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Lissodendoryx isodictyalis, a yellow marine animal of the Demospongiae class, was found to yield a series of closely related substances very active against the murine P388 lymphocytic leukemia. Separation studies guided by bioassay led to the isolation and character— ization of the strongly antineoplastic (P388 leukemia) bryostatins 4-6 (la-c) and 8 (141) accompanied by new bryostatins A and B. Yields of the bryostatins from 108 kg of wet Gulf of California L. isodictyalis ranged from 3.2 mg of bryostatin 4 to 900 g and 700 ig respectively of bryostatins A and B. The actual source of bryostatins 4-6 and 8 appeared to be from intrusion of the Bryozoan Bugula neritina. But bryostatins A (a deoxybryostatin 5) and B (a deoxybryostatin 4) have not hitherto been detected in . neritina and may represent metabolic transformations performed by the sponge. Marine Porifera have proved to be an exceptionally productive source of new substances with physiological activity (ref. 3). And starting, nearly 20 years ago, with initiation (ref. 4) of research directed at discovery of potentially useful marine animal antineoplastic constituents, we have been evaluating a broad selection of sponges from far-reaching geographical locations. As part of the program, specimens of the Gulf of California yellow sponge Lissodendoryx isodictyalis were collected in early 1972. Later a 2-propanol extract reached the U.S. National Cancer Institute's (NCI) confirmed active level by leading to 457, life extension (at 12.5 mg/kg) when used to treat the murine P388 lymphocytic leukemia (PS system). The antineoplastic activity displayed by the initial Mexican collection and recollections (from 1976-82) was surprising. Six collections (1968-74) of this yellow (interior) and very fibrous sponge from the coast of Florida and the Caribbean did not give PS active extracts (ref. 5). Due to very limited quantities of Gulf of California L. isodictyalis available from recollections obtained in several periods from 1976-1978 combined with the substantial challenges involved in isolating what appeared to be a series of complex antitumor constituents, present in only trace amounts, all efforts to solve this problem until 1982 were unrewarding. During a 1976 expedition we explored some 1,500 miles of the eastern Gulf of California and Pacific Ocean coasts of Mexico and only found the yellow sponge in one location: the original collection site in Bahia de Kino, Sonora. The sponge was originally found under an abandoned dredge (damaged by a storm) and grew from a few kg. when first sampled in 1972 to considerably more than 100 kg. when a 108 kg. recollection was made in early 1981. In the intervening period, almost that amount had been removed for preliminary studies. In that habitat L. isodictyalis obviously flourished and this may have been due to a symbiotic relationship with Bugula neritina (Bryozoa) and its potent cell growth inhibitory constituents described in the sequel. With the 1981 recollection and application of some of the most powerful isolation techniques (ref. 6) we developed to date for such challenging problems the active antineoplastic components were isolated as summarized in Scheme 1. Important features of the isolation now follow. After collection, the yellow sponge was stored in 2-propanol at ambient temperature and the solution phase became the first extract, The animal was next extracted with methanol-methylene chloride (1:1). The methylene chloride soluble fractions from each extract were subjected to a solvent partition sequence by dissolution in 9:1 methanol-water and successively partitioning the methylene chloride components between (9:1 4:1) hexane -, aRefer to ret. 1 b See ref. 2 cThe Papanicolaou Comprehensive Cancer Center, University of Miami, School of Medicine, Jackson Memorial Medical Center, Miami, Florida 33101.

Relationship of Bugula neritina (Bryozoa) antineoplastic constituents to the yellow sponge Lissodendoryx isodictyalis