Monographs on fragrance raw materials

Lichen-forming fungi are unique organisms, producing biologically active metabolites with a great variety of effects, including antibiotic, antimycobacterial, antiviral, anti-inflammatory, analgesic, antipyretic, antiproliferative and cytotoxic activities. However, only very limited numbers of lichen substances have been screened for their biological activities and their therapeutic potential in medicine. This is certainly due to the difficulties encountered in identification of the species, collection of bulk quantities, and the isolation of pure substances for structure determination and testing activity. Recently, possibilities for bypassing some of these former difficulties have arisen by the introduction of new techniques. This includes axenic cultivation for production of the genuine compounds or new ones, extraction of focused compounds, or synthesis of natural products or their derivatives for testing. Utilizing these new opportunities, the discovery of novel active metabolites, which could serve as lead compounds, is significantly facilitated. At the same time, the evolution of secondary metabolite patterns is studied using phylogenetic approaches. Yet, the genetic background of the complex chemical patterns is poorly understood. The scattered occurrence of some compounds suggests that their production evolved either in parallel or that ancient biosynthetic pathways are abandoned in many lineages. At least, studies on polyketide synthase genes from different lichen groups suggest a high level of gene paralogy. In this context, clades of orthologous polyketide synthase genes, which are often shared with distantly related non-lichenized fungi, can roughly be identified by their sequence similarity and their similar patterns of substitution rates. The functional assignment of paralogs is nevertheless difficult and reasonable only in a few cases. A global approach of the lichen metabolomic features appears to be essential in developing new and viable biotechnological processes which could afford suitable amounts of unique lichen compounds.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S1479262105000328

Lichens—a promising source of bioactive secondary metabolites

(1985). Present and Future Applications of Lipases. Biotechnology and Genetic Engineering Reviews: Vol. 3, No. 1, pp. 193-218.

https://www.tandfonline.com/doi/pdf/10.1080/02648725.1985.10647813

Present and future applications of lipases

The bizarre phenolic substances produced by many lichen-formingfungi are assumed to have important biological roles, an idea that has led various investigators to speculate on topics ranging from light-screening to rock mineralization At the present time, three proposed roles- antimicrobial, allelopathic and antiherbivore-are best supported by the available evidence Anti- microbial: The fact that lichens grow slowly and yet are resistant to decay microorganisms suggests that lichen substances, known to be clinically effective antibiotics, also have a protective role in nature Indeed, this may be their principal role However, there is little direct evidence from field studies Allelopathic: Recent studies show that lichen substances can inhibit seed germination of vascular plants and spore germination of mosses and lichens, demonstrating a possible allelopathic role for these substances The ecological significance of such inhibitory effects in natural species assemblages that include lichens, however, requires more research Antiherbivore: Despite their availabilty as food to generalist herbivores, lichens are seldom eaten, suggesting that lichen sub- stances deter feeding Recent research, done primarily with invertebrate consumers, indicates that some lichen compounds are capable of defending lichen thalli from predation The secondary chemicals produced by lichens have attracted the attention of investigators for over 100 years, and information about their structure, bio- genic origin and phylogenetic significance has ac- cumulated steadily over this period Indeed, the sec- ondary chemistry of few other groups of organisms is better known Yet our understanding of their pos- sible biological roles is meager This is unfortunate because the extent to which lichen secondary sub- stances can be expected to contribute to the solution of evolutionary problems depends on a better un- derstanding of their adaptive value What do these compounds do? Most lichenolo- gists assume that they do something, since it is dif- ficult to imagine how mechanisms resulting in the production of such a wide array of energetically ex- pensive compounds could have evolved in so many groups of energetically-depauperate lichen-forming fungi If these substances have no adaptive value at all, their relatively high energetic cost would ulti- mately lead to their disappearance over evolution- ary time Just the opposite appears to be happening, however In the most rapidly speciating lichen

Biological Role of Lichen Substances

Over 40 natural or synthetic lipophilic compounds were screened for antimicrobial activity. Gram (+) bacteria and yeasts but not Gram (-) bacteria were affected by these agents. Epimino and selena fatty acids are more active than their corresponding straight chain unsubstituted fatty acids. The position of selenium influenced the antimicrobial activity of the fatty acids. The presence and position of a double or triple bond, usually an important factor in long chain fatty acids (greater than C14) had little or no effect in C11 fatty acids. Optimum antimicrobial activity was found for fatty acids and their corresponding monoglycerides when the chain lenght was C12. The dilaurin derivative was not active.

Antimicrobial lipids: Natural and synthetic fatty acids and monoglycerides

Antitumor activity of normal saturated monocarboxylic acids and their ester derivatives was examined with Ehrlich ascites carcinoma in mice. The samples used were a) a series of fatty acids ranging in carbon chain length from C3 to C18, that is, propionic, butyric, valeric, caproic, caprylic, pelargonic, capric, lauric, myristic, palmitic, and stearic acids, b) their methyl esters, c) 1-O-acyl-β-D-glucopyranose tetraacetates derived from these fatty acids, and d) the so-called "sucrose monoesters" of caprylic, lauric, and myristic acids. Each agent was administered to mice by intraperitoneal injection at the dose of 400 mg/kg/day ×5, and the effect was evaluated with total packed cell volume ratio on the 7th day after the tumor implantation. Among eleven fatty acids tested, lauric and myristic acids were highly effective, while others were either ineffective or toxic. On the other hand, the methyl esters corresponding to the antitumor inactive fatty acids with a carbon chain length of C6 to C10 were found to possess significant effect. The most prominent activity was exhibited with methylcaprylate. All members of the group c proved to show negligible antitumor effect. In contrast, the sucrose monoesters, especially myristate, have been suggested to exert marked activity, although their strong toxicity could not be overlooked.

