Current Status of Indole-Derived Marine Natural Products: Synthetic Approaches and Therapeutic Applications

Abstract

Indole is a versatile pharmacophore widely distributed in bioactive natural products. This privileged scaffold has been found in a variety of molecules isolated from marine organisms such as algae and sponges. Among these, indole alkaloids represent one of the biggest, most promising family of compounds, having shown a wide range of pharmacological properties including anti-inflammatory, antiviral, and anticancer activities. The aim of this review is to show the current scenario of marine indole alkaloid derivatives, covering not only the most common chemical structures but also their promising therapeutic applications as well as the new general synthetic routes developed during the last years.

Keywords: biological activity; indole alkaloids; marine resources; synthetic strategies; therapeutic application.

Figure 1

Example of marine drugs accepted by the FDA.

Figure 2

Structure/activity relationships of indole derivatives.

Figure 3

Structure of some marine indole alkaloids with anticancer activity.

Figure 4

Structures of C3-acyclic substituted SIAs 1–5.

Figure 5

Structures of C3-carbaldehyde/carboxy-substituted SIAs 6–10.

Figure 6

Biogenetic route to obtain Anthranoside C (11).

Figure 7

Structures of prenylated SIAs 14–17.

Figure 8

Biogenesis of isomers 18 and 19.

Figure 9

Synthetic approaches in the preparation of functionalized SIAs.

Figure 10

Trachycladindole A–G (26–32), aplysinopsins (33), and their derivatives (34–40).

Figure 11

Trachycladindole hypothetical biosynthesis by A. Hentz.

Figure 12

Stanovnik and Svete’s synthesis of Aplysinopsin derivate 39.

Figure 13

Structure of Meridianins A–G (41–47).

Figure 14

Jing and Yang synthesis of Meridianin D (44).

Figure 15

Fresneda and Molina’s synthesis of Meridianins C (43) and D (44).

Figure 16

Structure of bis-indoles 50–53 and tris-indole 54.

Figure 17

Structure of bromodeoxytopsentin (55) and dibromodeoxytopsentin (56).

Figure 18

Structure of eusynstelamides A–B and D–F (57–61).

Figure 19

Structure of Hamacanthins A–B (62–63).

Figure 20

Janosik et al. [64] synthesis of Rhopaladin C (53).

Figure 21

Basic structures of Simple Diketopiperazines.

Figure 22

Chemical structures of simple DKPs 64–68 with C3-methylene bridge.

Figure 23

Chemical structures of simple DKPs 69–82 with C3-methylene bridge.

Figure 24

Chemical structures of simple DKPs 83–102 with C3-ethylidene bridge.

Figure 25

Chemical structures of bis-indol DKPs 103–105.

Figure 26

Possible disconnections of a 2,5-diketopiperazine ring.

Figure 27

Aza-Wittig cyclization to synthesize DKPs 107.

Figure 28

Synthesis and biosynthesis of Brevianamide F (64).

Figure 29

Synthesis of Neochenulin A (94).

Figure 30

Synthesis of Aspergilazine A (103).

Figure 31

Structures of compounds 113–118.

Figure 32

Structures of compounds 119–129.

Figure 33

Example of synthesis of breviamides 132–135.

Figure 34

Synthesis of dimethyhydropyranoindole nucleus.

Figure 35

Structures of compounds 136–146.

Figure 36

Structures of compounds 147–165.

Figure 37

Synthesis of Indole diketopiperazine alkaloids.

Figure 38

Structures of compounds 173 and 174.

Figure 39

Classical synthesis of Flustramine C (178).

Figure 40

Synthesis of the flustramines analogs 179.

Figure 41

Synthetic routes of tricyclic HPI.

Figure 42

Structures of compounds 182–185.

Figure 43

Structures of compounds 186–203.

Figure 44

Structures of compounds 204–206.

Figure 45

Structures of compounds 207–213.

Figure 46

Structures of compounds 214–216.

Figure 47

Representative commercialized β-carboline drugs.

Figure 48

Structure of Norharmane 217.

Figure 49

C1-substituted βC compounds 217–237.

Figure 50

C1-substituted βC compounds 238–245.

Figure 51

C1-substituted βC compounds 246–248.

Figure 52

C1-substituted βC compounds 249–251.

Figure 53

C1-substituted βC compounds 252–260.

Figure 54

C1-substituted βC compounds 261–268.

Figure 55

C1-substituted βC compounds 269–270.

Figure 56

C1-substituted βC compounds 271–277.

Figure 57

Chemical structure of Shishijimicin A–C (278–280).

Figure 58

Chemical structures of Manzamines 281–291.

Figure 59

Chemical structures of Manzamines 292–297.

Figure 60

Chemical structures of Manzamines 298–306.

Figure 61

Chemical structures of Manzamines 307–312.

Figure 62

N2-substituted βC compounds 313–317.

Figure 63

C3-substituted βC compounds 318–325.

Figure 64

Chemical structures of Hyrtioerectine B (326).

Figure 65

Annelated C1-N2 βC compounds 327–339.

Figure 66

Annelated βC compounds 340–341.

Figure 67

Naturally occurring marine βC 1,1-dimers 342–344.

Figure 68

Structure of marine βC 9,9-dimer 345.

Figure 69

Structure of manzamine hybrid dimers 346–348.

Figure 70

Structure of Kauluamine (349).

Figure 71

Most employed synthetic routes for synthesizing βCs.

Figure 72

Other classical general synthetic routes towards the synthesis of βCs.

Figure 73

Representative modern approaches towards the synthesis of βCs.