Gregory M. L. Patterson

Tjipanazoles, new antifungal agents from the blue-green alga Tolypothrix tjipanasensis

Abstract Bioactivity-directed isolation of the extract of the cyanophyte Tolypothrix tjipanasensis has led to the isolation of fifteen new N-glycosides of indolo[2,3-a]carbazoles designated tjipanazoles A1, A2, B, C1, C2, C3, C4, D, E, F1, F2, G1, G2, I and J. The structures of the alkaloids were determined by physical methods, chemical degradation and synthesis. Tjipanazole J is the only compound having the pyrrolo[3,4-c] ring of previously described indolo[2,3-a]carbazoles.

Toxins from cyanophytes belonging to the scytonemataceae

Two highly cytotoxic substances, scytophycins A and B, have been isolated from cultured Scitonema pseudohofmanni. Gross structures are proposed for scytophycins A and B, mostly on the basis of nuclear magnetic resonance spectral studies. The scytophycins are structurally related to tolytoxin, a toxic lipid found in field-collected Tolypothrix conglutinata var. colorata, another blue-green alga belonging to the family Scytonemataceae. At sublethal doses the scytophycins display moderate activity against P-388 lymphocytic leukemia and Lewis lung carcinoma in mice.

ANTIVIRAL ACTIVITY OF CULTURED BLUE‐GREEN ALGAE (CYANOPHYTA)1

Lipophilic and hydrophilic extracts from approximately 600 strains of cultured cyanophytes, representing some 300 species, were examined for antiviral activity against three pathogenic viruses. Approximately 10% of the cultures produced substances that caused significant reduction in cytopathic effect normally associated with viral infection. The screening program identified the order Chroococcales as commonly producing antiviral agents.

Fischerindole L, a new isonitrile from the terrestrial blue-green alga fischerella muscicola

Abstract Fischerindole L ( 3 ) is a novel octahydroindeno[2,1- b ]indole isonitrile from the terrestrial cyanophyte Fischerella muscicola that possesses the same relative stereochemistry as hapalindole L ( 4 ).

FUNGAL CELLWALL POLYSACCHARIDES ELICIT AN ANTIFUNGAL SECONDARY METABOLITE (PHYTOALEXIN) IN THE CYANOBACTERIUM SCYTONEMA OCELUTUM2

The addition of fungal cell‐wall homogenates of Penicillium notatum and Cylindrocladium spathiphylli markedly stimulated the accumulation of tolytoxin, an antifungal secondary metabolite, in cultures of the cyanobacterium Scytonema ocellatum Lyngbye ex Bornet et Flahault. Evaluation of polysaccharides, proteins, and other polymers established that a limited range of polysaccharides, especially chitin and carboxymthylcellulose, selectively elicited enhanced tolytoxin accumulation in S. ocellatum. The elicitor activity of fungal cell‐wall preparations could be correlated with the chitin content of the preparation. Polymeric chitin was half‐maximally effective at a concentration (EC50) of 19 mg.L‐1, whereas chitin oligoments were more effective (EC50= 3.3 mg.L‐1) in eliciting enhanced tolytoxin accumulation. The elicitor activity of either purified chitin or an elicitor‐active fungal cell‐wall preparation could be destroyed by treatment with chitinase. The results suggest an ecological role for tolytoxin as an inducible chemical defense agent (phytoalexin) capable of protecting S. ocellatum against fungal invasion.

Biological effects of tolytoxin (6-hydroxy-7-O-methyl-scytophycin b), a potent bioactive metabolite from cyanobacteria

Tolytoxin, a macrocyclic lactone, is a potent antifungal antibiotic, exhibiting MICs in the range of 0.25 to 8 nanomolar. Tolytoxin also inhibits the growth of a variety of mammalian cells at similar doses, without specific inhibition of macromolecular synthesis. The effects in mammalian cells are primarily cytostatic, with cell death being time-and dose-dependent. Tolytoxin is highly toxic to mice, exhibiting an LD50 (ip) of 1.5 mg/kg. No antibacterial, antiviral, or hemolytic activities were observed.

Discovery of cryptophycin-1 and BCN-183577 : Examples of strategies and problems in the detection of antitumor activity in mice

Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected IV.

A90720A, a serine protease inhibitor isolated from a terrestrial blue-green alga Microchaete loktakensis

Abstract The isolation and structure elucidation of A90720A, 1 , a cyclic depsipeptide from the terrestrial blue-green alga Microchaete loktakensis is described. 1 was isolated on the basis of its thrombin inhibitory activity and its structure was determined using spectral methods and amino acid analysis. The absolute configurations of the constituent amino acids were found to be as follows: the nucleus contains L -threonine, L -arginine, L -3-amino-6-hydroxy-2-piperidone (Ahp, i.e., glutamic acid-γ-car☐aldehyde), L -leucine, L -N-methyl-tyrosine and L -valine. The side chain off the L -threonine amino group contains D -leucine, followed by a 3-O-sulfated R -glycerate moiety.

Further tolyporphins from the Blue-Green alga Tolypothrix nodosa.

Abstract Eight new porphinoids, tolyporphins B-I (2–9), along with the known tolyporphin A (1) have been isolated from a lipophilic extract of the Pacific cyanophyte, Tolypothrix nodosa. Their structures have been elucidated using 1- and 2-D NMR spectroscopic experiments and the tolyporphins showed varying activities in drug accumulation and competitive binding assays for multidrug resistance (MDR) reversal.

Scytophycins from a blue-green alga belonging to the nostocaceae

Abstract Scytophycin B, 6-hydroxyscytophycin B, scytophycin E, and 6-hydroxy-7-O-methylscytophycin E account for the cytotoxicity and fungicidal activity of the terrestrial blue-green algaCylindrospermum muscicola.