Hapalindoles from the Cyanobacterium Hapalosiphon sp. Inhibit T Cell Proliferation

Abstract

Supporting information available online at http://www.thieme-connect.de/products ABSTR AC T Novel immunomodulating agents are currently sought after for the treatment of autoimmune diseases and cancers. In this context, a screening campaign of a collection of 575 cyanobacteria extracts for immunomodulatory effects has been conducted. The screening resulted in several active extracts.Here we report the results of subsequent studies on an extract from the cyanobacterium Hapalosiphon sp. CBT1235. We identified 5 hapalindoles as the compounds responsible for the observed immunomodulatory effect. These indole alkaloids are produced by several strains of the cyanobacterial family Hapalosiphonaceae. They are known for their anti-infective, cytotoxic, and other bioactivities. Modulation of the activity of human immune cells has not yet been described. The immunomodulatory activity of the hapalindoles was characterized in vitro using flow cytometry-based measurements of T cell proliferation after carboxyfluorescein diacetate succinimidyl ester staining, and apoptosis and necrosis induction after annexin V/propidium iodide staining. The most potent compound, hapalindole A, reduced T cell proliferation with an IC 50 of 1.56 µM, while relevant levels of apoptosis were measurable only at 10-fold higher concentrations. Hapalindole A-formamide and hapalindole J-formamide, isolated for the first time from a natural source, had much lower activity than the nonformylated derivatives while, at the same time, being less selective for antiproliferative over apoptotic effects.

Cooperative Biocatalysis Enables Assembly of a Prenylated Indole Alkaloid

“…The hapalindole metabolites are a family of indole alkaloids consisting of the hapalindoles, fischerindoles, ambiguines and welwitindolinones, all isolated from the cyanobacterial order Stigonematales [1] . This family has been shown to have antimicrobial, [2–5] antimycotic, [6,7] antitumor, [8–10] and immunomodulatory activity [11] . The family is defined by three notable features: a polycyclic ring system, diverse stereochemistry, and the presence of unique functional groups such as isonitriles, isothiocyanates, the late‐stage introduction of halogen atoms, and hydroxyl groups.…”

“…[1] This family has been shown to have antimicrobial, [2][3][4][5] antimycotic, [6,7] antitumor, [8][9][10] and immunomodulatory activity. [11] The family is defined by three notable features: a polycyclic ring system, diverse stereochemistry, and the presence of unique functional groups such as isonitriles, isothiocyanates, the latestage introduction of halogen atoms, and hydroxyl groups. In recent years, a number of groups have expressed and characterized the prenyltransferases, cyclases and halogenases responsible for the biosynthesis of these complex compounds.…”

Structural Diversification of Hapalindole and Fischerindole Natural Products via Cascade Biocatalysis

“…Along with their related compounds, fischerindoles, ambiguines, and welwitindolinones, there have been at least 81 members isolated from over 18 cyanobacterial strains . They have also been shown to have antimicrobial, antimycotic, , anticancer, and immunomodulatory activity . Hapalindole/fischerindole metabolites possess three distinguishing features: a polycyclic ring system, diverse stereochemical variations, and the late-stage introduction of a range of functional groups such as additional rings, halogens, hydroxyls, isothiocyanate, and others.…”

Total Synthesis of the Chlorinated Pentacyclic Indole Alkaloid (+)-Ambiguine G

“…The ambiguines are a subset of the large hapalindole family of more than 80 cyanobacteria metabolites that also includes the fischerindoles and welwitindolinones. 1 , 2 The first of the ambiguines were identified by Smitka and Moore in 1992 while screening fungicidal extracts primarily from the terrestrial cyanophytes Fischerella ambigua . 3 Although the full bioactivity profiles of these alkaloids have yet to be fully assessed, several members have displayed useful properties.…”