Exploring the active site of phenylethanolamine N-methyltransferase: 3-alkyl-7-substituted-1,2,3,4-tetrahydroisoquinoline inhibitors

Grunewald, Gary L.; Romero, F. Anthony; Chieu, Alex D.; Fincham, Kelcie J.; Bhat, Seema R.; Criscione, Kevin R.

doi:10.1016/j.bmc.2004.11.015

Cited by 9 publications

(10 citation statements)

References 21 publications

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“…The product was identified by 1 H-1 H and 1 H- 13 Cc orrelation NMR spectra, as wella sb yt he comparison of the spectra with those of the independently synthesized 3-substituted isomer 3a. [27] Apart from the spectrald ata the formation of 4-substituted product was additionally confirmed by the X-ray diffraction study of the related benzyl-derivative 4i (Figure 2). Preliminary structurala ssignment of the isomers 3 and 4 can be also made from simple 1 HNMR spectra:b ecause of the electron-acceptor effect of the nitrogen atom the adjacent protons have rather high chemical shift values 3.3-3.8 ppm, while the protons adjacent to the phenyl ring have lower chemical shifts 2.7-3.0 ppm.…”

Section: Resultsmentioning

confidence: 75%

“…The reaction of O ‐Boc‐phenylhydroxamic acid ( 1 a ) with 1‐heptene ( 2 a , 2 equiv) smoothly proceeded at room temperature in the presence of 2 mol % of the catalyst 5 and gave exclusively 4‐substituted dihydroisoquinolone 4 a in excellent 97 % yield (Scheme ). The product was identified by 1 H– 1 H and 1 H– 13 C correlation NMR spectra, as well as by the comparison of the spectra with those of the independently synthesized 3‐substituted isomer 3 a . Apart from the spectral data the formation of 4‐substituted product was additionally confirmed by the X‐ray diffraction study of the related benzyl‐derivative 4 i (Figure ).…”

Section: Resultsmentioning

confidence: 87%

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Rhodium(III) Complex with a Bulky Cyclopentadienyl Ligand as a Catalyst for Regioselective Synthesis of Dihydroisoquinolones through C−H Activation of Arylhydroxamic Acids

Trifonova

Ankudinov

Kozlov

et al. 2018

Chemistry A European J

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Catalytic reaction of arylhydroxamic acids with alkenes represents a convenient method for preparation of biologically active dihydroisoquinolones. Here, the rhodium(III) complex [(C H tBu CH tBu)RhCl ] , which allows one to carry out such reactions with high regioselectivity to obtain 4-substituted dihydroisoquinolones in 72-97 % yields, is described. The regioselectivity is provided by the bulky cyclopentadienyl ligand of the catalyst, which is formed through a [2+2+1] cyclotrimerization of tert-butylacetylene. The catalytic reaction tolerates various distant functional groups in alkenes, but is inhibited by bulky (e.g., tBu) or strongly coordinating (e.g., imidazolyl) substituents. Some of the prepared dihydroisoquinolones effectively inhibit growth of phytopathogenic fungi.

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Section: Resultsmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 87%

Rhodium(III) Complex with a Bulky Cyclopentadienyl Ligand as a Catalyst for Regioselective Synthesis of Dihydroisoquinolones through C−H Activation of Arylhydroxamic Acids

Trifonova

Ankudinov

Kozlov

et al. 2018

Chemistry A European J

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“…It is well established that an increase in steric bulk at the 3-position of THIQ results in a decrease in PNMT inhibitory potency, 48 as illustrated by the biochemical results from a study of 7-bromo-and 7-nitro-THIQs having increasingly larger alkyl groups in the 3-position (Table 4, compounds 11d-f and 15d-f). However, when the 3-fluoroalkyl-7-substituted-THIQs (11a-c and 15a-c) are compared to the corresponding 3-alkyl-THIQs (11d-f and 15d-f), a correlation between the steric bulk of the 3-substituent [according to the Charton, 45 Taft (E s ), 46 or Dubois (E s ′) 47 parameters] and PNMT inhibitory potency is not observed (Table 4).…”

