Synthesis of 6- or 7-substituted 1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acids

A straightforward approach for the synthesis of several new, aryl-substituted derivatives of the conformationally constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) is described. Tic, nitro-substituted at the 6 or 7 position, was prepared by base-catalyzed cyclization of diethyl acetamidomalonate with ,-dibromo-4-nitro-o- xylene followed by decarboxylation and deacylation under refluxing conditions in aqueous HCl. Catalytic hydrogenation of nitro-Tic in the presence of 10% Pd/C afforded amino-Tic, which was then converted to iodo-Tic by a modified Sandmeyer reaction. Both amino- Tic and iodo-Tic can easily be transformed to other substituents.     

Side reactions in the preparation of 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid

Summary During a study on the preparation of the conformationally restricted analogue of tryptophan into 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid1 by a Pictet-Spengler condensation with formaldehyde, two site products were detected:N-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid2 and a dimer3 of two 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid units linked by a methylene group. Their structures were determined by HPLC-MS and 2D NMR spectroscopy. By changing the isolation procedure, theN-hydroxymethyl compound was removed. Treatment of the mixture with TFA in water converted the dimer into 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid1.     

Discovery and development of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as Bcl-2/Mcl-1 inhibitors

Bcl-2 family proteins play a vital role for cancer cell in escaping apoptosis, and small-molecule anti-apoptotic Bcl-2 protein inhibitors have been developed as new anticancer therapies. In current study, a series of substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were developed based on the lead compound 1 (K_i = 5.2 µM against Bcl-2 protein). The fluorescence polarization assays suggested that active compounds possessed potent binding affinities to both Bcl-2 and Mcl-1 protein, but had minor or no binding affinities to Bcl-X_L protein. MTT assays showed that these compounds had certain anti-proliferative activities against cancer cells. Furthermore, it was found that active compound 11t could induce cell apoptosis and caspase-3 activation in a dose-dependent manner in Jurkat cells.     

Stereoselective routes towards the synthesis of unusual bis(amino acids) and cyclic amino acids

Summary Stereoselective syntheses are described of bridged bis(glycines) as conformationally constrained substitutes for cystine, and of cyclic α-amino acids where the α-carbon of the amino acid is part of a five-, six- or seven-membered ring which may hold a hydroxy group as a threonine analogue.     

Stereoselective routes towards the synthesis of unusual bis(amino acids) and cyclic amino acids

Stereoselective syntheses are described of bridged bis(glycines) as conformationally constrained substitutes for cystine, and of cyclic -amino acids where the -carbon of the amino acid is part of a five-, six- or seven-membered ring which may hold a hydroxy group as a threonine analogue.     

Inhibition of flowering by hexahydrofluorene-9-carboxylic acids related to allogibberic acid

1,2,3,4,4a,9a-hexahydrofluorene-9-carboxylic acid isomers have been prepared by reduction of fluorene-9-carboxylic acid. Hexahydrofluorene-9-carboxylic acid (5) produce inhibition of flowering and vegetative frond development in Lemna perpusilla 6746 similar to that observed with allogibberic acid. The stereochemical requirements for this type of biological activity in allogibberic acids and hexahydrofluorene-9-carboxylic acids are considered.     

Optically active aromatic amino acids. part V: Some N-t-butyloxycarbonyl-O-methyl-L-tyrosine analogues with ring substitution at position 3

Six new derivatives of Boc-L -Tyr(Me)-OH have been prepared, with the following substituents at ring position 3: −CO₂Me, −CO₂Et, −CHO, −CH₂OH, −CH₂OBzl and −(E)−CH=NOH. © 1997 European Peptide Society and John Wiley & Sons, Ltd. J. Pep. Sci.3: 354–360 No. of Figures: 2. No. of Tables: 1. No. of References: 16     

Synthesis of non-proteinogenic (D)- or (L)-amino acids by asymmetric hydrogenation

