Polyamines steroids

The novel steroidal polyamine squalamine (Figure 6.133) has been isolated in very small amounts (about 0.001%) from the liver of the dogfish shark (Squalus acanthias), and is... 

Lehn synthesised guanidinium-based cationic steroids incorporating an acylhy-drazone linker using the approach shown in Fig. 9 [141]. The synthesis was developed from a polyamine scaffold by guanidination of the primary amino groups and alkylation of the secondary amine with methyl chloroacetate to introduce the ester moiety required to form a hydrazide group by reaction with hydrazine monohydrate. Cationic steroid hydrazones were then prepared via an acetic acid catalysed reaction with cholestanones, which demonstrated high transfection efficiency and low toxicity in a variety of cell lines [141]. 

Using the principle of ion pair formation between ammonium cations and the phosphate anions of lipids, Matile et al.33 prepared 8, an amphiphilic polyamine dendrimer. Rather than acting as a membrane channel, 8 was expected to form reversible membrane defects in the lipid bilayer. The steroid moiety was expected to act as the hydrophobic anchor for bilayer orientation and steric bulk was expected to prevent the polyamine penetrating the bilayer. Proton transport was assessed in unilamellar vesicles using the pH-fluorescence technique in which the external pH was increased to 7.8 relative to the internal pH at 7.4. The results demonstrated that 8 was almost as active as gramicidin, and maximal flux was achieved in ca. 20 s. 

Numerous squalamine analogs have been prepared and examined for biological activity (Figure 9.1). The squalamine structure has been varied through the length of the polyamine chain [41-44] the nature of the anionic functional group [41] the position of the polyamine [43-45], sulfate [45,46], and free hydroxyl [41,43,44,47] on the steroid scaffold the stereochemistry and substitution at C-3, C-7, and C-24 [41-44] the length of the steroid side chain [41,45,46] and the unsaturation of the steroid [43,44]. 

Olfaction, the sense of smell, is an important neural system in various animal species, including fish, for their life. Fish can detect a variety of odorants emitted from objects and dissolved in the water, such as amino acids, bile salts, nucleotides, polyamines, prostaglandins, and steroids. The fish olfactory system is extensively developed to receive and discriminate these odorant molecules, to transmit their signals to the brain, and to mediate fundamental behaviors such as food finding, alarm response, predator avoidance, social communication, reproductive activity, and spawning migration (Sorensen and Caprio 1998 Zielinski and Hara 2007). 

Fluorescence detection is often used where no other property of the solute (e.g. UV of RI detection) is convenient and can be either an intrinsic property of the solute itself or a derivatised form of the solute. Solution studies have indicated that the sensitivity of detection can be increased by up to three orders of magnitude over UV. This has increased the popularity of post-column fluorescence detection methods for may compounds, including physiological fluids, catecholamines, and other polyamines. A popular use of fluorescence detection is in peptide chemistry where no convenient intrinsic chro-mophore is present. Derivatising agents such as orthophthalaldehyde and fluorescamine are used extensively in both pre- and post-column systems allowing detection of low picomole quantities (Chapter 11). In addition, detection can be performed using the intrinsic fluorescence of many compounds such as steroids, vitamins, and nucleotides. 

Thus, Amoore suggests that, if we have a specific olfactory receptor for a given odorant then that odorant might be naturally given off by the body. The sweaty odor of isovaleric acid is probably part of the foot odor and is produced by the action of skin bacteria on apocrine secretion (see below). Pyrolline, the spermous odor, has been shown to be produced by enzymatic breakdown of the polyamines in semen (40). Androst-16-en-3-one, the urinous primary odor, has axillary-like odor the related androstenol, which is found in urine, is perceived as a musky odor to some individuals (41). Both steroids are found in axillary sweat and may be formed as metabolites of apocrine secretion. Chemicals which fit the malty anosmia have not as yet been reported from human odor sources. The natural musks, such as cycloheptadecenone (civet), were first obtained from animal scent glands. 

