Pulchellalactam: A CD45 Protein Tyrosine Phosphatase Inhibitor from the Marine Fungus Corollospora pulchella.

Abstract

CD45 protein tyrosine phosphatase is a largemolecular mass transmembrane glycoprotein expressed on all hematopoietic cells except erythrocytes.1) It is a member of the receptor-like transmembrane protein tyrosine phosphatase2) (PTPase) family. Expression of CD45 has been shown to be important for activation of both B and T cells via their antigen-specific receptors3,4) and has generated considerable interest in the study of lymphocyte activation as well as a possible target for drug intervention in various auto-immune and/or inflammatory diseases.As a part of our effort to find enzyme inhibitors from microbial sources, we identified a fungal extract which exhibited very potent activity in our CD45 assay. Bioassay directed fractionation of the crude extract yielded a novel pulchellalactam (1) from Upstate Biotechnology and the activity was also measured employing the same procedure described for CD45 phosphatase activity. Corollospora pulchella (ATCC 62554) was isolated from a sample of driftwood from Peleliu. It is a marine Ascomycete of the family Halosphaeriaceae. The genus is characterized by having ascospores with hyaline, ribbon like appendages all around the middle and at each apex, developing by the peeling off of the exospore; most species have a long spine-like appendage at each end.6) extract agar with artificial seawater (yeast extract 0.4%, malt extract 1%, glucose 0.4%, agar 2%; prepared in 50% Instant Ocean artificial seawater) and trace elements with 0.5% trace element solution (ferrous sulfate heptahydrate 0.1%, manganese sulfate 0.1%, cupric chloride dehydrate 0.0025%, calcium chloride 0.0132%, boric acid 0.0056%, ammonium molybdate tetrahydrate 0.0019%, zinc sulfate 0.02%; prepared in 0.6N HCl).A 1.0ml aliquot of spore and mycelia homogenate was inoculated into a 250ml Erlenmeyer flask containing 25ml of seed medium (glucose 2%, Pharmamedia 1.5%, ammonium sulfate 0.3%, zinc sulfate 0.003%, calcium carbonate 0.4%, yeast extract 0.5%; prepared in 50% Instant Ocean artificial seawater). The seed culture was

Total Synthesis of Pulchellalactam via an RCM Strategy

“…At present, there are five total syntheses reported for Pulchellalactam (1). [3 -7] Li et al [3] reported the first total synthesis of (1) in six-steps starting from N-boc-glycine in overall yield of 32%.…”

“…(Z ) Pulchellalactam (1), a pyrrolidinone isolated in 1997 from the marine fungus Corollospora pulchella by Alvi et al, [1] has been the focus of some attention owing to its potent inhibitory action against protein tyrosine phosphatase, (PTP) CD45, which in turn activates B and T cells. Protein tyrosine phosphatase has been a target implicated in autoimmune and antiinflamatory diseases.…”

“…[2] The scarcity of effective inhibitors of protein tyrosine phosphatase has led to a search for other small molecule inhibitors. Pulchellalactam (1) has been shown to possess remarkable inhibitory action against CD45. However, because of its limited availability from the marine source, there is a need to obtain this molecule in sufficient amounts through synthetic endeavors.…”

Recent Advances in Application of Amino Acids: Key Building Blocks in Design and Syntheses of Heterocyclic Compounds

“…Pulchellalactam is isolated from the marine fungus Corollospora pulchella, exhibiting high inhibitory activity toward CD45 (98JAN515). In order to have sufficient amounts for biological screening and evaluation and its geometry determination, syntheses of both E-pulchellalactam 70 and Z-pulchellalactam 71 was attempted.…”

Synthesis of new aryl substituted 5-alkylidene-2(5H)-furanones

“…8,10 Synthetic fimbrolide 2 (R = Br) was found to reduce P. aeruginosa levels in the lungs by three orders of magnitude in a pulmonary mouse model. 9 Intrigued by the exocyclic iso-propyl moiety in the structurally related natural product pulchellalactam 12 3 as well as the presence of the similar tert-butyl group in various antibacterial compounds, 13,14 we set out to synthesize brominated furanones 4 (R 1 or R 2 = Br) carrying a vinylic iso-propyl or tert-butyl substituent at the C5 position ( Figure 2). Compounds where the C4-bromine was switched to the C3 position were also targeted to afford a more comprehensive library of furanones for structure-function investigations.…”