Steroid-pyrazine

Pettit et al. (24), working on the marine worm Cephalodiscus gilchristi (order Cephalodisicida, phyla Hemichordata, class Pterobranchia) collected from the Indian Ocean off Southeast Africa, have isolated a number of bioactive bis-steroidal pyrazine alkaloids, the cephalostatins 1-15 (11-25). 

Ritterella tokioka Kott, a tunicate of the family Polyclinidae, collected from the Izu Peninsula 100 km southwest of Tokyo, on extraction and partitioning between a number of solvent systems followed by repeated chromatography, afforded another series of bis-steroidal pyrazine alkaloids, ritterazines A-M (26-38). Structures of these alkaloids were found to be related to the cephalostatins isolated from the hemichordate Cephalo-discus gilchristii. 

C. Synthesis of Unsymmetrical Bis-Steroidal Pyrazines Related to Cephalostatin 1 (11)... 

In 1992 Heathcock and Smith developed efficient routes for the synthesis of symmetrical and unsymmetrical bis-steroidal pyrazines from readily available precursors such as 3-cholestanone and androstanone (40). In a later publication they synthesized the unsymmetrical bis-steroidal pyrazines by the reaction of appropriate a-acetoxy ketones with a-amino oximes. Heating either 2/3,17/3-dihydroxyandrostan-3-one diacetate or 2/3-17/3-dihydroxyhecogenin-3-one diacetate with 2-amino-3-methoxyimino-cholestane in toluene at 145°C gave the corresponding symmetrical pyrazine in moderate yields. 

When Two Steroids are Better than One The Dimeric Steroid-Pyrazine Marine Alkaloids... 

SYNTHETIC STEROID-PYRAZINE DIMERS VIA a-AMINO KETONES... 

Another route to unsymmetrical steroidal pyrazines is the likely biosynthetic process of differentiation of a symmetrical dimer, as accomplished21 by Winterfeldt s group. Starting from... 

The family of dimeric steroid-pyrazine alkaloids isolated from Cephalodiscus and Ritteria now stands at thirty members. There are undoubtedly other examples of this group of steroidal alkaloids that have yet to be discovered, and it is probable that members common to both sources will be found. 

In 1994, a steroid-pyrazine dimer was reported [5] from an unexpected source. Fuse-tani s group isolated ritterazine A, with an ED50 of 10 pg mL against P388, from the tunicate Ritterella tokioka collected off Japan. Twelve other ritterazines have since been described [6] (Fig. 2), including one homodimer, ritterazine K. A possible mecha-... 

Initial synthetic attention focused on preparation [7] of symmetrical steroid-pyrazine dimers by the classical condensation of a-amino ketones (Scheme 2). Interestingly, dimer 1 is itself weakly cytotoxic, with an ED50 around 10 / g mL against tumor cell lines. 

Together with cephalostatins, isolated from the marine worm Cephalodiscus gilchristi, they make up a imique family of 45 trisdecacyclic bis-steroidal pyrazines (Figures 1 and 2) that display extremely potent cytotoxicity against human tumors with unique cell selectivity and apoptotic response [Reviewed in 109, 110],... 

Ganesan, A., 1996. The dimeric steroid-pyrazine marine alkaloids challenges for isolation, synthesis, and biological studies. Angew. Chem. Int. Ed. Engl 35, 611-615. 

Ganesan, A. (1996) When two steroids are better than one the dimeric steroid-pyrazine marine alkaloids, in Studies in Natural Products Chemistry, vol. 18 (ed. Atta-ur-Rahman), Elsevier Science, Amsterdam, Oxford, New York, pp. 875-906. 

Heathcock, C.H. and Smith, S.C. (1994) Synthesis and biological activity of unsymmetrical bis-steroidal pyrazines related to the cytotoxic marine natural product cephalostatin 1. J. Org. Chem., 59, 6828-6839. Erratum J. Org. Chem., 60, 6641 (1995). 

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