Aminosterols from the Dogfish Shark Squalus acanthias

Abstract

Seven new aminosterols related to squalamine (8) were isolated from the liver of the dogfish shark Squalus acanthias. Their structures (1-7) were determined using spectroscopic methods, including 2D NMR and HRFABMS. These aminosterols possess a relatively invariant cholestane skeleton with a trans AB ring junction, a spermidine or spermine attached equatorially at C3, and a steroidal side-chain that may be sulfated. The structure of the lone spermine conjugate, 7 (MSI-1436), was confirmed by its synthesis from (5alpha,7alpha, 24R)-7-hydroxy-3-ketocholestan-24-yl sulfate. Some members of this family of aminosterols exhibit a broad spectrum of antimicrobial activity comparable to squalamine.

Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

“…In addition to the active site-directed PTP1B inhibitors described above, there is also substantial interest in an allosteric PTP1B inhibitor trodusquemine (also known as MSI-1436; compound 6), which was discovered serendipitously. Trodusquemine was originally discovered among a family of aminosterol compounds in the tissues of dogfish shark with broad-spectrum antimicrobial activity as well as potent appetite suppressant and antidiabetic properties [106][107][108]. Subsequent investigation revealed that trodusquemine functioned as a potent noncompetitive inhibitor of PTP1B with a 200-fold preference (IC50 of 1 μM vs. 224 μM) over TCPTP [83].…”

Identification of squalamine in the plasma membrane of white blood cells in the sea lamprey, Petromyzon marinus

“…Primary amine oxidation and 7-OH sulfation of squalamine can produce PADS, suggesting that both compounds share biosynthetic pathways. The biosynthetic strategy that evolved in sea lamprey to produce an array of closely related aminosterol compounds with different biological functions seems to be similar to that found in sharks, in which squalamine and its analogs are produced (31,32).…”

“…There have been a few nonpeptide antimicrobial factors identified in fishes, in addition to squalamine and squalamine-related aminosterols from the sharks (32). A low molecular weight antimicrobial factor has been identified from channel catfish leukocytes (21).…”

Quaternary Alkylammonium Conjugates of Steroids: Synthesis, Molecular Structure, and Biological Studies

“…In turn, Rao and co-workers isolated six other aminosterols (43)(44)(45)(46)(47)(48) from the liver of the dogfish shark ( Figure 4) [15]. The authors presented a very accurate spectral analysis based on 2D NMR (COSY, HETCOR, HMBC) as well as low-and high-resolution mass spectra (FAB, ESI, MALDI).…”

“…The steroid-polyamine conjugate was isolated from the liver tissues of the dogfish shark (Squalus acanthias) [11][12][13][14]. This aminosterol is a novel broad-spectrum antibiotic and exhibits a biocidal activity against Gram-positive and Gram-negative bacteria, fungi, protozoa, and viruses [15][16][17][18][19][20][21][22][23]. The antimicrobial activity of the squalamine has inspired work to design and synthesize new derivatives of steroidal-polyamine conjugates [24][25][26][27][28][29][30][31][32].…”