Anti-tuberculosis activity and structure–activity relationships of oxygenated tricyclic carbazole alkaloids and synthetic derivatives

Börger, Carsten; Brütting, Christian; Julich‐Gruner, Konstanze K.; Hesse, Ronny; Kumar, V. Pavan; Kutz, Sebastian K.; Rönnefahrt, Marika; Thomas, C. Barry; Wan, Baojie; Franzblau, Scott G.; Knölker, Hans Joachim

doi:10.1016/j.bmc.2016.12.038

Cited by 33 publications

(20 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Figure S7). Several biological activities have been reported for indolocarbazole alkaloids including antituberculosis [65], anticancer [55], and antitumour [31,55] activities. However, there are no records in the literature for the bioactivity of BE-13793C 1 in HT-29 cell-based bioassays.…”

Section: Antimicrobial/antibiofilm Assays For Be-13793cmentioning

confidence: 99%

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

et al. 2020

View full text Add to dashboard Cite

Whole-genome sequence data of the genus Streptomyces have shown a far greater chemical diversity of metabolites than what have been discovered under typical laboratory fermentation conditions. In our previous natural product discovery efforts on Streptomyces sp. MA37, a bacterium isolated from the rhizosphere soil sample in Legon, Ghana, we discovered a handful of specialised metabolites from this talented strain. However, analysis of the draft genome of MA37 suggested that most of the encoded biosynthetic gene clusters (BGCs) remained cryptic or silent, and only a small fraction of BGCs for the production of specialised metabolites were expressed when cultured in our laboratory conditions. In order to induce the expression of the seemingly silent BGCs, we have carried out a co-culture experiment by growing the MA37 strain with the Gram-negative bacterium Pseudomonas sp. in a co-culture chamber that allows co-fermentation of two microorganisms with no direct contact but allows exchange of nutrients, metabolites, and other chemical cues. This co-culture approach led to the upregulation of several metabolites that were not previously observed in the monocultures of each strain. Moreover, the co-culture induced the expression of the cryptic indole alkaloid BGC in MA37 and led to the characterization of the known indolocarbazole alkaloid, BE-13793C 1. Neither bacterium produced compound 1 when cultured alone. The structure of 1 was elucidated by Nuclear Magnetic Resonance (NMR), mass spectrometry analyses and comparison of experimental with literature data. A putative biosynthetic pathway of 1 was proposed. Furthermore, BE-13793C 1 showed strong anti-proliferative activity against HT-29 (ATCC HTB-38) cells but no toxic effect to normal lung (ATCC CCL-171) cells. To the best of our knowledge, this is the first report for the activity of 1 against HT-29. No significant antimicrobial and anti-trypanosomal activities for 1 were observed. This research provides a solid foundation for the fact that a co-culture approach paves the way for increasing the chemical diversity of strain MA37. Further characterization of other upregulated metabolites in this strain is currently ongoing in our laboratory.

show abstract

Section: Antimicrobial/antibiofilm Assays For Be-13793cmentioning

confidence: 99%

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

et al. 2020

View full text Add to dashboard Cite

show abstract

“…4 These compounds showed no significant inhibition in a preliminary assay. 5 The MIC90 value for 3-methoxy-2-methylcarbazole-1,4-quinone served as benchmark for comparison with the anti-TB activities of carbazoles found in our previous studies [34]. Although olivacine (1) shows an activity comparable to our benchmark compound, the SI value is considerably lower (SI = 3.8) due to its toxicity.…”

Section: Biological Activitymentioning

confidence: 84%

“…A weak anti-tuberculosis (anti-TB) activity was described in early reports for some simple tricyclic carbazole alkaloids [29][30][31]. Based on that work, we investigated the anti-TB activity of a range of oxygenated carbazole alkaloids and their derivatives and found very promising results for several compounds [32][33][34]. Therefore, we also tested olivacine (1) and its oxygenated derivatives 4, 5, 19b and 19c for their anti-TB activities ( [35,36].…”

Section: Biological Activitymentioning

confidence: 99%

Synthesis and Anti-Tuberculosis Activity of Olivacine and Oxygenated Derivatives

Schmidt¹,

Theumer²,

Jäger³

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…5 A weak inhibiting activity against M. tuberculosis was described in early reports for some simple tricyclic carbazole alkaloids [34][35][36]. Based on that work, we investigated the inhibiting activity of a range of oxygenated carbazole alkaloids and their derivatives and found very promising results for several compounds [37][38][39]. Therefore, we also tested olivacine (1) [40,41].…”

Section: Resultsmentioning

confidence: 99%

“…The MIC90 value for 3-methoxy-2-methylcarbazole-1,4-quinone served as benchmark for comparison with the inhibiting activities of carbazoles found in our previous studies [39]. Although olivacine (1) shows an activity comparable to our benchmark compound, the SI value is considerably lower (SI = 3.8) due to its toxicity.…”

Section: Biological Activitymentioning

confidence: 89%

Synthesis and Activity Against <em>Mycobacterium tuberculosis</em> of Olivacine and Oxygenated Derivatives

Schmidt

Theumer

Jäger

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

The tetracyclic pyrido[4,3-b]carbazole olivacine and four of its oxygenated derivatives have been synthesized by a late-stage palladium-catalyzed Heck-type cyclization of the pyrrole ring as key step. In a test for inhibition of the growth of Mycobacterium tuberculosis 9-methoxyolivacine showed the most significant inhibiting activity against Mycobacterium tuberculosis with an MIC90 value of 1.5 μM.

show abstract

Anti-tuberculosis activity and structure–activity relationships of oxygenated tricyclic carbazole alkaloids and synthetic derivatives

Cited by 33 publications

References 47 publications

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

A Co-Culturing Approach Enables Discovery and Biosynthesis of a Bioactive Indole Alkaloid Metabolite

Synthesis and Anti-Tuberculosis Activity of Olivacine and Oxygenated Derivatives

Synthesis and Activity Against <em>Mycobacterium tuberculosis</em> of Olivacine and Oxygenated Derivatives

Contact Info

Product

Resources

About