Summary Non-proteinogenic amino acids play an increasing role in oligopeptide chemistry. Their pharmacological and chemical properties, caused by D-configuration and unnatural residues, are more and more used for drug design. Different methods of asymmetric synthesis have been developed during the last decade to prepare unusual amino acids. One of them, the asymmetric hydrogenation of dehydroamino aids catalyzed by chiral rhodium (I) complexes, will be described. A series of examples, D- and L-configured, like naphthyl-, thienyl-, furyl-, and pyridylalanines, as well as phenylalanines substituted by chlorine, fluorine, p-nitro, p-methyl, p-trifluoromethyl, p-isopropyl, and p-tert-butyl have been prepared and characterized. Some analytical data like melting points and values of optical rotation are summarized in tables.Abbreviations (–)-DIOP (4R,5R)-4,5-Bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane - (–)-BPPM (2S,4S)-N-tert-Butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine - Ph--glup Phenyl 4,6-O-(R)-benzylidene-2,3-O-bis(diphenylphosphino)--D-glucopyranoside - DuPHOS 1,2-bis-(phospholano)benzene - PROPRAPHOS 2,3-O,N-bis(diphenylphosphino)-1-(naphthoxy)-2-hydroxy-3-isopropylamino propane - PINDOPHOS 2,3-O,N-bis(diphenylphosphino)-1-(4-indolyloxy)-2-hydroxy-3-isopropylamino propane     

Increasing dispensable amino acids in diets of kittens fed essential amino acids at or below their requirement increases the requirement for arginine

Summary Kittens fed diets containing 0.75 × the NRC (1986) essential amino acid requirement (EAArq) and 210 to 560g crude protein(CP)/kg diet exhibited, with increasing CP: 1) decreasing weight gain, 2) decreasing plasma arginine concentrations, 3) increasing urinary orotic acid excretion, 4) increasing plasma glutamic acid concentrations, and 5) plasma isoleucine concentrations at levels that suggest a marginal isoleucine deficiency. Kittens fed a control diet (CD) containing 1.5 × EAArq and 350 g CP/kg diet had maximal weight gains and no orotic aciduria. It was concluded that the decreased weight gain and adverse metabolic effects were caused by arginine deficiency and possibly glutamic acid toxicity induced by high dietary dispensable amino acids. Kittens fed the diets containing 1.0 × EAArq and 350 and 560 g CP/kg diet had depressed plasma arginine and elevated glutamic acid concentrations and orotic aciduria. These results indicate that 10 g arg/kg diet is not adequate at CP concentrations above 280 g/kg and the calculated requirement of arginine is (0.02 g arginine/g CP) × (Y g CP/kg diet) + (4.0 g arginine/kg diet) where Y is the dietary CP level.Abbreviations CD control diet - CP crude protein (g CP/kg diet = g nitrogen/kg diet × 6.25) - DAA dispensable amino acids - EAA essential amino acids - EAArq essential amino acid requirement     

Study of the conformational profile of the norbornane analogues of phenylalanine.

The conformational profile of the eight stereoisomeric 2-amino-3-phenylnorbornane-2-carboxylic acids (2-amino-3-phenylbicyclo[2.2.1]heptane-2-carboxylic acids) has been assessed by computational methods. These molecules constitute a series of four enantiomeric pairs that can be considered as rigid analogues of either L- or D-phenylalanine. The conformational space of their N-acetyl methylamide derivatives has been explored within the molecular mechanics framework, using the parm94 set of parameters of the AMBER force field. Local minimum energy conformations have been further investigated at the ab initio level by means of the Hartree-Fock and second order Moller-Plesset perturbation energy calculations using a 6-31G(d) basis set. The results of the present work suggest that the bulky norbornane structure induces two kinds of conformational constraints on the residues. On one hand, those of a steric nature directly imposed by the bicycle on the peptide backbone and, on the other hand, those that limit the orientations attainable by the phenyl ring which, in turn, reduces further the flexibility of the peptide backbone. A comparative analysis of the conformational profile of the phenylnorbornane amino acids with that of the norbornane amino acids devoid of the beta-phenyl substituent suggests that the norbornane system hampers the residue to adopt extended conformations in favour of C7-like structures. However, the bicycle itself does not impart a clear preference for any of the two possible C7 minima. It is the aromatic side chain, which is forced to adopt an almost eclipsed orientation, that breaks this symmetry introducing a marked preference for a single region of the (phi, psi) conformational space in each of the phenylalanine norbornane analogues investigated.     

Chemical ribosylation of 5-substituted 1,2,4-triazole-3-carboxylates

The chemical ribosylation pathways of 5-substituted-1,2,4-triazole-3-carboxylates are discussed. For the products of the chemical synthesis of the 3(5)-alkyl- or 3(5)-aryl-substituted ribavirin analogues the anomer configuration and isomer composition were determined.     

Synthesis of dihydroquinopimaric acid conjugates with amino acids

Synthesis of dihydroquinopimaric acid amides and their 2β-succinyl and 2β-phthalyl derivatives containing residues of amino acids was carried out for the first time. Antiviral properties of the compounds synthesized were investigated.     

