
Synthesis and structure-activity relationships of phenyl-substituted coumarins with anti-tubercular activity that target FadD32
Kawate, Tomohiko,Iwase, Noriaki,Shimizu, Motohisa,Stanley, Sarah A.,Wellington, Samantha,Kazyanskaya, Edward,Hung, Deborah T.
supporting information, p. 6052 - 6059 (2013/11/06)
In an effort to develop new and potent agents for therapy against tuberculosis, a high-throughput screen was performed against Mycobacterium tuberculosis strain H37Rv. Two 6-aryl-5,7-dimethyl-4-phenylcoumarin compounds 1a and 1b were found with modest activity. A series of coumarin derivatives were synthesized to improve potency and to investigate the structure-activity relationship of the series. Among them, compounds 1o and 2d showed improved activity with IC90 of 2 μM and 0.5 μM, respectively. Further optimization provided compound 3b with better physiochemical properties with IC90 0.4 μM which had activity in a mouse model of infection. The role of the conformation of the 4- and 6-aryl substituents is also described.
Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT1 melatoninergic ligands
Mésangeau, Christophe,Pérès, Basile,Descamps-Fran?ois, Carole,Chavatte, Philippe,Audinot, Valérie,Coumailleau, Sophie,Boutin, Jean A.,Delagrange, Philippe,Bennejean, Caroline,Renard, Pierre,Caignard, Daniel H.,Berthelot, Pascal,Yous, Sa?d
experimental part, p. 3426 - 3436 (2010/11/04)
Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions at melatonin receptors. Several of these liga
Solvolysis and ring closure of quinone methides photogenerated from biaryl systems
Shi, Yijian,Wan, Peter
, p. 1306 - 1323 (2007/10/03)
A variety of biaryl quinone methides have been photogenerated with a range of efficiencies from biaryl precursors 4-6 and 8, 10, and 11, all having hydroxyl and hydroxymethyl substituents on alternate rings. These novel biaryl quinone methides, which cannot be readily generated via thermal chemistry, are trapped by added nucleophiles such as MeOH and ethanolamine; two that cannot undergo electrocyclic ring closure (from 8 and 11) are readily observable by nanosecond laser photolysis, with long wavelength maxima (λ max) of 600 and 520 nm, respectively. Photogenerated o,o′-biaryl quinone methides undergo electrocyclic ring closure to give the corresponding chromene (pyran) products in high yield. Since the precursor biaryl alcohols have highly twisted structures in the ground state (dihedral angle of up to 90° by molecular mechanics calculations), a significant twisting motion to planarity is required to achieve reaction. Using steady-state fluorescence studies, we present evidence to suggest that the mechanism of quinone methide formation may occur via one of the following mechanisms: (i) dissociation of the proton from ArOH that precedes twisting; or (ii) ArOH dissociation and twisting taking place either simultaneously or in quick succession.
Design, modelling, synthesis and biological evaluation of peptidomimetic phosphinates as inhibitors of matrix metalloproteinases MMP-2 and MMP-8
Bianchini, Gianluca,Aschi, Massimiliano,Cavicchio, Giancarlo,Crucianelli, Marcello,Preziuso, Serena,Gallina, Carlo,Nastari, Adele,Gavuzzo, Enrico,Mazza, Fernando
, p. 4740 - 4749 (2007/10/03)
Three novel peptidomimetic phosphinate inhibitors have been synthesized and evaluated as inhibitors of matrix metalloproteinases MMP-2 and MMP-8. Their IC50 values are in the micromolar range, and one of them showed to be the most effective inh
