| 1. |
- Carlsson, Anna-Carin, 1976, et al.
(författare)
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Microwave-assisted synthesis of the Schollkopf chiral auxiliaries: (3S)- and (3R)-3,6-dihydro-2,5-diethoxy-3-isopropyl-pyrazine
- 2006
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Ingår i: Tetrahedron Letters. - : Elsevier BV. - 0040-4039. ; 47:29, s. 5199-5201
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Tidskriftsartikel (refereegranskat)abstract
- A practical and efficient methodology for the laboratory scale preparation of Schollkopf's bis-lactim ether chiral auxiliaries (3S)- and (3R)-3,6-dihydro-2,5-diethoxy-3-isopropyl-pyrazine has been developed. The key step is the preparation of the 2,5diketopiperazine derivative by microwave-assisted heating in water. The protocol avoids reactions at low temperature and the use of high boiling solvents. Only inexpensive and readily available starting materials are required. The bis-lactim ethers were produced in high yields on a multigram scale. (c) 2006 Elsevier Ltd. All rights reserved.
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| 2. |
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| 3. |
- Gullbo, Joachim, et al.
(författare)
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Antitumor activity of the novel melphalan containing tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester) : Comparison with its m-L-sarcolysin analogue P2
- 2003
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 2:12, s. 1331-1339
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Tidskriftsartikel (refereegranskat)abstract
- Peptichemio (PTC), a mixture of six oligopeptides all containing m-L-sarcolysin, has previously shown impressive results in clinical trials. The tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester) has been suggested as the main contributor to PTC activity. In contrast to its analogue melphalan, m-L-sarcolysin never reached clinical use. To allow a direct comparison, the corresponding melphalan containing tripeptide J3 (L-prolyl-L-melphalanyl-p-L-fluorophenylalanine ethyl ester) was synthesized and its activity was compared with that of P2; the activities of melphalan and m-L-sarcolysin were studied in parallel. Cytotoxic activity in human tumor cell lines and some fresh human tumor specimens were analyzed as well as effects on cellular metabolism, macromolecular synthesis, and preliminary evaluation of the cell death characteristics. The results show that melphalan and m-L-sarcolysin display similar activity in these systems and that the tripeptides were more active than their parent monomers. Surprisingly however, the melphalan containing tripeptide J3 demonstrated a significantly more rapid and stronger activity than the m-L-sarcolysin analogue P2. Finally, the in vivo toxicity and activity of melphalan and J3 were investigated in mice bearing human leukemia cells in s.c. fibers. The in vitro results seem translatable into the in vivo situation, demonstrating better antileukemic effect of J3 but similar side effects as melphalan.
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| 4. |
- Gullbo, Joachim, et al.
(författare)
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Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo.
- 2004
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Ingår i: Investigational new drugs. - 0167-6997. ; 22:4, s. 411-20
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Tidskriftsartikel (refereegranskat)abstract
- The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters. Melphalan and J1 appeared equitoxic with no statistically significant differences. Subsequently a mouse hollow fiber model was employed with subcutaneous implantation of fibers containing human tumor cells. Three different human tumor cell lines as well as two samples of primary human tumor cells (ovarian carcinoma and chronic lymphatic leukemia) were used as tumor models. At the dose level tested there was a marked and statistically significant decrease in both T-cell leukemia CCRF-CEM and small cell lung cancer NCI-H69 tumor cell growth and viability in response to J1 as compared with both placebo and melphalan treated groups. In primary ovarian carcinoma cells only J1 treatment resulted in significant tumor regression (net cell kill). In summary the results indicate that, despite an expected short half time in the blood circulation, the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation. At equal doses of alkylating units J1, compared to melphalan, was more active in the mouse hollow-fiber model, but showed similar general toxicity.
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| 5. |
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| 6. |
- Gullbo, Joachim, et al.
