Solid Phase Synthesis Without Repetitive Acidolysis

Meienhofer, Johannes; Waki, Michinori; Heimer, Edgar P.; Lambros, Theodore; Makofske, Raymond; Chang, Chi‐Deu

doi:10.1111/j.1399-3011.1979.tb01847.x

Cited by 300 publications

(56 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results compare favorably with the best values reported in the literature (26,33,37,5556) with N"-amino protecting groups such as Boc, Bpoc, and Fmoc. Equally relevant, with otherwise identical resins and reagents of comparable purity in our hanh, the results of Dts are slightly better than those with Fmoc (24), and appreciably better than those with Boc.++.…”

Section: Figuresupporting

confidence: 86%

“…Aminomethylcopoly-(styrene-1 %-diviny1benzene)-resin was from Peptides International (Louisville, Kentucky) and had a substitution level of 0.62 mmol/g, or was made in this laboratory according to Mitchell et al (28) and had a substitution level of 0.18 mmol/g by picric acid titration (71). A (4-hydroxymethylphenoxy)methylcopoly(styrene-1 %-diviny1benzene)-resin (palkoxybenzyl alcohol-resin) was from Chemical Dynamics (South Plainfield, NJ) and had a substitution level of 1 .O mmol/g; it was converted according to Meienhofer et al (33) with Fmoc-valine, DCC, and DMAP (1.3 equiv. each) in CH,CI,-DMF (4:1), overnight at 25", into an Fmoc-Val-resin determined to contain 0.70mmol Val/g by amino acid analysis after Fmoc removal.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Mild, orthogonal solid‐phase peptide synthesis: use of Nα‐dithiasuccinoyl (Dts) amino acids and N‐(iso‐propyldithio)carbonylproline, together with p‐alkoxybenzyl ester anchoring linkages*

Alberício

Bárány

1987

International Journal of Peptide and Protein Research

View full text Add to dashboard Cite

Several Nα‐dithiasuccinoyl (Dts) amino acids (1) have been esterified without race‐mization by use of either N,N'‐dicyclohexylcarbodiimide or 1‐(3‐dimethylamino‐propyl)‐3‐ethylcarbodiimide hydrochloride, each in the presence of 4‐dimethylaminopyridine (0.1 equiv.), to 2, 4, 5‐trichlorophenyl 4′‐hydroxymethylphenoxyacetate (10) or the corresponding propionate (11). The resultant handle derivatives (8,9) were purified and then quantitatively attached onto aminomethyl supports by couplings using as solvent N,N‐dimethylformamide containing 1‐hydroxybenzotriazole (0.1 M). This methodology facilitates anchoring of Dts‐amino acids as p‐alkoxybenzyl esters, which can be cleaved in good yields by trifluoroacetic acid‐dichloromethane (1:1) at 25°. Model experiments established that quantitative thiolytic removal (>99.8%) of the Dts group occurs with (i) β‐mercaptoethanol (0.5M)‐N,N‐diisopropylethylamine (0.5M) in dichloromethane, 2 times 2min; (ii) N‐methylmercaptoacetamide (0.5M)‐N‐methylmorpholine (0.5M) in dichloromethane, 2 times 2min; and (iii) N‐methylmercaptoacetamide (0.5M)‐1‐hydroxybenzotriazole (0.1M) in N,N‐dimethylformamide, 2 times 2 min. The susceptibility of the Dts functionality to nucleophiles was also defined, including demonstration of tertiary amine‐catalyzed hydantoin formation from Dts‐dipeptidyl units, but side reactions from these processes are entirely avoided under appropriate conditions relevant to peptide synthesis. These observations were exploited to devise efficient, racemization‐free solid‐phase syntheses of a number of model peptides in high yields and purities, including L‐leucyl‐L‐alanylglycyl‐L‐valine, H‐Gly6‐Val‐OH, H‐Met‐Ala‐Gly‐OH, methionine‐enkephalin, and bradykinin.

show abstract

Section: Figuresupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Mild, orthogonal solid‐phase peptide synthesis: use of Nα‐dithiasuccinoyl (Dts) amino acids and N‐(iso‐propyldithio)carbonylproline, together with p‐alkoxybenzyl ester anchoring linkages*

Alberício

Bárány

1987

International Journal of Peptide and Protein Research

View full text Add to dashboard Cite

show abstract

“…Proteins were prepared using standard FMOC chemistry 45 by the University of Texas, Southwestern Medical Center (Dallas, TX). Proteins were purified using prep scale reverse phase HPLC, buffer A: 0.1% trifluoroacetic acid in water, buffer B: 0.1% trifluoroacetic acid in acetonitrile.…”

Section: Methodsmentioning

confidence: 99%

Partial High-Resolution Structure of Phosphorylated and Non-phosphorylated Leucine-Rich Amelogenin Protein Adsorbed to Hydroxyapatite

