- Exploring the synthetic potential of a marine transaminase including discrimination at a remote stereocentre
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The marine transaminase, P-ω-TA, can be employed for the transamination from 1-aminotetralins and 1-aminoindanes with differentiation of stereochemistry at both the site of reaction and at a remote stereocentre resulting in formation of ketone products with up to 93% ee. While 4-substituents are tolerated on the tetralin core, the presence of 3- or 8-substituents is not tolerated by the transaminase. In general P-ω-TA shows capacity for remote diastereoselectivity, although both the stereoselectivity and efficiency are dependent on the specific substrate structure. Optimum efficiency and selectivity are seen with 4-haloaryl-1-aminotetralins and 3-haloaryl-1-aminoindanes, which may be associated with the marine origin of this enzyme. This journal is
- Schwarz, Maria,Murphy, Edel J.,Foley, Aoife M.,Woods, David F.,Castilla, Ignacio Abreu,Reen, F. Jerry,Collins, Stuart G.,O'gara, Fergal,Maguire, Anita R.
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supporting information
p. 188 - 198
(2021/01/18)
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- Metal free decarboxylative aminoxylation of carboxylic acids using a biphasic solvent system
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The smooth oxidative radical decarboxylation of carboxylic acids with TEMPO and other derivatives as radical scavengers is reported. The key to success was the use of a two-phase solvent system to avoid otherwise predominant side reactions such as the oxidation of TEMPO by persulfate and enabled the selective formation of synthetically useful alkoxyamines. The method does not require transition metals and was successfully used in a new synthetic approach for the antidepressant indatraline.
- Schulz, G?ran,Kirschning, Andreas
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supporting information
p. 273 - 278
(2021/01/14)
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- Enantiopurity determination of the enantiomers of the triple reuptake inhibitor indatraline
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The present study describes the development of two approaches for the determination of the enantiopurity of both enantiomers of indatraline. Initially, a method was developed using different chiral solvating agents (CSAs) for diastereomeric discrimination regarding signal separation in 1H nuclear magnetic resonance (NMR) spectroscopy, revealing MTPA as a promising choice for the differentiation of the indatraline enantiomers. This CSA was also tested for its ideal molar ratio, temperature, and solvent. Optimized conditions could be achieved that made determination of enantiopurity for (1R,3S)-indatraline up to 98.9% enantiomeric excess (ee) possible. To quantify even higher enantiopurities, a high-performance liquid chromatography (HPLC) method based on a modified β-cyclodextrine phase was established. The influence of buffer type, concentration, pH value, percentage and kind of organic modifier, temperature, injection volume as well as sample solvent on chromatographic parameters was investigated. Afterwards, the reliability of the established HPLC method was demonstrated by validation according to the ICH guideline Q2(R1) regarding specificity, accuracy, precision, linearity, and quantitation limit. The developed method proved to be strictly linear within a concentration range of 1.25-1000 μM for the (1R,3S)-enantiomer and 1.25-750 μM for its mirror image that enables a reliable determination of enantiopurities up to 99.75% ee for the (1R,3S)-enantiomer and up to 99.67% ee for the (1S,3R)-enantiomer.
- Grimm, Stefanie H.,Allmendinger, Lars,Hoefner, Georg,Wanner, Klaus T.
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supporting information
p. 923 - 933
(2014/01/06)
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- Synthesis of optically pure 1-amino-3-aryl indanes exemplified by (+)-indatraline
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A versatile procedure for the synthesis of optically pure 1-amino-3-aryl indanes is presented, exemplified by the synthesis of the triple uptake inhibitor (+)-indatraline (1). Georg Thieme Verlag Stuttgart · New York.
- N?rager, Niels Gr?n,Lorentz-Petersen, Linda Luise Reeh,Lyngs?, Lars Ole,Kehler, Jan,Juhl, Karsten
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supporting information; experimental part
p. 1753 - 1755
(2011/09/16)
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- Synthesis and Evaluation of Indatraline-Based Inhibitors for Trypanothione Reductase
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The search for novel compounds of relevance to the treatment of diseases caused by trypanosomatid protozoan parasites continues. Screening of a large library of known bioactive compounds has led to several drug-like starting points for further optimisation. In this study, novel analogues of the monoamine uptake inhibitor indatraline were prepared and assessed both as inhibitors of trypanothione reductase (TryR) and against the parasite Trypanosoma brucei. Although it proved difficult to significantly increase the potency of the original compound as an inhibitor of TryR, some insight into the preferred substituent on the amine group and in the two aromatic rings of the parent indatraline was deduced. In addition, detailed mode of action studies indicated that two of the inhibitors exhibit a mixed mode of inhibition. Give these inhibitors a TryR: Indatraline is a CNS-active inhibitor of trypanothione reductase (TryR) revealed in a previous high-throughput screen. For this study we prepared analogues of indatraline and tested their capacity to inhibit TryR and the proliferation of Trypanosoma brucei cells. Inhibitors of micromolar potency with a mixed mode of inhibition were identified.