Synthesis of α- and β-N-oxalyl-l-α,β-diaminopropionic acids and their isolation from seeds of Lathyrus sativus

The α- and β-N-oxalyl derivatives of l-α,β-diaminopropionic acid have been chemically synthesized and also isolated from seed extracts of Lathyrus sativus. Chemical and physical properties of the natural and synthetic isomers were in good agreement. The toxicity of the α-isomer to chicks was evaluated and compared with that of the β-isomer.     

Design and synthesis of chiral peptidic nucleic acids

Summary Due to the increasing interest in the use of oligonucleotide analogues as antisense and antigene drugs, we designed a chiral analogue constituted of a peptidic frame bearing nucleobases in suitable positions (C-PNA). We recently reported the synthesis of four nonnatural α-amino acids with the DNA bases in the lateral chain. In this paper we present an improved synthesis of the Fmoc monomers and their polymerisation to polypeptidic oligonucleotide analogues using a modification of the standard protocol for solid phase peptide synthesis.     

Design and synthesis of chiral peptidic nucleic acids

Due to the increasing interest in the use ofoligonucleotide analogues as antisense and antigenedrugs, we designed a chiral analogue constituted of apeptidic frame bearing nucleobases in suitablepositions (C-PNA). We recently reported the synthesisof four nonnatural -amino acids with the DNAbases in the lateral chain. In this paper we presentan improved synthesis of the Fmoc monomers and theirpolymerisation to polypeptidic oligonucleotideanalogues using a modification of the standardprotocol for solid phase peptide synthesis.     

l-threo- and l-erythro-2-amino-3-hydroxyhex-4-ynoic acids: New amino acids from Tricholomopsis rutilans

2-Amino-3-hydroxyhex-4-ynoic acid, reported previously from Tricholomopsis rutilans, was shown to be a mixture of its threo- and erythro-forms. They were separated from each other and characterized by elementary analysis, optical rotation, TLC, IR, NMR spectra, catalytic hydrogenation, and by chemical synthesis. Their configurations were determined by the comparison of their hydrogenation products with known threo- and erythro-2-amino-3-hydroxyhexanoic acids.     

Thia-analogues of amino acids synthesis of peptide derivatives containing 3-thia-analogues of amino acids

Summary N-Protected dipeptides containing L-3-thia-analogues of phenylalanine, p-nitro-phenylalanine, lysine and leucine respectively were prepared applying an enantioselective enzymatic reaction step. Racemic synthetic intermediates of the type acyl-NH-CH(R¹)-CO-D,L-NH-CH(S-R²)-COOBzl were selectively deprotected at the C-terminus by enzymatic hydrolysis using thermitase or trypsin.Abbreviations Ac acetyl - AcOEt ethyl acetate - AcOH acetic acid - Boc tert.-butyloxycarbonyl - Bz benzoyl - Bzl benzyl - DMF dimethyl-formamide - EtOH ethanol - THF tetrahydrofuran - Z benzyloxycarbonyl Dedicated to Prof. D. Cavallini at the occasion of his 75th birthday.     

Synthesis and biological activity of new glycyrrhizic acid conjugates with amino acids and dipeptides

New glycyrrhizic acid (GA) conjugates were synthesized with the use of tert-butyl esters of amino acids or benzyl esters of dipeptides; they contained two residues of L-amino acids (Met, Phe, Pro, and Ile or dipeptides Gly-Leu and Gly-Phe). Activation of GA carboxy groups was carried out with the help of N-hydroxysuccinimide, N,N′-dicyclohexylcarbodiimide, or N-hydroxybenzotriazole with dicyclohexylcarbodiimide. A proline-containing GA derivative is a low-toxic substance; it raises the level of agglutinins by 3.7 times in the blood of mice and 3 times that of hemolysins compared with the control. Dipeptide GA derivatives possess an expressed anti-HIV-1 activity in cultures of MT-4 cells and are 90-70 times less cytotoxic than azidothymidine. The selectivity index of the compounds exceeds those of GA by 110 and 34 times, respectively.     