Masica¹,

Gray²,

Shaw

2011

J. Phys. Chem. C

View full text Add to dashboard Cite

The formation of biogenic materials requires the interaction of organic molecules with the mineral phase. In forming enamel, the amelogenin proteins contribute to the mineralization of hydroxyapatite (HAp). Leucine-rich amelogenin protein (LRAP) is a naturally occurring splice variant of amelogenin that comprises amelogenin's predicted HAp binding domains. We determined the partial structure of phosphorylated and non-phosphorylated LRAP variants bound to HAp using combined solid-state NMR (ssNMR) and ssNMR-biased computational structure prediction. New ssNMR measurements in the N-terminus indicate a largely extended structure for both variants, though some measurements are consistent with a partially helical N-terminal segment. The N-terminus of the phosphorylated variant is found to be consistently closer to the HAp surface than the non-phosphorylated variant. Structure prediction was biased using 21 ssNMR measurements in the N- and C-terminus at five HAp crystal faces. The predicted fold of LRAP is similar at all HAp faces studied, regardless of phosphorylation. Largely consistent with experimental observations, LRAP's predicted structure is relatively extended with a helix-turn-helix motif in the N-terminal domain and some helix in the C-terminal domain, and the N-terminal domain of the phosphorylated variant binds HAp more closely than the N-terminal domain of the non-phosphorylated variant. Predictions for both variants show some potential binding specificity for the {010} HAp crystal face, providing further support that amelogenins block crystal growth on the a and b faces to allow elongated crystals in the c-axis.

show abstract

“…Solid-phase synthesis was carried out in plastic syringes with polyethylene frits (20 mm) obtained from Applied Separations Inc. Resin loading was determined by measuring the UV absorbance of the piperidine-dibenzofulvene adduct (l max = 300 nm). [20] Analytical thin-layer chromatography (TLC) and R f values were determined on Merck precoated silica-gel 60 F-254 (0.25 mm) plates. Spots were visualized with UV light, ninhydrin, or Cl 2 /N,N,N',N'-tetramethyl-4,4'-diaminodiphenylmethane (TDM).…”

Section: Methodsmentioning

confidence: 99%

Spacer Effects on in vivo Properties of DOTA‐Conjugated Dimeric [Tyr3]Octreotate Peptides Synthesized by a “Cu^I‐Click” and “Sulfo‐Click” Ligation Method

Yim¹,

Wildt²,

Dijkgraaf³

et al. 2011

ChemBioChem

View full text Add to dashboard Cite

We report on the SSTR2-binding properties of a series of four dimeric [Tyr3]octreotate analogues with different spacer lengths (nine, 19, 41, and 57 atoms) between the peptides. Two analogues (9 and 57 atoms) were selected as precursors for the design, synthesis, and biological evaluation of DOTA-conjugated dimeric [Tyr3]octreotate analogues for tumor targeting. These compounds were synthesized by using a two-stage click ligation procedure: a Cu(I) -catalyzed 1,3-dipolar cycloaddition ("copper-click" reaction) and a thio acid/sulfonyl azide amidation ("sulfo-click" reaction). The IC(50) values of these DOTA-conjugated [Tyr3]octreotate analogues were comparable, and internalization studies showed that the nine-atom (111) In-DOTA-labeled [Tyr3]octreotate dimer had rapid and high receptor binding. Biodistribution studies with BALB/c nude mice bearing subcutaneous AR42J tumors showed that the (111) In-labeled [Tyr3]octreotate dimer (nine atoms) had a high tumor uptake at 1 h p.i. (38.8 ± 8.3 % ID g(-1) ), and excellent tumor retention at 4 h p.i. (40.9 ± 2.5 % ID g(-1) ). However, the introduction of the extended hydrophilic 57 atoms spacer led to rapid clearance from the circulation; this limited tumor accumulation of the radiotracer (21.4 ± 4.9 % ID g(-1) at 1 h p.i.). These findings provide important insight on dimerization and spacer effects on the in vivo properties of DOTA-conjugated [Tyr3]octreotate dimers.

show abstract

Solid Phase Synthesis Without Repetitive Acidolysis

Cited by 300 publications

References 37 publications

Mild, orthogonal solid‐phase peptide synthesis: use of Nα‐dithiasuccinoyl (Dts) amino acids and N‐(iso‐propyldithio)carbonylproline, together with p‐alkoxybenzyl ester anchoring linkages*

Mild, orthogonal solid‐phase peptide synthesis: use of Nα‐dithiasuccinoyl (Dts) amino acids and N‐(iso‐propyldithio)carbonylproline, together with p‐alkoxybenzyl ester anchoring linkages*

Partial High-Resolution Structure of Phosphorylated and Non-phosphorylated Leucine-Rich Amelogenin Protein Adsorbed to Hydroxyapatite

Spacer Effects on in vivo Properties of DOTA‐Conjugated Dimeric [Tyr3]Octreotate Peptides Synthesized by a “Cu^I‐Click” and “Sulfo‐Click” Ligation Method

Contact Info

Product

Resources

About

Solid Phase Synthesis Without Repetitive Acidolysis

Cited by 300 publications

References 37 publications

Mild, orthogonal solid‐phase peptide synthesis: use of Nα‐dithiasuccinoyl (Dts) amino acids and N‐(iso‐propyldithio)carbonylproline, together with p‐alkoxybenzyl ester anchoring linkages*

Mild, orthogonal solid‐phase peptide synthesis: use of Nα‐dithiasuccinoyl (Dts) amino acids and N‐(iso‐propyldithio)carbonylproline, together with p‐alkoxybenzyl ester anchoring linkages*

Partial High-Resolution Structure of Phosphorylated and Non-phosphorylated Leucine-Rich Amelogenin Protein Adsorbed to Hydroxyapatite

Spacer Effects on in vivo Properties of DOTA‐Conjugated Dimeric [Tyr3]Octreotate Peptides Synthesized by a “CuI‐Click” and “Sulfo‐Click” Ligation Method

Contact Info

Product

Resources

About

Spacer Effects on in vivo Properties of DOTA‐Conjugated Dimeric [Tyr3]Octreotate Peptides Synthesized by a “Cu^I‐Click” and “Sulfo‐Click” Ligation Method