The Biological and Chemical Diversity of Tetramic Acid Compounds from Marine-Derived Microorganisms

Abstract

Tetramic acid (pyrrolidine-2,4-dione) compounds, isolated from a variety of marine and terrestrial organisms, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities. In the past decade, marine-derived microorganisms have become great repositories of novel tetramic acids. Here, we discuss the biological activities of 277 tetramic acids of eight classifications (simple 3-acyl tetramic acids, 3-oligoenoyltetramic acids, 3-decalinoyltetramic acid, 3-spirotetramic acids, macrocyclic tetramic acids, N-acylated tetramic acids, α-cyclopiazonic acid-type tetramic acids, and other tetramic acids) from marine-derived microbes, including fungi, actinobacteria, bacteria, and cyanobacteria, as reported in 195 research studies up to 2019.

Keywords: bioactivity; marine natural product; marine-derived microorganisms; tetramic acid.

Figure 1

Classification of the 277 tetramic acids (TAs) from marine microorganisms into eight classes. Some examples of typical molecules belonging to these classes are illustrated: simple 3-acyl-tetramic acids (penicillenol A₁), 3-oligoenoyltetramic acids (tirandamycin A), 3-decalinoyltetramic acids (equisetin), 3-spirotetramic acids (pseurotin A), macrocyclic tetramic acids (from left to right, ikarugamycin, GKK1032A₂), N-acylated tetramic acids (symplostatin 4), α-cyclopiazonic acid (CPA)-type tetramic acids (α-cyclopiazonic acid), and other tetramic acids (vermelhotin). The main characteristics of each chemical class are highlighted in red.

Figure 2

Chemical structures of simple 3-acyl tetramic acids (1–26).

Figure 3

Chemical structures of 3-oligoenoyltetramic acids (27–39).

Figure 4

Chemical structures of 3-decalinoyltetramic acids (40–74).

Figure 4

Chemical structures of 3-decalinoyltetramic acids (40–74).

Figure 5

Chemical structures of 3-spirotetramic acids (75–108).

Figure 5

Chemical structures of 3-spirotetramic acids (75–108).

Figure 6

Chemical structures of macrocyclic tetramic acids-polycyclic tetramate macrolactams (109–146).

Figure 6

Chemical structures of macrocyclic tetramic acids-polycyclic tetramate macrolactams (109–146).

Figure 7

Chemical structures of macrocyclic tetramic acids-pyrrocidine tetramate alkaloids (147–165).

Figure 8

Chemical structures of N-acylated tetramic acids (166–209).

Figure 8

Chemical structures of N-acylated tetramic acids (166–209).

Figure 9

Chemical structures of CPA-type tetramic acids (210–235).

Figure 10

Chemical structures of other tetramic acids (236–277).

Figure 10

Chemical structures of other tetramic acids (236–277).

Figure 11

(a) The tetramic acids (TAs) from marine microorganisms in this review divided by the origin of microorganisms, indicating that fungi are the dominant source. (b) The pie chart provides more in-depth insight into the fungi.

Figure 12

The relationship between different chemical groups of TAs and their producer (marine microorganisms). This number corresponds to the number of TA compounds in different chemical classes.

Figure 13

The TAs from marine microorganisms were divided by their sources (habitats); 277 TAs were isolated from 120 species of microorganisms in 120 habitats.

Figure 14

The percentage represents the proportion of one activity compared to the whole occurrence of activities of 202 bioactive TAs from marine microorganisms (n = 327). Some compounds present various activities and are counted in more than one category.

Figure 15

Classification of the 202 bioactive TAs according to their activities and chemical classes. The number of compounds is symbolized by the disc diameters for each bioactivity and each chemical class. The colors correspond to the different categories of the activity targets. Gray represents a mixed target; yellow mainly represents a cell line target, blue primarily represents the specific cellular mechanism, green represents the enzyme target, and purple represents the entire organism target.