(författare)
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Structure activity relationship for alkylating dipeptide nitrogen mustard derivatives
- 2003
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Ingår i: Oncology Research. - : Computers, Materials and Continua (Tech Science Press). - 0965-0407 .- 1555-3906. ; 14:3, s. 113-132
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Tidskriftsartikel (refereegranskat)abstract
- The strategy of using small peptides for effective targeting of tumor cells in chemotherapy has proven beneficial. Recently we showed that J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), an alkylating nitrogen mustard-containing dipeptide, exhibited strong cytotoxic activity in fresh human tumor samples in addition to rapid and pronounced inhibition of macromolecular syntheses and cellular respiration in the human tumor lymphoma cell line U-937 GTB. In this study, an additional series of 17 nitrogen mustard-containing dipeptides has been synthesized and analyzed for cytotoxic activity in a panel of 10 human tumor cell lines. The results were compared to the single amino acid mustard derivative melphalan and its ethyl and isopropyl esters. Also P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester), a tripeptide that previously has shown impressive effects in human tumor cells, was used as reference. The tested compounds displayed various activities in the different cell lines but also showed a high correlation, indicating a similar mechanism of action. Factors like amino acid composition, amino acid sequence, modifications of the C- and N-termini, and to a minor extent the lipophilicity of the dipeptide derivatives appear to influence the in vitro activity. The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities.
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| 7. |
- Jam, Fariba, 1967, et al.
(författare)
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Microwave assisted synthesis of spiro-2,5-diketopiperazines
- 2007
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 63, s. 9881-9889
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Tidskriftsartikel (refereegranskat)abstract
- A general and efficient method for the synthesis of spiro-2,5-diketopiperazines (spiro-DKPs) is described. Cyclization of Boc-protected dipeptides containing spiro-amino acids by microwave assisted heating in water furnished the corresponding spiro-DKPs. The spiro-amino acids were prepared by combining stereoselective alkylation reactions using the Schöllkopf methodology for amino acid construction with Grubbs ring-closing metathesis (RCM) methodology using ruthenium complexes. The RCM reactions and all subsequent transformations to the spiro-DKPs were run with microwave assisted heating, resulting in high yields and short reaction times for all steps.
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| 8. |
- Kvedaraite, Egle, et al.
(författare)
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Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142−/low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142−/low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.
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| 9. |
- Minta, Karolina, et al.
(författare)
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Dynamics of extracellular matrix proteins in cerebrospinal fluid and serum and their relation to clinical outcome in human traumatic brain injury
- 2019
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Ingår i: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 57:10, s. 1565-1573
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Tidskriftsartikel (refereegranskat)abstract
- Brevican, neurocan, tenascin-C and tenascin-R are extracellular matrix proteins present in brain that show increased expression in experimental animal models of brain injury. However, little is known about the dynamics of these proteins in human body fluids, such as cerebrospinal fluid (CSF) and serum, after traumatic brain injury (TBI). The aims of this study were to investigate if matrix proteins in CSF and serum are associated with functional outcome following traumatic brain injury, if their concentrations change over time and to compare their levels between brain injured patients to controls. In total, 42 traumatic brain injury patients, nine healthy controls and a contrast group consisting of 38 idiopathic normal pressure hydrocephalus patients were included. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the concentrations of proteins. Increased concentrations of brevican, tenascin-C and tenascin-R in CSF correlated with unfavourable outcome, with stronger outcome prediction ability compared to other biomarkers of brain tissue injury. CSF brevican, tenascin-R and serum neurocan gradually decreased with time (p = 0.04, p = 0.008, p = 0.005, respectively), while serum tenascin-C (p = 0.01) increased. CSF concentrations of brevican, neurocan and tenascin-R (only in time point 3) after TBI were lower than in the idiopathic normal pressure hydrocephalus group (p < 0.0001, p < 0.0001, and p = 0.0008, respectively). In serum, tenascin-C concentration was higher and neurocan lower compared to healthy controls (p = 0.02 and p = 0.0009). These findings indicate that levels of extracellular matrix proteins are associated with clinical outcome following TBI and may act as markers for different pathophysiology than currently used protein biomarkers. © 2019 Walter de Gruyter GmbH, Berlin/Boston.
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| 10. |
- Tullberg, Marcus, 1974, et al.
(författare)
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Efficient synthesis of 2,5-diketopiperazines using microwave assisted heating
- 2006
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 62:31, s. 7484-7491
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Tidskriftsartikel (refereegranskat)abstract
- In this study a general, efficient and environmentally benign solution phase synthesis of 2,5-diketopiperazines (DKPs) using microwave assisted heating in water is described. A series of 11 structurally different DKPs have been synthesized from dipeptide methyl esters. A range of common laboratory solvents have been tested as well as different reaction times and temperatures. Both classic thermal and microwave assisted heating have been investigated. Microwave assisted heating for 10 min using water as solvent proved, by far, to be the most efficient method of cyclization giving moderate to excellent yields (63-97%) of DKPs. In contrast to other published procedures, this method seems independent of the amino acid sequence. (c) 2006 Elsevier Ltd. All rights reserved.
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