Chemical and biochemical studies on carbohydrate esters. III. Antitumor activity of unsaturated fatty acids and their ester derivatives against Ehrlich ascites carcinoma.

From six species of lichens, a variety of polysaccharide fractions were prepared and their antitumor effects were tested against the sarcoma 180 implanted in mice. These fractions were characterized by chemical and physicochemical methods. The active principle of Lasallia pensylvanica has been determined as GE-3 type glucan (a partially O-acetylated β-(1→6)-glucan). Another highly effective β-glucan, containing (1→3)-and (1→4)-linkages in the ratio 3 : 7, was isolated from Usnea rubescens, and it has been identified with lichenin. In addition, presence of so far unknown heteropolysaccharides with moderate antitumor effect has been suggested in the minor fraction of the lichen. Four Cladonia lichens, i.e.C. crispata, C. mitis, C. rangiferina subsp. grisea, and C. squamosa, were also examined, and it has been revealed that, in all of them, complex heteroglycans consisting chiefly of mannose, galactose, and glucose occur commonly as predominant, cold-water soluble polysaccharides, together with a small amount of α-glucan presumed to be PC-3 type (an α-glucan possessing (1→3)- and (1→4)-linkages alternately). Both the heteroglycan fraction and the glucan fraction of C. squamosa were shown to exert moderate antitumor effect.

Studies on the Water Soluble Constituents of Lichens. II. Antitumor Polysaccharides of Lasallia, Usnea, and Cladonia Species

Regioselective Syntheses of Mono-O-acylglucoses

Selective fatty acylation of maltose was carried out by heating an equimolar mixture of the disaccharide and an appropriate acid chloride in pyridine. The resulting crude product was chromatographed to furnish two preparations, termed maltose-[mono]- and-[high]-esters ; the former preparation was an isomeric mixture of monoesters among which the 1-, 6-, and 6'-isomers were presumably predominant, and the latter consisted of di-, tri-, and poly-esters, as indicated by gas-liquid and thin-layer chromatographies. The antitumor effects of the maltose-[mono]-esters of stearic, palmitic, myristic, lauric, and caprylic acids towards Ehrlich ascites carcinoma in mice were tested by the total packed cell volume method, by intraperitoneal injection. The stearic, palmitic, and myristic esters proved to be effective, while the lauric and caprylic esters exhibited a slight effect and no effect, respectively. The antitumor effect of the maltose-[mono]-stearate upon the same tumor was compared with that of the analogous derivative of sucrose by survival bioassay (intraperitoneal administration) at various doses. Both compounds showed similar antitumor results, giving especially marked effects at the dose of 50 mg/kg/day×5. These two compounds also exerted moderate growth-inhibitory effects against solid sarcoma 180 in mice when they were administered subcutaneously ; in the case of sucrose-[mono]-stearate, intramuscular injection was also effective. The maltose-[high]-esters of stearic, palmitic, and myristic acids failed to exert marked activity upon this solid tumor by either administration route.

Chemical and Biochemical Studies on Carbohydrate Esters. IX. Antitumor Effects of Selectively Fatty Acylated Products of Maltose

Accrding to the procedure of Osipow, sucrose was partially acylated with palmitic, stearic, hydnocarpic, and ricinoleic acids. In the similar manner, the selective esterification of trehalose was performed, using caprylic, lauric, myristic, and stearic acids. The ester compositions of the resulting preparations were preliminarilly analysed by means of thin-layer chromatography and gas chromatography, and the major components contained in them were tentatively assigned to the 6-monoesters of these disaccharides. All the preparations obtained proved to exert considerable antitumor effect against Ehrlich ascites carcinoma in mice by intraperitoneal administration.

Chemical and Biochemical Studies on Carbohydrate Esters. V. Anti Ehrlich Ascites Tumor Effect and Chromatographic Behaviors of Fatty Acyl Monoesters of Sucrose and Trehalose

Yoshihiro Nishikawa

Papers

Chemical and biochemical studies on carbohydrate esters. III. Antitumor activity of unsaturated fatty acids and their ester derivatives against Ehrlich ascites carcinoma.

Studies on the Water Soluble Constituents of Lichens. II. Antitumor Polysaccharides of Lasallia, Usnea, and Cladonia Species

Regioselective Syntheses of Mono-O-acylglucoses

Chemical and Biochemical Studies on Carbohydrate Esters. IX. Antitumor Effects of Selectively Fatty Acylated Products of Maltose

Chemical and Biochemical Studies on Carbohydrate Esters. V. Anti Ehrlich Ascites Tumor Effect and Chromatographic Behaviors of Fatty Acyl Monoesters of Sucrose and Trehalose