Finally, a range of steroidal polyamines were found to promote transport across cell/liposome membranes or bind to nucleic acids and promote gene transfection. Although these compounds have not in general been studied as receptors, their interactions with anionic centers are presumably central to their activities. For example, 22 and 23 were incorporated in vesicle membranes and shown to discharge pH gradients across the membranes. Their mechanisms of action are... 

Hsieh. H.-P. Muller, J.G. Burrows, C.J. Structural effects 30. in novel steroidal polyamine-DNA binding. J. Am. Chem. 

Digital glycosides, nucleosides, pesticides, pharmaceuticals, phospholipids, steroids DNA adducts, DNA and RNA fragments, dyes for food, inorganic ions, steroids Amines, amino acids, inorganic ions, peptides, purine and pyrimidine derivatives Amines, amino acids, indole derivatives, ohgopeptides, polyamines, sulfonamides Barbiturates, carboxylic acid esters, fatty acid derivatives, nitrophenols, polychlorobiphenyls (PCBs), peptides, pesticides, phenols, steroids, surfactants, triazines... 

Steroidal frameworks have been much used in synthetic ion transport designs. Cholate oligomers synthesized from polyamines and cholic acid derivatives represent another class of ion transporters (Figure 12). These compounds, inspired by squalamine antibiotic, are also known as molecular umbrellas because of their amphomorphism. Depending on the polarity of the medium, the hydrophilic cholate faces are exposed or hidden to the surface of the umbrella. These compounds such as 22 are active sodium... 

The crucial role played by vitamin Bg in the nervous system and in neuroendocrinology is based on the fact that various putative neurotransmitters as well as taurine, sphingolipids, and polyamines are synthesized by pyridoxal phosphate (PLP)-dependent enzymes. There are numerous biological effects of vitamin Bg unrelated to the role of PLP as a coenzyme. PLP is an antagonist of both the voltage-mediated and the ATP-mediated calcium transport systems. PLP modulates the activities of steroid hormone receptors and transcription factors. The preventive effect of vitamin Bg on tumorigenesis might also derive from the antioxidant functions of this vitamin. 

We presently report the use of vibrational spectroscopy for the study of several molecules of recognized biological significance, namely chemotherapeutic agents, biogenic polyamines and polyamine metal chelates with potential anticancer activity, cardiovascular protectors, non-steroid antiinflammatory drugs (NSAID s), drugs of abuse (e.g. amphetamines and... 

To date, polycationic moieties have been used for a variety of drugs to enhance their cellular uptake. Most of them are either based on naturally occurring polycationic peptides 83a-c, polycationic peptides such as poly-or oHgo- arginines or lysines 84, 85 or their analogous b-peptides 86, on oligocarbamates 88, on other polycationic peptide scaffolds 87 (Fig. 16) or on polyamine-modified liposomes comprising the polyamine moiety covalently bound to lipids or steroids 41,88,90 as well as on polyamine-modified dendrimers (Fig. 17), as discussed in the next section. 

Squalamine is a simple molecule, but original. This compound can be regarded as a bolaphile (see above), because it includes an apolar central part (a steroid) with two polar ends (a polyamine and a sulfate group). Squalamine derives from 7a-hydroxy-cholestanol substituted at 24(3 with a sulfate group the 3(3-OH group is replaced by spermidine (Moore et al, 1993 Wehrh et al, 1993). °... 

The biosynthesis of squalamine seems to imply the condensation of spermidine with a steroid, but it has not been confirmed that this biosynthesis is actually performed by sharks and the possibility of exogenous origin cannot be ruled out (Kobayashi and Ishibashi, 1999, pp. 474-475). The specificity of squalamine is still an unresolved issue, because the publications that report its extraction concern only the single species Squalus acanthias. The presence of polyamines, and in particular spermidine in natural substances has been reviewed by Ganem (1982). 

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