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Laxaphycins are responsible for the antifungal and cytotoxic activity of crude ethanolic extracts from the cultured blue-green alga Anabaena laxa. These cyclic peptides exhibit an unusual biological synergism when tested for antifungal or cytotoxic effects. The isolation procedure for the peptides, their characterization and biological activities are described here along with experiments demonstrating synergism between the two major laxaphycins. 1451Blue-green algae (cyanobacteria) have been recognized in the last several years as a source of novel cytotoxic and antifungal metabolites. Someof these metabolites are providing potential leads for the development of new pharmaceutical compounds. Knownantifungal compoundsare frequently toxic when used at levels high enough to be reliably therapeutic, especially for the systemic infections encountered in immunocompromisedpatients. New families of compounds that exhibit synergism either with one another or with known antifungal drugs offer the potential for reducing required dosages, thereby mitigating toxicity and providing more effective antifungal treatment regimens.Wereport here the isolation of a group of cyclic peptides from a cyanophyte that act synergistically with one another to inhibit the growth of fungi and yeasts. These cyclic peptides also show synergistic cytotoxic effects. Isolation and CharacterizationThe cyclic peptides were isolated from the methanol-soluble portion of a crude 7 : 3 ethanol -water extract of the cyanophyte Anabaena laxa Rabenhorst (UH strain FK-1-2) by reversed-phase chromatography. The total yield ofpeptides based on the dried weight of the alga was 1.3%. The complexity of the mixture of peptides is indicated by the HPLCchromatogram shown in Fig. 1. All marked peaks correspond to cyclic peptides with molecular weights ranging from 1,150 to 1,400 daltons as determined by FABmass spectrometry. Unmarkedpeaks probably correspond to additional cyclic peptides that have not yet been characterized. Table 1 lists the yield, relative abundance in the crude extract, and the molecular weight for the individual laxaphycins isolated.Laxaphycins A, B, C, D, and E have been purified by reversed-phase HPLC, while the remaining characterized peptides have been only partially purified. Peaks marked H, I, and P are known to be mixtures. The two peaks markedN correspond to a laxaphycin in the expected mass range and to another compoundwhich is probably not a cyclic peptide. All the peptides isolated were found to fall into two groups-those related to laxaphycin A with

A large‐scale screening program was initiated to evaluate laboratory‐cultured blue‐green algae (cyanobacteria) as a source of novel antineoplastic agents. Approximately 1000 cyanophyte strains from diverse habitats were cultured to provide extracts for testing. The screening program identified the families Scytonemataceae and Stigonemataceae as prolific producers of novel cytotoxic compounds. Rates of rediscovery of known compounds were relatively low.

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Tubercidin, toyocamycin, and the corresponding 5'-o:-D-glucopyranose derivatives of the nucleosides are frequently responsible for muchof the cytotoxicity and antimycotic activity associated with extracts of cultured cyanophytes belonging to the family Scytonemataceae.The 5'-a:-D-glucopyranoses of tubercidin and toyocamycin, for example, are the major cytotoxic and fungicidal nucleosides in Fijian Plectonema radiosum and Hawaiian Tolypothrix tenuis, respectively.The blue green algae provide an excellent source of new bioactive compounds15. Over the past 6 years we have mass cultured over 700 clonal isolates from a variety of terrestrial, freshwater and marine environments and screened hydrophilic and lipophilic extracts of these cyanophytes for cytotoxicity and antifungal activity. About 6% of the extracts show cytotoxicity at <20 jug/ml against the KBcell line (a human epidermoid carcinoma of the nasopharynx) and roughly 9 % of the extracts show antifungal activity at 500 /^g/disc against one or more test organisms, viz. Aspergillus oryzae, Candida albicans, Penicillium notatum, Saccharomyces cerevisiae and Trichophyton mentagrophytes.Several of the active hydrophilic extracts (obtained with 30 % ethanol in water) show both cytotoxicity and antifungal activity and many are cyanophytes belonging to the family Scytonemataceae. Twodistinct classes of compoundsare responsible for the cytotoxicity and fungicidal activity of the Scytonemataceae listed in Table 1 , viz. scytophycin-type macrolides and tubercidin/toyocamycintype nucleosides. Scytophycins account for the cytotoxicity and antifungal activity of Scytonema pseudohofmanni (strain BC-l-2)2>3).Tolytoxin, a scytophycin-related compound that was first isolated from field-collected Tolypothrix conglutinata var. colorata°, is responsible for both the cytotoxicity and antifungal activity of Scytonema mirabile (BY-8-1) and Scytonema ocellatum (DD-8-1) (unpublished results). In an earlier report we showed that tubercidin