Interest in the physiological activities and potential clinical uses of the pineal hormone melantonin (N-acetyl-5-methoxytryptamine) has grown enormously in recent years. The hormone has been implicated in the regulation of phenomena as diverse as the sleep-wake cycle, depression, sexual urge, neuroimmunomodulation, mammary cancer, etc. Such multiplicity of actions in different tissues suggests a multiplicity of receptors for the same molecule. Studies to date indicate a receptor pocket for a large nonpolar group at C-2, such as iodine or phenyl, these analogs of melatonin showing greatly increased binding capacity. Thus, a bulky, chemically reactive substituent at the same position should provide an affinity label for one or more classes of receptor. Stepwise chemical syntheses of such molecules would very involved; we have, therefore, aimed for direct synthesis by use of the carbonyl function of the corresponding oxindole. We have now developed reversible blocking groups for the oxindole nitrogen which render the ring carbonyl more ketonic in character and amenable to nucleophilic addition. The first test of this route has been successful, in the Grignard addition provides a series of 2-alkyl or 2-aryl indoles. Thus, a 3-step synthesis is now available to provide a variety of melatonin analogs with functional groups at C-2. Melatonin has been claimed to show immunostimulant activity and even some positive effect against breast cancer, but the mechanism of its action remains unknown. A minor metabolic pathway for melatonin involves oxidative cleavage of the pyrrole ring to give melakynurenine, a product analogous to that formed by oxidative cleavage of tryptophan. Comparison of the geometry of this metabolite with that of muramic acid, the glucosamine component of muramyl dipeptide, shows a remarkable degree of resemblance. Since muramyl dipeptide is the most frequently used adjuvant in vaccine preparations, it is quite possible that the immunoadjuvant property of melatonin may actually arise from melakynurenine. We have prepared melakynurenine and several analogs thereof; potential immunostimulant activities will soon be e valuated by Prof. John Hadden, univ. of South Florida School of Medicine.
| Smith, B P; Tyler, M J; Kaneko, T et al. (2002) Evidence for biosynthesis of pseudophrynamine alkaloids by an Australian myobatrachid frog (pseudophryne) and for sequestration of dietary pumiliotoxins. J Nat Prod 65:439-47 |
| Dumbacher, J P; Spande, T F; Daly, J W (2000) Batrachotoxin alkaloids from passerine birds: a second toxic bird genus (Ifrita kowaldi) from New Guinea. Proc Natl Acad Sci U S A 97:12970-5 |