- Walton, Jeffrey G. A.,Jones, Deuan C.,Kiuru, Paula,Durie, Alastair J.,Westwood, Nicholas J.,Fairlamb, Alan H.
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scheme or table
p. 321 - 328
(2012/01/12)
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- Synthesis of indatraline using a Suzuki cross-coupling reaction and a chemoselective hydrogenation: A versatile approach
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Indatraline and its derivatives can be obtained in five steps from indanone by using a Suzuki cross-coupling reaction and a chemoselective hydrogenation catalyzed by Wilkinson's catalyst.
- Cossy, Janine,Belotti, Damien,Maguer, Aude
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p. 1515 - 1517
(2007/10/03)
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- Slow-onset, long-duration 3-(3′,4′-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse
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A series of 3-(3′,4′-dichlorophenyl)-1-indanamine monoamine reuptake blockers have been synthesized in an effort to develop a compound that could be used as a maintenance therapy to treat cocaine abuse. Since the effects of cocaine on dopamine (DA) and serotonin (5HT) transporters are important components of its pharmacological activity, the focus was on nonselective inhibitors of monoamine transport. To reduce or eliminate the abuse potential of a DA reuptake blocker, the compounds were designed to be slow-onset, long-duration prodrugs whose N-demethylated metabolites would have increased activity over the parent compound with the ideal being a parent compound that has little or no activity. To achieve this, pairs of compounds with different groups on the amine nitrogen and with and without an additional N-methyl group were synthesized. All of the synthesized compounds were screened for binding and reuptake at the cloned human DA, 5HT, and norepinephrine (NE) transporters. As previously found, trans isomers are nonselective blockers of DA, 5HT, and NE reuptake, cis isomers with small N-alkyl groups are selective blockers of 5HT reuptake, and tertiary amines of the trans compounds are less potent than the corresponding N-demethylated secondary amines as blockers of DA reuptake. Larger N-alkyl groups in both the trans and cis series were found to reduce activity for the 5HT and NE transporters with less effect at DA transporters. Selected trans compounds were also screened for locomotor activity in mice and generalization to a cocaine-like profile in rats. With intraperitoneal administration, all of the trans isomers showed a slow onset of at least 20 min and an extremely long duration of action in the locomotor assays. Several of the trans compounds also fully generalized to a cocaine-like pharmacological profile. An initial lead compound, the N,N-dimethyl analogue trans-1b, was resolved into chirally pure enantiomers. Surprisingly, both enantiomers were found to have significant affinity for the DA transporter and to cause locomotor activation. This is in contrast to the N-methyl compound in which only the (+)-enantiomer had significant activity. The absolute configuration of the more active enantiomer was determined by X-ray crystallography to be 3R,1S.
- Froimowitz,Wu,Moussa,Haidar,Jurayj,George,Gardner
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p. 4981 - 4992
(2007/10/03)
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- Neuroleptic activity and dopamine-uptake inhibition in 1-piperazino-3-phenylindans
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A series of 1-piperazino-3-phenylindans was synthesized and tested for neuroleptic and thymoleptic activity. Neuroleptic activity was found only in trans racemates and was associated with one of the enantiomers only. The potent and long-acting neuroleptic compound trans-4-[3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-yl]-1-piperazineeth anol (Lu 18-012, tefludazine) was developed by systematic variation of structural components. Thymoleptic activity was optimized, especially with respect to dopamine-uptake inhibition. No geometrical stereoselectivity was found with regard to dopamine-uptake inhibition, but a high enantioselectivity could be demonstrated for both cis and trans racemates. The most potent compounds were 1-piperazino-3-(3,4-dichlorophenyl)indans with IC50 values of about 2 nM for inhibition of dopamine uptake.
- Bogeso
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p. 935 - 947
(2007/10/02)
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