Indolocarbazoles (ICZs) are a class of compounds that are under current study due to their potential as anti-cancer as well as antimicrobial drugs and the prospective number of derivatives and uses found from the basic backbone alone. First isolated in 1977, a wide range of structures and derivatives have been found or developed throughout the world. Due to the extensive number of structures available, this review will focus on the more important groups here while covering their occurrence, biological activity, biosynthesis, and laboratory synthesis.
Chemical classification Indolocarbazoles belong to the alkaloid sub-class of bisindoles. The most frequently isolated indolocarbazoles are Indolo(2,3-a)carbazoles; the most common subgroup of the Indolo(2,3-a)carbazoles are the Indolo(2,3-a)pyrrole(3,4-c)carbazoles. These can be divided into two major classes - halogenated (chlorinated) with a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond and the second class consists of both indole nitrogen glycosylated, non-halogenated, and a fully reduced C-7 carbon.
Occurrence The first isolated ICZ, dubbed staurosporine (STA) was in 1977 from a culture of Streptomyces staurosporeus found in a soil sample from Iwate Prefecture, Japan. The proper stereochemistry was not proven until 1994. Over the course of the next decade, further study of the compound showed some fungal inhibition, hypotensive activity, and most importantly, a broad protein kinase inhibitor. The next landmark discovery came with the detection of rebeccamycin (REB) in a sample of Lechevalieria aerocolonigenes, again in soil, but this time in a sample from Panama. REB was found to act against leukemia and melanoma in mice, and also against human adenocarcinoma cells. Since 1977, ICZs have been discovered all over the world in actinomycetes, bacteria commonly found in soil. Numerous forms have tested positive for anti-tumor activity, such as 7-hydroxy-STA and 7-oxo-STA2. Some of the strains from which ICZ compounds have been found are Actinomadura melliaura in Bristol Cove, San Diego County, California, Streptomyces hygroscopicus in Numazu Prefecture, Japan, Micromonospora sp. L-31-CLO-002 from Fuerteventura Island, Canary Islands, Spain, and Actinomadura sp. Strain 007 from Jiaozhou Bay, Shandong, China. The wide distribution of the various strains that produce these compounds is not surprising due to the number of properties these compounds can take on with limited functionalization on the species's part. In addition to actinomycetes, ICZs have been found in slime molds (myxomycetes), blue-green algae (cyanobacteria, and marine invertebrates. Like the ones derived from actinomycetes, the ones found in myxomycetes cover an expansive range of derivatives and functionalizations. Two of the more important ones to date have been Arcyriacyanin A, which was found to inhibit a panel of human cancer cells by effecting PKC and protein tyrosine kinase, and lycogalic acid dimethyl ester A (found in Tokushima, Japan from Lycogala epidendrum), which showed strong antiviral activity. A few of the strains of myxomycetes studied are Arcyria ferruginea and Arcyria cinerea, both from Kochi Prefecture, Japan. Three species of cyanobacteria has been found to produce ICZ compounds. Nostoc sphaericum from Manoa Hawaii, Tolypothrix tjipanasensis from Vero Beach, Florida, and Fischerella ambigua strain 108b from Leggingen, Switzerland. An interesting note on the first two is that many of the ICZ derived from them do not have the annelated pyrrolo[3,4-c] unit. The final major group in which ICZs are found are various marine invertebrates. Three species of tunicate, one mollusk, one flatworm, and one sponge have been discovered in places ranging from Micronesia to New Zealand. Testing for further invertebrate production is ongoing by both genetic and phylum-based studies.
… excerpt ends here. Continue reading the full article.
