Brasilicardin A, a natural immunosuppressant, targets amino Acid transport system L.

Lymphocytes in T cell activation require extracellular nutrients to provide energy for cellular proliferation and effector functions. Therefore, inhibitors of nutrient transporters are expected to be a new class of immunosuppressant. Here, we report that the molecular target of brasilicardin A (BraA), an immunosuppressive compound, is the amino acid transporter system L. BraA inhibited the cell-cycle progression of murine T cell lymphocyte CTLL-2 cells in G1 phase, and potently inhibited the uptake of amino acids that are substrates for amino acid transport system L. Moreover, BraA stimulated the GCN2 activation and, subsequently, the phosphorylation of eIF2alpha. These results suggest that the immunosuppressive activity of BraA is induced by amino acid deprivation via the inhibition of system L and that the amino acid transporter is a target for immunosuppressant.

Paratunamides A-D, oxindole alkaloids from Cinnamodendron axillare.

Four new oxindole alkaloids, paratunamides A-D (1-4), containing a secologanin unit, were isolated from the bark of Cinnamodendron axillare, and their structures and relative configurations were elucidated by spectroscopic data. The absolute configuration at C-7 in 1-4 was assigned as S, S, R, and S, respectively, on the basis of the CD spectra.

Brasilibactin A, a cytotoxic compound from actinomycete Nocardia brasiliensis.

A new cytotoxic compound, brasilibactin A (1), has been isolated from the actinomycete Nocardia brasiliensis IFM 0995, and the structure was elucidated on the basis of spectroscopic data and chemical means.

SAR studies of brasilicardin A for immunosuppressive and cytotoxic activities.

Eleven derivatives (5-13, 15, and 16) of an immunosuppressive and cytotoxic tricyclic terpenoid, brasilicardin A (1), were prepared and assayed for inhibitory effects to the mouse mixed lymphocyte reaction (MLR) and seven human tumor cell lines. The 17N-methyl form (8) of 1 showed the most potent immunosuppressive activity in mouse MLR, while induction of more bulky group for N-17 resulted in significant decrease of the activity. Compound 8 also showed potent cytotoxic activity against DLD-1, Lu-65, A549, K562, and MOLT-4 cells, while the benzyl ester (13) of 1 exhibited potent cytotoxicity against K562, MOLT-4, and jarkat leukemia cell lines. The 17N-acetyl derivative (11) of 1 selectively inhibited the cell growth of DLD-1 cells. The methyl ester (5) of 1 showed potent cytotoxic activity against K562, MOLT-4, and Ball-1 cell lines, the last of which was resistant to 1, 8, and 13.

Brasilicardins B-D, new tricyclic terpenoids [correction of terpernoids] from actinomycete Nocardia brasiliensis.

Three new tricyclic terpenoids, brasilicardins B-D (2-4), were isolated together with brasilicardin A (1), a potent immunosuppressive compound, from the cultured broth of a pathogenic actinomycete Nocardia brasiliensis IFM0406, and the structures and stereochemistry were determined by spectroscopic data and a single crystal X-ray diffraction analysis. The immunosuppressive and cytotoxic activities of 2-4 were examined in the comparison with 1.

Absolute stereochemistry of immunosuppressive macrolide brasilinolide A and its new congener brasilinolide C.

Brasilinolide A (2) is a 32-membered polyhydroxyl macrolide with immunosuppressive activity isolated from a pathogenic actinomycete, Nocardia brasiliensis IFM0406. The absolute configurations at 26 chiral centers of 2 and its new congener, brasilinolide C (1), were determined on the basis of the spectral data of 1 and degradation products derived from 1 and 2.

Subincanadines A-C, novel quaternary indole alkaloids from Aspidosperma subincanum.

Three novel quaternary indole alkaloids with an unprecedented 1-azoniatricyclo[4.3.3.0(1,5)]undecane moiety, subincanadines A-C (1-3), as well as two new indole alkaloids with a 1-azabicyclo[5.2.2]undecane moiety, subincanadines D (4) and E (5), and a new indole alkaloid with a 1-azabicyclo[4.3.1]decane moiety, subincanadine F (6), have been isolated from the barks of Aspidosperma subincanum Mart, and the structures of 1-6 and the stereochemistry of 1-3 were elucidated by spectroscopic data and chemical means.

Renealtins A and B, new diarylheptanoids with a tetrahydrofuran ring from the seeds of Renealmia exaltata.

Two new diarylheptanoids, renealtins A (1) and B (2), have been isolated from the seeds of the Brazilian medicinal plant Renealmia exaltata ("Pacová-catinga", Zingiberaceae), and their structures were elucidated by spectroscopic data. Renealtins A (1) and B (2) are the first example of naturally occurring diarylheptanoids containing a tetrahydrofuran ring.

Echinodolides A and B, new cembrane diterpenoids with an eight-membered lactone ring from the leaves of Echinodorus macrophyllus.

Two new cembrane diterpenoids with an eight-membered lactone ring, echinodolides A (1) and B (2), were isolated from the leaves of the Brazilian medicinal plant Echinodorus macrophyllus ("Chapéu-de-couro"), and the structures and relative stereochemistry were elucidated from their spectroscopic data.

Brasilicardin A. A Novel Tricyclic Metabolite with Potent Immunosuppressive Activity from Actinomycete Nocardiabrasiliensis.

A novel tricyclic metabolite, brasilicardin A (1), with potent immunosuppressive activity has been isolated from the cultured broth of the actinomycete Nocardia brasiliensis IFM 0406, and the structure including absolute stereochemistry was established on the basis of spectroscopic data, chemical means, and X-ray analysis. Brasilicardin A (1) is the first tricyclic compound consisting of an anti/syn/anti-perhydrophenanthrene skeleton with a rhamnose, an N-acetylglucosamine, and an amino acid moiety.