Organic Letters
Letter
7n (1) (Figure 4a). Furthermore, 5aTHQ-8i (2) and 5aTHQ-8n
(3) were less potent but more selective than the smaller congener
5aTHQ-7n (1) and more potent but less selective than the larger
congener 5aTHQ-9i (4) (Figure 4 and Figure S5, Supporting
Information). We previously reported the occurrence of a similar
tendency in heronamide C and its congener, polyene macro-
lactams that target membrane lipids: heronamide C potently
inhibited growth of both wild-type and erg mutant cells, while 8-
deoxyheronamide C, a less potent congener, inhibited growth of
wild-type cells but showed apparently lower effect to erg mutant
cells.5 This fact implied that these 5aTHQ compounds could also
be targeting membrane lipids. Interestingly, the addition of a
methyl group at the ω-2 position had a significant impact on the
potency and the selectivity, e.g., compare 5aTHQ-7n (1) with
5aTHQ-8i (2), 5aTHQ-8n (3) with 5aTHQ-9i (4), or 5aTHQ-
9n (5) with 5aTHQ-10i (7) (Figure S5, Supporting
Information). The molecular processes underlying these
chemical genetic interactions are of considerable interest, and
further research is therefore required to develop a deeper
understanding of the driving forces behind these interactions.
The 1,2,3,4-THQ structure can be found in several natural
products, as well as a wide range of pharmacologically important
reagents.25−27 Several natural products belonging to this
structural class have been isolated from a variety of different
sources, including actinomycetes, fungi, plants and several other
organisms. Among them, 5aTHQs represent one of the simplest
structures. Angustureine and several related metabolites are
another group of simple THQ compounds isolated from plants
where the substitution is at C-2 rather than C-5 both with and
without N-methylation.28,29
In conclusion, we have isolated a series of novel 5aTHQ
alkaloids from the combined culture of S. nigrescens HEK616 and
T. pulmonis TP-B0596. These 5aTHQ compounds exhibited
inhibitory activity toward the growth of yeast cells, most likely by
targeting the membrane lipids. The length and methylation
pattern of the side chain at the C5-position of these compounds
had a critical effect on their potency and selectivity toward the
growth of yeast cells. These 5aTHQ compounds could be useful
chemical tools for studying the structure and function of cell
membranes. Further SAR study would be helpful for the mode of
action study and drug development. The biosynthetic mecha-
nisms and physiological functions of 5aTHQs in the producing
organism are also of considerable interest because these
metabolites were only produced under coculture conditions.
Research aimed at addressing these issues is currently underway
in our laboratory.
ACKNOWLEDGMENTS
■
We thank Dr. K. Takegawa (Kyushu University) for kindly
providing the mutant yeast strains. This work was supported in
part by research grants from the Japan Society for the Promotion
of Science (JSPS), the Ministry of Education, Culture, Sports,
Science, and Technology of Japan (MEXT), the Ministry of
Health, Labour and Welfare of Japan (MHLW), and Institute for
Fermentation, Osaka (IFO).
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* Supporting Information
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Corresponding Authors
Notes
The authors declare no competing financial interest.
1921
Org. Lett. 2015, 17, 1918−1921