Cephalodiscus

Cephalostains 1-6 (507-512), powerful cell growth inhibitory substances against the PS cell line, were isolated from the marine worm Cephalodiscus gilchristi collected in the Indian Ocean 406-408). The structure of cephalostatin 1 (507) was determined by X-ray analysis. Cephalostatins apparently result from a biosynthetic condensation of 2-amino-3-oxosteroid units to yield dimeric steroidal molecules connected by a pyrazine ring. 

FIGURE 3.11 Selected metabolites from a polychaete and a hemichordate 3.11.1 Thelepin, from the poly-chaete Thelepus setosus.222 3.11.2 Cephalostatin 10, from Cephalodiscus gilchristi223... 

The synthesis of the potent in vitro active compound, cephalostatin 1, isolated from a rare marine worm, Cephalodiscus gilchristi, has recently been reported, and scale-up... 

Prominent amongst these marine discoveries are the bryostatins from the marine bryozoan Bugula neritincr, the dolastatins from the shell-less mollusc Dolabella auricularia the cephalostatins from the South African marine worm (a mere 5 mm long) Cephalodiscus gilchristi the sponge... 

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). 

Pettit et al., have proposed a biogenetic pathway for the dimeric pyrazine-containing steroidal alkaloids, the cephalostatins isolated from the marine worm Cephalodiscus gilchristi and the tunicate Ritterella tokioka. These alkaloids contain at least 13 fused rings, which constitutes the largest such system known in marine animals. 

This chapter reviews the history of a remarkable family of natural products first isolated from the marine tube-inhabiting invertebrate worm Cephalodiscus gilchristi. C. gilchristi, found in the temperate Southern Hemisphere, is often attached to bryozoans and sponges. This tiny worm ( 5 mm in tube colonies) can exist independently of the coenicium (worm tube), and exposure to predators during such moments may have aided the evolution of chemical defence mechanisms. 

Samples of the synthetic compounds were provided to Professor Pettit s group, who confirmed the identity of cephalostatins 7 and 12 based on NMR and chromatographic comparison. If this mechanism for pyrazine formation occurs in C. gilchristi, one would expect it to also produce ritterazine K. A search among the currently unidentified residual Cephalodiscus extracts revealed a substance with identical chromatographic profile to ritterazine K. However, it was present in only microgram quantities, and its identity could not be confirmed by NMR. 

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 1974, extracts of the tiny ( 5 mm) marine tube worm Cephalodiscus gilchristi collected off South Africa were found to be active in the NCI s primary assay, the murine lymphocytic leukemia P388. Fifteen years of relentless research by Pettit s group culminated in the isolation of 139 mg of the major bioactive component, cephalostatin 1, from 166 kg wet weight of the tube worm, and its structural elucidation. [2] This phase was summarized [3] as follows Interest in such a powerfully antileukemic agent as cephalostatin 1. .. has prompted Americans to dive extensively at a depth of 20 meters to collect... 

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],... 

The cephalostatins are a group of cytotoxic dimeric steroid derivatives from the marine worm Cephalodiscus gilchristi. Tietze and Krahnert prepared a group of natural product analogs using multiple Heck reactions using derivative 106 obtained from the Hajos-Wiechert reaction their approach is outlined below. ... 

Subsequently, several other cephalostatins were isolated from the same species, Cephalodiscus gilchristi, the two most recent being cephalostatins 18 and 19, characterized in 1998. All these derivatives have major structural similarities since all cephalostatins currently known are derived mainly from cephalostatin 1, the major component in mixtures, by modification of the west moiety, or from cephalostatin 2 by modification of the east moiety (Figures 27.2 and 27.3). Four publications deal with the structures, antitumor activities, and synthesis of cephalostatins (Ganesan, 1996 Li and Dias, 1997 Dirsch and Vollmar, 2005 Lopez-Anton et al., 2006 Moser, 2008 Rudy et al., 2008). 

Despite the interest in cephalostatins, it is paradoxical that Cephalodiscus gilchristi is the only species of pterobranch to have been studied for its metabolites. However, this apparent lack of interest may be related to the difficulty of obtaining enough material for study. These organisms are fragile and difficult to keep alive, and no information on the possibility of culturing them artificially appears to be available. 

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