Structural Diversity and Biological Activities of Indole Diketopiperazine Alkaloids from Fungi

Abstract

Indole diketopiperazine alkaloids are secondary metabolites of microorganisms that are widely distributed in filamentous fungi, especially in the genera Aspergillus and Penicillium of the phylum Ascomycota or sac fungi. These alkaloids represent a group of natural products characterized by diversity in both chemical structures and biological activities. This review aims to summarize 166 indole diketopiperazine alkaloids from fungi published from 1944 to mid-2015. The emphasis is on diverse chemical structures within these alkaloids and their relevant biological activities. The aim is to assess which of these compounds merit further study for purposes of drug development.

Indolediketopiperazine Alkaloids from Eurotium cristatum EN-220, an Endophytic Fungus Isolated from the Marine Alga Sargassum thunbergii

“…Indole diketopiperazine alkaloids are characterized by condensation of the tryptophan with a second amino acid such as L -alanine, L -proline, or L -tryptophan, forming the ring of diketopiperazine unit [10]. The isolated compounds of E. cristatum EN-220, featuring with the second amino acid of L -alanine, showed potent brine shrimp lethality and antioxidative activity against DPPH.…”

“…[5], and E. herbariorum [6], have been characterized from the brown alga of Sargassum thunbergii [3], red alga of Asparagopsis taxiformis [4] and Bostrychia tenella [5], and green alga of Epiactis prolifera [6]. Compared to its unknown ecological role, the fungal genus Eurotium has attracted more interests on its profilic source of indolediketopiperazine derivatives containing L -tryptophan and L -alanine units, generally characterized by a reverse isoprene chain at C-2 of the indole nucleus [3,7,8,9,10]. These compounds were reported to possess antibacterial [3,9], nematicidal [11], antioxidative (DPPH assay) [12,13], moderate immunosuppressive [14], and anti HIV-1 replication activities [15], as well as cytotoxic effects against P388 [12] and A-549 cells [16].…”

Stereodivergent Synthesis of Bispyrrolidinoindoline Alkaloidal Scaffolds and Generation of a Lead Candidate with Stereospecific Antiproliferative Activity

“…These dimeric alkaloids and their variants exhibit a wide variety of pharmacological effects, such as antifungal, antiviral, antitumor, and antinematodal activities, as well as inhibitory activities against topoisomerases and histone methyl transferases . Barrow and co‐workers reported that the dimeric alkaloid WIN 64821 ( 1 ) was a potent and competitive antagonist of the peptide hormone substance P (nerokinine‐1) receptor .…”

Synthesis of 3a‐hydroxyhexahydropyrrolo[2,3‐B]Indole‐2‐carboxamide, an oxidation product of tryptophan present in natural products

“…Many HO‐HPIC alkaloids, such gypsetin ( 2 ), fellutanine ( 3 ) and the okaramine family of products contain a diketopiperazine (DKP) motif (piperazinedione alkaloids, indole diketopiperazine) intertwined around two HO‐HPIC moieties (Figures and ). They are secondary metabolites commonly isolated from fungi of the genera Aspergillus and Penicillium . The biosynthetic machinery catalyzes the condensation of a tryptophan and a second amino acid to form a diketopiperazine that is then oxidized to form the HO‐HPIC.…”

“…The biosynthetic machinery catalyzes the condensation of a tryptophan and a second amino acid to form a diketopiperazine that is then oxidized to form the HO‐HPIC. Quite a few of these products demonstrated promising antimicrobial, antiviral, anticancer, immunomodulatory, antioxidant, and insecticidal activities . Gypsetin ( 2 ) became the focus of synthetic efforts based on its promise as an agent that could lower cholesterol levels by inhibiting acyl‐CoA:cholesterol acyltransferase (ACAT) thereby attenuating the risk of coronary heart disease .…”