1: J Org Chem. 2004 Aug 20;69(17):5712-9.

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Total syntheses of (+)- and (-)-cacospongionolide B, cacospongionolide e, and related analogues. Preliminary study of structural features required for phospholipase a2 inhibition.

Cheung AK, Murelli R, Snapper ML.

Department of Chemistry, Merkert Chemistry Center, Boston College, 2609 Beacon Street, Chestnut Hill, Massachusetts 02467, USA.

The total syntheses of the antiinflammatory marine sponge metabolites (+)-cacospongionolide B and E are described. The pivotal steps in the synthetic route include a three-step sequence that couples the two main regions of the natural product, as well as generates the side chain dihydropyran ring. The activity of the synthetic analogues against bee venom phospholipase A2 suggests that the cacospongionolides have enantiospecific interactions with the enzyme that may be independent of the gamma-hydroxybutenolide moiety.
Copyright 2004 American Chemical Society

PMID: 15307744 [PubMed - indexed for MEDLINE]

2: J Am Chem Soc. 2002 Oct 2;124(39):11584-5.

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Total syntheses of (+)- and (-)-cacospongionolide B: new insight into structural requirements for phospholipase A(2) inhibition.

Cheung AK, Snapper ML.

Department of Chemistry, Merkert Chemistry Center, Boston College, 2609 Beacon Street, Chestnut Hill, MA 02467, USA.

The first total synthesis of the antiinflammatory marine sponge metabolite (+)-cacospongionolide B has been accomplished in 12 linear steps. The pivotal transformations include a three-step sequence coupling the two main regions of the natural product as well as generating the side chain dihydropyran ring. The activity of the synthetic analogues against bee venom phospholipase A(2) suggests that cacospongionolide B has an enantiospecific interaction with the enzyme that is independent of the gamma-hydroxybutenolide moiety.

PMID: 12296709 [PubMed - indexed for MEDLINE]

3: J Protein Chem. 1992 Jun;11(3):275-80.

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Mast cell degranulating (MCD) peptide analogs with reduced ring structure.

Buku A, Reibman J, Pistelli A, Blandina P, Gazis D.

Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029-6574.

Mast cell degranulating (MCD) peptide, a component of bee venom, is a 22 amino acid peptide with two disulfide bridges. In this first structure-activity study of MCD peptide, three analogs were synthesized and tested: two analogs shortened by omitting sequences 6-10 and 8-13, respectively, and one analog lacking the disulfide bridge between cysteine residues 5 and 19. These analogs were synthesized by solid-phase methods and were compared to MCD peptide in two assays for inflammation: histamine release from mast cells and superoxide anion release from neutrophils. All three analogs produced histamine release, although with only about one fifth of the activity of MCD peptide. Superoxide anion-releasing activity, however, did not parallel histamine release. MCD peptide did not release superoxide anion, while the 6-10 and 8-13 deletion analogs were strong and weak stimulants, respectively, of this anion. CD spectra showed that the secondary structures of the three analogs were very similar to that of MCD peptide, so that a change in secondary structure cannot completely explain the changes in releasing activities. Charge differences between the two deletion analogs and MCD peptide may explain some of the differences in activity. This is the first demonstration that the various activities of MCD peptide can be separated, and provides a lead through which the purported antiinflammatory activity of MCD peptide may possibly be explored in the future.

PMID: 1382440 [PubMed - indexed for MEDLINE]

4: Inflammation. 1986 Jun;10(2):175-82.

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Bee venom melittin blocks neutrophil O2- production.

Somerfield SD, Stach JL, Mraz C, Gervais F, Skamene E.

Bee venom (BV) is used in folk medicine to treat arthritis. It has antiinflammatory effects in animal models of rheumatic disease. We have studied the effects of BV on human neutrophil production of superoxide (O2-) and hydrogen peroxide, finding potent, nontoxic, dose-dependent production inhibition. Melittin, the major fraction of BV (50-70%) shows high-affinity calmodulin binding (Kd 3 nM). Drugs which bind calmodulin, such as trifluoperazine, inhibit O2- production by human neutrophils. For these reasons we have investigated the effect of melittin and other BV peptides on O2- production by human peripheral blood leukocytes. We show that melittin inhibited O2- production both pre- and poststimulation in contrast to other BV fractions which were without effect. Oxygen radicals and their derivatives from inflammatory cells are implicated in the tissue damage occurring during inflammation. The inhibition is due to a direct effect on cells, and not indicator medium, dismutation, toxic or scavenging effects. We propose that melittin may serve as a prototype small (mol wt 1280), cationic, amphipathic, calmodulin-binding, membrane-active, superoxide-production-inhibiting peptide, providing a model for peptides which could have a role in in vivo regulation of radical production.

PMID: 3011670 [PubMed - indexed for MEDLINE]

5: Acta Physiol Pharmacol Bulg. 1985;11(2):50-5.

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Further investigation on the antiinflammatory properties of adolapin--bee venom polypeptide.

Koburova KL, Michailova SG, Shkenderov SV.

Adolapin is a basic polypeptide (M. W. 11500) isolated from bee venom. It showed marked antiinflammatory and analgetic properties and inhibited cyclooxygenase. It was found that adolapin inhibited also the activity of bee venom phospholipase A2 (7 nmole/ml producing about 80% inhibition of 2.5 nmole/ml phospholipase). In addition it inhibited the lipoxygenase from human platelets (4.5 nmole/ml inhibited about 80% of the activity of 0.8 mg protein/ml). Adolapin (20 micrograms/kg) caused an elevation of c-GMP level in rat spleen and brain as well as a decrease of c-AMP in rat spleen. Adolapin was tested by the "tail flick" method which allowed the demonstration of its analgetic action. The partial inhibition of the analgetic effect of adolapin induced by naloxon, proved the participation of a central mechanism of action. Similar to other nonsteroid analgetics, adolapin displayed antipyretic effect (40 micrograms/kg caused an inhibition of the mean temperature rise about 62%.

PMID: 2996298 [PubMed - indexed for MEDLINE]

6: Inflammation. 1984 Dec;8(4):385-91.

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Bee venom inhibits superoxide production by human neutrophils.

Somerfield SD, Stach JL, Mraz C, Gervais F, Skamene E.

Investigation of the antiinflammatory properties of bee venom demonstrates that it inhibits production of superoxide anion by human neutrophils in a potent, selective, nontoxic, dose-dependent fashion, both pre- and poststimulation by particulate and soluble activators of the neutrophil oxidative metabolism burst. The effect is not due to receptor competition, superoxide dismutase, and/or catalase activity, scavenging, or indicator media effects. These findings may explain the antiinflammatory effects of whole bee venom in experimental systems, its widespread use in folk medicine, and lead to the development of potent, new antiinflammatory substances for therapeutic use in man.

PMID: 6097547 [PubMed - indexed for MEDLINE]