Aminosteroids

A stereospecific synthesis of funtuphyllamine A (7) has been reported (G. Demailly and G. Solladig, Tetrahedron Letters, 1975, 2471) diborane reduction of the chiral iminopregnane (6), followed by hydrogenolysis, yields the alkaloidal base (7) sterospecifically. 

A new alkaloid holacetine (8) occurs in the root bark of Holarrhena antidysenterioa its structure has been settled by chemical correlation with the known funtumafrine C (R. N. Rej et al., Phytochem., 1976, 1, 1173). 

untidysenterioa seeds have yielded a new alkaloid hoi arnicine (9), formulated after detailed spectroscopic and chemical studies. It has been correlated with holarrhimine (10) by Clemmensen reduction, and its two carbonyl functions were located by analysis of its mass spectral fragmentation pattern (S. Siddiqui and B. S. Siddiqui, Chem. Abs., 1983, 98, 50327). 

Irehdiamine F has been isolated from the roots of Vahadenia laurentii its structure (11) has been settled by X-ray diffraction analysis of its hydrochloride (J. Lamotte et at., Acta Cryst., 1977, B33, 2392). 20-Epi-irehdiamine I (12), found in seeds of Funtumia elastioa, has been formulated on the basis of its nmr and mass spectra its structure has been corroborated by a synthesis from progesterone by an unexceptional pathway (M. D. L. Tolela and P. Foche, Planta Med., 1979, 35, 48). 

The mechanism of the backbone rearrangement of conessine into isoconessine and into neoconessine has been investigated by and H-nmr spectroscopy. The rearrangements were carried out with catalysis by D2S0 and HTSO4, and the spectra of the products were analysed carefully and positions of incorporation discerned (Frappier et al., J. org. Chem., 1982, 7, 3783). Neoconessine (19) has been assigned 14g stereochemistry on the basis of this study. 

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A family of 3-aminosteroids reportedly inhibit lipid peroxidation while acting as anti-inflammatories. These activities were attributed to the combination of the steroid and the amine as neither component was, by itself, efiective (Spyriounis et /., 1993). In this sense, they resemble the 21-aminosteroid lazaroids. These 3-aminosteroids most probably inhibit lipid peroxidation through a physicochemical mechanism. 

Spyriounis, D.M., Tani, E., Rekka, E., Demopoulos, V.J. and Kourounakis, P.N. (1993). Novel AT-substituted 3-aminosteroids which exhibit anti-inflammatory properties and influence free radical processes. Eur. J. Med. Chem. 28, 521-525. 

Alkylation of enamines, although highly successful in many alicyclic systems [221], failed to give useful results with 3-aminosteroidal 3,5-dienes (9 R — Me) [221]. These compounds... 

Reductive amination. Reductive amination of 3-ketosteroids with ammonia, hydrogen, and Pd-C gives 3)3-aminosteroids, but in poor yield. It is preferable to use benzylamine the intermediate secondary amine undergoes hydrogenolysis. The reaction is selective for 3-ketosteroids carbonyl functions at C17 and Cm are not affected. Thus hydrogenation of progesterone in the presence of benzylamine and Pd-C afforded 3/3-amino-5)3-pregnane-20-one in 71% yield. 

Ally lie trifluoroacetoxylation. This salt is more reactive than mercury(II) acetate for allylic hydroxylation. Thus cholesterol esters are converted, after hydrolysis, into -3j3,6j3-dihydroxy steroids, even at 0°. Yields are about 50%. A -3/3-Aminosteroids are converted into mixtures of A -3 3-amino-4/3-hydroxy-... 

Only one example of this interesting and possible useful transformation has been reported. DeFlines and co-workers (D-148) described the conversion of conessine to A -conenin-3-one by Gloeosporium cyclaminis and Hypomyces haematococcus. Rich sources of 3-aminosteroids have been found in the Funtumia sp. of African plants. ... 

Olefins are also the products of hydroboratlon of enamines, followed by treatment of the organoborane products with hot acid (543,544). The reduction of enamines with sodium borohydride and acetic acid (545) and the selective reduction of dienamines with sodium borohydride to give homo-allylic tertiary amines (138-140,225,546,547), has been applied to the synthesis of conessine (548) and other aminosteroid analogs (545,549-552). Further examples of the reduction of imonium salts by sodium borohydride can be found in the reduction of Bischler-Napieralski products, and other cyclic imonium salts (102). 

The rate of non-lgE-mediated immediate hypersensitivity reactions usually varies between 20 and 50% [1-7, 9], They are assumed to result from direct non-specific mast cell and basophil activation, which causes direct histamine release [19], Histamine release is predominantly found with the use of the benzylisoquinoUnes d-tubocurarine, atracurium and mivacurium, and the aminosteroid rapacuronium. Severe bronchospasm related to rapacuronium administration has been reported in children and adults. It might be related to the higher affinity of rapacuronium for M2 versus M3 muscarinic receptors [20]. Rapacuronium has been withdrawn from the market in the USA. 