Synthesis of novel acetylene-containing amino acids

Summary.  Novel synthetic procedures for the modification of non-proteinogenic acetylene-containing amino acids have been developed. The functionalization either proceeds via zinc/copper-mediated introduction of alkyl substituents, or via tungsten-catalyzed ring-closing alkyne metathesis reactions. Received March 28, 2002 Accepted October 3, 2002 Published online December 18, 2002 Acknowledgements These investigations are supported (in part) by the Netherlands Research Council for Chemical Sciences (CW) with financial aid from the Netherlands Technology Foundation (STW). Authors' address: Floris P. J. T. Rutjes, Prof. Dr., Department of Organic Chemistry, University of Nijmegen, Toernooiveld 1, NL-6525 ED Nijmegen, The Netherlands, E-mail: rutjes@sci.kun.nl  2, selected data: ¹H NMR (300 MHz, CDCl₃) δ 5.32 (d, J = 7.7 Hz, 1H), 4.44–4.40 (m, 1H), 3.76 (s, 3H), 2.75–2.73 (d, J = 5.0 Hz, 2H), 1.44 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 171.0, 155.0, 80.3, 74.6, 52.6, 51.9, 41.7, 28.3, 24.0; mp = 55°C.  Typical procedure for 5: zinc dust (116 mg, 1.408 mmol) was weighed into a 20 mL flask, which was repeatedly evacuated (with heating using a heat gun) and flushed with argon. Dry DMF (0.5 mL, distilled from CaH₂) and 1,2-dibromoethane (9.2 μL, 0.106 mmol) were added and the flask was heated at 80°C for 40 min. The reaction mixture was allowed to cool to room temperature, trimethylsilyl chloride (4 μL, 0.035 mmol) was added and the resulting mixture was stirred vigorously for a further 30 min under argon. Iodocyclohexane (69 μl, 0.528 mmol) was added and stirred at room temperature for 3 h more after which stirring was ceased to settle the zinc. CuCN (41 mg, 0.458 mmol) and LiCl (40 mg, 0.915 mmol) were heated to 150°C for 2 h and cooled to room temperature. Addition of DMF (1 mL) formed a soluble CuCN·2LiCl complex within 5 min. After cooling the Cu-complex to −15°C, the organozinc reagent was added dropwise followed by the bromoacetylene 2 (116 mg, 0.352 mmol). The mixture was allowed to stir overnight at room temperature. Water was added and the suspension was extracted using heptane, washed with brine, dried (MgSO₄) and concentrated. Purification using flash column chromatography (10% EtOAc in heptane) yielded 5 (100 mg, 81%) as a colorless oil. 5: IR ν 3355, 2929, 2852, 2359, 2337, 1749, 1717, 1498, 1447, 1365, 1251, 1181, 1060; ¹H NMR (300 MHz, CDCl₃) δ 5.28 (d, J = 7.7 Hz, 1H), 4.43–4.38 (m, 1H), 3.73 (s, 3H), 2.69–2.63 (m, 2H), 2.13 (m, 1H), 1.73–1.22 (m, 10H), 1.43 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 171.4, 155.0, 88.1, 79.9, 73.8, 52.3, 32.7, 32.7, 28.8, 28.2, 25.8, 24.6, 23.1; HRMS (EI): calculated for C₁₇H₂₇NO₄ 309.1940, found 309.1937.  A solution of the tungsten catalyst (7 mg, 10 mol%) in C₆H₅Cl (2 mL) was treated with a solution of 14 (49.0 mg, 0.120 mmol) in C₆H₅Cl (5.0 mL) under an argon atmosphere and the resulting mixture was heated at 80°C for 3 h. Evaporation followed by flash column chromatography (80% EtOAc in heptane) afforded 15 (21.0 mg, 50%; 64% after correction for starting material) and 14 (16 mg, 33%) as colorless oils. 15: [α]_D =–14.6 (c = 1, CH₂Cl₂); IR ν 3313, 2931, 2865, 2249, 1744, 1667, 1520, 1366, 1170; ¹H NMR (400 MHz, CDCl₃) δ 7.14 (d, J = 8.7 Hz, 1H), 6.08 (d, J = 8.3 Hz, 1H), 4.78 (q, J = 6.8 Hz, 1H), 4.27 (q, J = 7.9 Hz, 1H), 3.73 (s, 3H), 2.17–2.15 (m, 4H), 2.07–1.96 (m, 2H), 1.79–1.52 (m, 4H), 1.45 (s, 9H), 0.89–0.83 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 173.2, 171.8, 155.8, 80.4, 80.2, 79.3, 53.8, 52.5, 51.2, 32.8 (2×), 28.1, 24.6, 24.2, 18.3 (2×); HRMS (EI): calculated for C₁₈H₂₈N₂O₅