Section: Pnmtmentioning

confidence: 99%

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

et al. 2006

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Abstract3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the α 2 -adrenoceptor. Fluorination of the methyl group lowers the pK a of the THIQ amine from 9.53 (CH 3 ) to 7.88 (CH 2 F), 6.42 (CHF 2 ), and 4.88 (CF 3 ). This decrease in pK a results in a reduction in affinity for the α 2 -adrenoceptor. However, increased fluorination also results in a reduction in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochemical evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often non-selective due to significant affinity for the α 2 -adrenoceptor, while the latter were devoid of α 2 -adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pK a properties and thus have enhanced selectivity versus the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency versus the corresponding 3-trifluoromethyl-7-substituted-THIQs. Using the "Goldilocks Effect" analogy, the 3-fluoromethylTHIQs are too potent (too hot) at the α 2 -adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the α 2 -adrenoceptor. This seems to be the first successful use of the β-fluorination of aliphatic amines to impart selectivity to a pharmacological agent while maintaining potency at the site of interest.

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“…The interaction between Tyr222 and lipophilic 3-substituents of THIQ is well established. 10,24,46 Crystallographic studies have shown that the benzene ring of substrates 54 or THIQ-type inhibitors 7,14,15,20 is positioned between the side chains of Phe182 and Asn39. The distance between the aromatic ring of 6 14 ( Figure 2) or 8 15 and the aromatic ring of Phe182 is 3.8 Å or 3.7 Å, respectively, which implies the presence of a π-stacking interaction.…”

Section: Docking Studies Comparing the Binding Of Thtps With Thiqsmentioning

confidence: 99%

Synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines and comparison with their isosteric 1,2,3,4-tetrahydroisoquinolines as inhibitors of phenylethanolamine N-methyltransferase

Grunewald

Seim

Bhat

et al. 2008

Bioorganic & Medicinal Chemistry

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A series of substituted 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (THTPs) was synthesized and evaluated for their human phenylethanolamine N-methyltransferase (hPNMT) inhibitory potency and affinity for the α 2 -adrenoceptor. The THTP nucleus was suggested as an isosteric replacement for the 1,2,3,4-tetrahydroisoquinoline (THIQ) ring system on the basis that 3-thienylmethylamine (18) was more potent as an inhibitor of hPNMT and more selective towards the α 2 -adrenoceptor than benzylamine (15). Although the isosterism was confirmed, with similar influence of functional groups and chirality in both systems on hPNMT inhibitory potency and selectivity, the THTP compounds proved, in general, to be less potent as inhibitors of hPNMT than their THIQ counterparts, with the drop in potency being primarily attributed to the electronic properties of the thiophene ring. A hypothesis for the reduced hPNMT inhibitory potency of these compounds has been formed on the basis of molecular modeling and docking studies using the X-ray crystal structures of hPNMT co-crystallized with THIQ-type inhibitors and S-adenosyl-L-homocysteine as a template.

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Exploring the active site of phenylethanolamine N-methyltransferase: 3-alkyl-7-substituted-1,2,3,4-tetrahydroisoquinoline inhibitors

Cited by 9 publications

References 21 publications

Rhodium(III) Complex with a Bulky Cyclopentadienyl Ligand as a Catalyst for Regioselective Synthesis of Dihydroisoquinolones through C−H Activation of Arylhydroxamic Acids

Rhodium(III) Complex with a Bulky Cyclopentadienyl Ligand as a Catalyst for Regioselective Synthesis of Dihydroisoquinolones through C−H Activation of Arylhydroxamic Acids

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines and comparison with their isosteric 1,2,3,4-tetrahydroisoquinolines as inhibitors of phenylethanolamine N-methyltransferase

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Exploring the active site of phenylethanolamine N-methyltransferase: 3-alkyl-7-substituted-1,2,3,4-tetrahydroisoquinoline inhibitors

Cited by 9 publications

References 21 publications

Rhodium(III) Complex with a Bulky Cyclopentadienyl Ligand as a Catalyst for Regioselective Synthesis of Dihydroisoquinolones through C−H Activation of Arylhydroxamic Acids

Rhodium(III) Complex with a Bulky Cyclopentadienyl Ligand as a Catalyst for Regioselective Synthesis of Dihydroisoquinolones through C−H Activation of Arylhydroxamic Acids

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines and comparison with their isosteric 1,2,3,4-tetrahydroisoquinolines as inhibitors of phenylethanolamine N-methyltransferase

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Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination