Comparison of FK‐506, Rapamycin, Ascomycin, and Cyclosporine in Mouse Models of Host‐versus‐Graft Disease and Heterotopic Heart Transplantation

Mollison, Karl W.; Fey, Thomas A.; Krause, R. A.; Thomas, Veena A.; Mehta, Ajita; Luly, Jay R.

doi:10.1111/j.1749-6632.1993.tb35851.x

Cited by 13 publications

(12 citation statements)

References 3 publications

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“…The NOEs are nearly identical in the spectra of the two complexes. Similarly, the 4D [ 13 C, 1 H, 13 C, 1 H] NOE data is the same in the two complexes (see Supporting Information). Thus the NOE data indicates that the complexes formed between FKBP12 and ascomycin and the C24 deoxy analogue are structurally very similar.…”

Section: Resultsmentioning

confidence: 72%

“…11 Transformation to the ∆ 23,24 -enone was selectively and efficiently achieved by using p-toluenesulfonic acid in toluene at 75-80 °C. Evidence for formation of the dehydration product, which like ascomycin and FK506 exists as a mixture of amide rotamers, was obtained from the 13 ∆ 23,24 -enone was then accomplished by exposure to hydrogen gas in the presence of palladium on activated carbon at room temperature. The 13 C and 1 H NMR spectra obtained were consistent with the reduction of the enone moiety and retention of the two trisubstituted olefins.…”

Section: Resultsmentioning

confidence: 99%

“…The immunosuppressive activities of these compounds were examined in an in vitro model of allogeneic T lymphocyte activation (MLR) 3 as well as in an in vivo model of lympho-proliferation, the popliteal lymph node (PLN) 13 assay. In the MLR assay, human peripheral blood mononuclear leukocytes (PBL) were exposed to a pool of mitomycin C-treated PBL.…”

Section: Resultsmentioning

confidence: 99%

“…To further investigate possible differences in the conformation of FKBP12 when bound to the two ligands, a 4D [ 13 C, 1 H, 15 N, 1 H] NOESY and a 4D [ 13 C, 1 H, 13 C, 1 H] NOESY was recorded on both complexes. Two 2D ω 1 , ω 2 slices from the 4D [ 13 C, 1 H, 15 N, 1 H] NOESY spectra at the same 15 N (ω 3 ) and 1 H (ω 4 ) amide frequencies of Gln-53 and Glu-54 in both complexes were compared.…”

Section: Resultsmentioning

confidence: 99%

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Retention of Immunosuppressant Activity in an Ascomycin Analogue Lacking a Hydrogen-Bonding Interaction with FKBP12

Wiedeman¹,

Fesik²,

Petros³

et al. 1999

J. Med. Chem.

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C24-Deoxyascomycin was prepared in a two-step process from ascomycin and evaluated for its immunosuppressant activity relative to ascomycin and FK506. An intermediate in the synthetic pathway, Delta(23,24)-dehydroascomycin, was likewise evaluated. Despite lacking the hydrogen-bonding interactions associated with the C24-hydroxyl moiety of ascomycin, C24-deoxyascomycin was found to be equipotent to the parent compound both in its immunosuppressive potency and in its interaction with the immunophilin, FKBP12. Conversely, Delta(23,24)-dehydroascomycin which also lacks the same hydrogen-bonding interactions did not exhibit this potency. NMR studies were conducted on the FKBP12/C24-deoxyascomycin complex in an attempt to understand this phenomenon at the molecular level. The NMR structures of the complexes formed between FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not important for complex formation.

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Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Retention of Immunosuppressant Activity in an Ascomycin Analogue Lacking a Hydrogen-Bonding Interaction with FKBP12

Wiedeman¹,

Fesik²,

Petros³

et al. 1999

J. Med. Chem.

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show abstract

“…Recipients were killed on day 4 and PLN from both hind limbs from vehicle control rats, or the right PLN from drug-treated rats, were dissected free and weighed individually on a microbalance. The average weight of PLN from the left leg of vehicle-treated animals was used as the background control (Mollison et al, 1993), and percentage inhibition was calculated using the…”

Section: Rat Popliteal Lymph Node (Pln) Hyperplasia Assay Spleens Frommentioning

confidence: 99%

A Macrolactam Inhibitor of T Helper Type 1 and T Helper Type 2 Cytokine Biosynthesis for Topical Treatment of Inflammatory Skin Diseases1

Mollison

Fey

Gauvin

et al. 1999

Journal of Investigative Dermatology

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T lymphocytes play a critical part in inflammatory skin diseases but are targeted by available therapies that have only partial efficacy, significant side-effects, or both. Because psoriasis, atopic dermatitis, and allergic contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam ascomycin analog, ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple cytokines in human peripheral blood leukocytes which have been found in human skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-5) cytokines. ABT-281 was shown to have potent topical activity (ED50 = 0.6% in acetone/olive oil) in a stringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/olive oil over 25% of the body surface in swine resulted in undetectable blood levels. Compared with a wide potency range of topical corticosteroids in clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent steroids such as clobetasol propionate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance following uptake into the bloodstream, and its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis.

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Secondary Metabolites, Antibiotics

Strohl

1999

Encyclopedia of Bioprocess Technology

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Comparison of FK‐506, Rapamycin, Ascomycin, and Cyclosporine in Mouse Models of Host‐versus‐Graft Disease and Heterotopic Heart Transplantation

Cited by 13 publications

References 3 publications

Retention of Immunosuppressant Activity in an Ascomycin Analogue Lacking a Hydrogen-Bonding Interaction with FKBP12

Retention of Immunosuppressant Activity in an Ascomycin Analogue Lacking a Hydrogen-Bonding Interaction with FKBP12

A Macrolactam Inhibitor of T Helper Type 1 and T Helper Type 2 Cytokine Biosynthesis for Topical Treatment of Inflammatory Skin Diseases1

Secondary Metabolites, Antibiotics

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