Josiane Thierry

Manipulation of the cabboxyl groups of α-amino-acids and peptides using radical chemistry based on esters of N-hydroxy-2-thiopyridone

Abstract Photolysis of α-amino-acid or peptide esters derived from N -hydroxy-2-thiopyridone in the presence of t -butylthiol affords the expected decarboxylation products in good yield. The reaction can be applied to the α-carboxyl or to the side chain carboxyl of glutamic and aspartic acids and thus permits the preparation of a number of useful synthons. Photolysis of side chain esters in the presence of a suitable halogen atom transfer reagent gives halides often in good yield and, especially in the case of aspartic acid derivatives, without racemisation.

The free radical chemistry of carboxylic esters of 2-selenopyridine-N-oxide: a convenient synthesis of (L)-vinylglycine

Abstract Optically pure (L)-vinylglycine has been synthesised by two different methods. The first of these involves protected (L)-glutamate esters of N -hydroxy-2-seleno-pyridine. Such esters are shown to undergo the same decarboxylotive rearrangement as their thio-analogues. Oxidative elimination of the selenopyridine residue with ozone, and with the aid of hex-1-ene as sacrificial olefin for the work-up, gave the desired (L)-vinylglycine derivatives. Similarly, the modified Hunsdiecker reaction on the terminal carboxyl of suitably protected (L)-glutamic derivatives gave the nor-bromide which readily afforded the corresponding phenylselenides on treatment with phenylselenide anion. The sequence was then as above. Using the methyl ester with corbobenzyloxy protection for the amino-function an overall yield of crystalline optically pure (L)-vinylglycine of about 45% was obtained by either route.

Synthesis of novel α-amino-acids and derivatives using radical chemistry: synthesis of L- and D-α-amino-adipic acids, L-α

Abstract Radicals generated by photolysis (W light) of suitably protected amino-acid derivatives of N -hydroxy-2-thiopyridone add efficiently to activated olefins to afford satisfactory yields of adducts. Oxidation of the thiopyridyl residue to sulphoxide and thermal elimination afford excellent yields of the corresponding α, β-unsaturated derivatives. Lateral chain decarboxylation of suitably protected aspartic and glutamic acids provides convenient syntheses of L-α- and D-α-aminoadipic acids, of L -α-aminopimelic acid and of L -α-amino-δ- trans -dehydropimelic acid.

Concise syntheses of L-selenomethionine and of L-selenocystine using radical chain reactions

Abstract L-Selenomethionine and L-selenocystine were prepared in high overall yields from protected L-glutamic and L-aospartic acid derivatives respectively. Irradiation of the mixed anhydrides (esters) derived from 4 (e.g. 15 ) in the presence of dimethyldiselenide provided the protected L-selenomethionine 16 directly. We have shown that triselenocyanide Se3(CN)2 can serve as an efficient selenocyanating agent for radicals; the selenocyanide group is a good precursor for the diselenide moiety of L-selenocystine.

Captopril inhibits the proliferation of hematopoietic stem and progenitor cells in murine long-term bone marrow cultures.

Drugs used mainly for the treatment of hypertension, such as angiotensin I‐converting enzyme (ACE) inhibitors, can cause pancytopenia. The underlying cause of this side effect remains unknown. In the present study, long‐term bone marrow cultures (LTBMCs) were utilized to evaluate the role of captopril (D‐3‐mercapto‐2‐methylpropionyl‐L‐proline), one of the potent ACE inhibitors, in regulating hematopoietic stem/progenitor cell proliferation. Captopril (10−6 M final concentration) was added to LTBMCs at the beginning of the culture period and at weekly intervals for six weeks. There was no toxicity to the bone marrow cells as measured by the unchanged cell number in the nonadherent layer during the whole culture period, and there was an increased cellularity of the adherent layer at the end of the six weeks of treatment. However, captopril decreased the proportion of granulocyte‐macrophage colony‐forming cells (GM‐CFCs) in S phase at weeks 2 and 3 as well as that of high proliferative potential colony‐forming cells (HPP‐CFCs) at week 3 in the nonadherent layer. There was no change in the kinetics of the GM‐CFCs and HPP‐CFCs present in the adherent layer. These results suggest that captopril causes myelosuppression by inhibiting hematopoietic cell proliferation of progenitor and stem cells rather than depleting cells of the bone marrow microenvironment.

2-phenyl isopropyl esters as car☐yl terminus protecting groups in the fast synthesis of peptide fragments

The esters of Fmoc aminoacids derived from 2-phenylisopropanol have been prepared by using 2-phenylisopropyltrichloroacetimidate 1. They prevent diketopiperazine formation during amino deprotection of dipeptides and can be cleaved in the presence of Boc and O-But. They are thus well suited for the protection of C-terminus when a Fmoc strategy is used to build up peptide fragments.

Reductive radical decarboxylation of amino-acids and peptides

Radicals generated from N-protected α-amino-acids by photolysis of their N-hydroxypyridine-2-thione esters at room temperature are efficiently quenched by t-butyl thiol to give decarboxy-acids; comparable reactions have been carried out on the side chain carboxy groups of suitably protected aspartic and glutamic acids.

Synthesis of 2S, 3aS, 7aS- and of 2S, 3aR, 7aR-Perhydroindole-2-carboxylic acid derivatives from L-aspartic acid

Abstract Using carbon radicals generated by photolysis of N -hydroxy-2-thio-pyridone esters (mixed anhydrides) the chiral centre of L -aspartic acid has been easily incorporated into the perhydroindole structure of the title compounds.

2-Phenyl isopropyl and t-butyl trichloroacetimidates: Useful reagents for ester preparation of N-protected amino acids under neutral conditions

2-Phenylisopropyl and t-butyl trichloroacetamidates 1 and 2 are useful reagents for the esterification of N-protected aminoacids under mild neutral conditions. In the case of hydroxyl-containing amino acids, dialkylation occurs but no selectivity could be obtained.

Synthesis of chimeric tetrapeptide-linked cholic acid derivatives: impending synergistic agents

Tetrapeptides derived from glycine and beta-alanine were hooked at the C-3beta position of the modified cholic acid to realize novel linear tetrapeptide-linked cholic acid derivatives. All the synthesized compounds were tested against a wide variety of microorganisms (gram-negative bacteria, gram-positive bacteria and fungi) and their cytotoxicity was evaluated against human embryonic kidney (HEK293) and human mammary adenocarcinoma (MCF-7) cell lines. While relatively inactive by themselves, these compounds interact synergistically with antibiotics such as fluconazole and erythromycin to inhibit growth of fungi and bacteria, respectively, at 1-24 microg/mL. The synergistic effect shown by our novel compounds is due to their inherent amphiphilicity. The fractional inhibitory concentrations reported are comparable to those reported for Polymyxin B derivatives.