In studies in Alzheimer s brain, in vitro induction of lipid peroxidation by iron is more intense than in control cortical samples (Andorn et al., 1990 Subbarao et nL, 1990 McIntosh et al., 1991). The 21-aminosteroid U-74500A has been shown to effectively inhibit iron-induced lipid peroxidation in Alzheimer s brain samples (Subbarao et al., 1990). 

Hall, E.D., Pazara, K.E. and Braughler, M.J. (1988). 21-Aminosteroid lipid peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils. Stroke 19, 997-1002. 

Braughler, M.J., Hall, E.D., Jacobsen, E.J., McCall, J.M. and Means, E.D. (1989). The 21-aminosteroids potent inhibitors of lipid peroxidation for the treatment of central nervous system trauma and ischemia. Drugs Future 14, 143-152. 

Richards, J.M., Griffin, KL. and Fidler, S.F. (1992). Hyperoxic lung injury in rats effect of the 21-aminosteroid U-74389F. Inflammation Research Association Meeting, Sixth International Conference, White Haven, PA, September 20-24. 

R.H. Fabian, D.S. deWitt, and T.A. Kent, The 21-aminosteroid U-74389G reduces cerebral superoxide anion concentration following fluid percussion injury of the brain. J. Neurotroma. 15, 433 140 (1998). 

We have described a method with high stereoselectivity which will be useful in the synthesis of squalamine analogs.It is promising in synthetic applications and will prove significant in the preparation of 3a-aminosteroids. These results are summarized in Table 4.4. 

Figure 6.1 Chemical structures of currently used aminosteroid relaxants.

About a third of an administered dose of rocuronium is excreted in the urine, the rest being taken up by the liver and excreted unchanged in the bile. Its elimination half-life is just under 100 minutes (Table 6.4). Unlike other aminosteroid relaxants, only very small amounts of the metabolite 17-desacetyl rocuronium have been found in plasma. The clearance of rocuronium is reduced in patients with significant renal and hepatic disease, with a possible prolongation of effect. The same mechanisms are responsible for prolongation of the block in the elderly. 

Marion D. W. and White M. J. (1996) Treatment of experimental brain injury with moderate hypothermia and 21-aminosteroids. J. Neurotrauma 13, 139-147. 

Subsequently, it was found that the substitution of a complex amine on the non-glucocorticoid steroid nucleus in place of the 21-hydroxyl functionality results in a dramatic enhancement of the lipid antioxidant activity. Many of these 21-aminosteroid compounds effectively inhibit iron-catalyzed lipid peroxidation in rat-brain tissue homogenates under assay conditions where the glucocorticoid steroid methylprednisolone and the non-glucocorticoid analog U-72099E are completely ineffective [20,21]. Of these, U-74006F (tirilazad mesylate Fig. 2) has shown excellent activity in experimental models of spinal-cord and brain injury. 

Microinjection of ferrous iron (i.e. ferrous chloride) has also been shown to produce focal edema in rat brain, the degree of which is correlated with tissue levels of the lipid-peroxidation product malonyldialdehyde. Pretreatment with vitamin E (600 mg/kg intramuscularly once daily for 5 days) together with selenium (5 ppm in the drinking water) reduced the iron-induced edema and lipid peroxidation [54]. Similarly, the 21-aminosteroid U-74006F can also reduce iron-induced opening of the blood-brain barrier [53],... 

More recently, the cerebral antioxidant activity of the 21-aminosteroid U-74006F has been enhanced by replacing the steroid functionality, which possesses only weak antioxidant activity without the complex amino substitution, with a more potent and effective antioxidant. A series of compounds has been synthesized in which the steroid of U-74006F has been replaced by the antioxidant ring structure (i.e. chromanol) of a-tocopherol (vitamin E). One of these compounds, U-78517F (Fig. 2) has been demonstrated to have predictably more potent effects with regard to inhibition of lipid peroxidation in vitro and enhancement of early neurological recovery of head-injured mice [62]. 

Braughler, J.M., Pregenzer, J.F., Chase, R.L., McCall, J.M. and Jacobsen, E.J. (1987) Novel 21-aminosteroids as potent inhibitors of iron-dependent lipid peroxidation, J. Biol. Chem. 262, 10438-10440. 

Monyer, H., Hartley, D.M. and Choi, D.W. (1990) 21-Aminosteroids attenuate excitotoxic neuronal injury in cortical cell cultures, Neuron 5, 121-126. 

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