Natural Bioactive Compounds from Marine Invertebrates That Modulate Key Targets Implicated in the Onset of Type 2 Diabetes Mellitus (T2DM) and Its Complications

Abstract

Background: Type 2 diabetes mellitus (T2DM) is an ongoing, risky, and costly health problem that therefore always requires new treatment options. Moreover, although several drugs are available, only 36% of patients achieve glycaemic control, and patient adherence is a major obstacle. With monotherapy, T2DM and its comorbidities/complications often cannot be managed, and the concurrent administration of several hypoglycaemic drugs is required, which increases the risk of side effects. In fact, despite the efficacy of the drugs currently on the market, they generally come with serious side effects. Therefore, scientific research must always be active in the discovery of new therapeutic agents.

Discussion: The present review highlights some of the recent discoveries regarding marine natural products that can modulate the various targets that have been identified as crucial in the establishment of T2DM disease and its complications, with a focus on the compounds isolated from marine invertebrates. The activities of these metabolites are illustrated and discussed.

Objectives: The paper aims to capture the relevant evidence of the great chemical diversity of marine natural products as a key tool that can advance understanding in the T2DM research field, as well as in antidiabetic drug discovery. The variety of chemical scaffolds highlighted by the natural hits provides not only a source of chemical probes for the study of specific targets involved in the onset of T2DM, but is also a helpful tool for the development of drugs that are capable of acting via novel mechanisms. Thus, it lays the foundation for the design of multiple ligands that can overcome the drawbacks of polypharmacology.

Keywords: diabetes mellitus; drug discovery; enzymatic targets; marine invertebrates; marine natural products; metabolic diseases.

Figure 1

Structure of sulfircin (1), the first reported marine-derived PTP1B inhibitor.

Figure 2

Structures of natural and semisynthetic sesquiterpene quinones/hydroquinones 2–18.

Figure 3

Structures of avarone (19) and its methylamino derivatives 20 and 21.

Figure 4

Structure of hydoxybutenolide (22), microcionin-4 (23), and dihydropallescensin (24).

Figure 5

Structures of nakafuran-8 (25), O-methylnakafuran-8 lactone (26), euryspongins A–C (compounds 27–29), and the semisynthetic compound dehydrospongin A (30).

Figure 6

Structures of cinerols A–C (31–33) and cinerol F (34).

Figure 7

Structures of compound 35 and 36.

Figure 8

Structures of frondoplysins A (37) and B (38).

Figure 9

Structures of nakijinol G (39) and its inactive congeners nakijinol B (40) and agelasine G (41).

Figure 10

Structures of sesquiterpenes 42–44.

Figure 11

Structures of compounds 45–47.

Figure 12

Structures of diterpenoids 48–59.

Figure 13

Structures of strongylophorines (60–66).

Figure 14

Structures of the diterpene-type compounds 67–70.

Figure 15

Structure of hippolide derivatives 71–77.

Figure 16

Structures of scalarane-type sesterterpenes: hyattellactones A and B (78 and 79), phyllofolactones F and G (80 and 81), and compounds 82–83.

Figure 17

Structures of (7E, 12E, 20Z, 18S)-variabilin and (12E, 20Z, 18S)-8-hydroxyvariabilin (84 and 85, respectively), as well as furospongin-1 (86) and 11-O-acetylfurospongin-1 (87).

Figure 18

Structures of hyrtiosal (88) and stellettin G (89).

Figure 19

Structures of sterols 90–95.

Figure 20

Structure of polybromodiphenyl ether derivatives 96–104.

Figure 21

Structures of bromo-spiroalkaloids (compounds 105 and 106) and brominated lipid (compound 107).

Figure 22

Structure of phosphoeleganin (108) and its semisynthetic derivatives 109 and 110.

Figure 23

Structure of woodylide C (111).

Figure 24

Structures of melophlin C (112) and some active polyacetylene derivatives 113–116.

Figure 25

Structures of 5-alkylpyrrole-2-carboxaldehyde derivatives 117–123.

Figure 26

Structures of sulfates isolated from Penares sp. (124–129).

Figure 27

Structures of polyacetylenic acids from marine sponges (130–133).

Figure 28

Structures of unsaturated fatty acids 134 and 135, as well as the tricyclic spiroketal compound 136.

Figure 29

Structures of glycosides 137–141, gallic acid (142), and its methyl ether derivative (143). Helianthamide and magnificamide are reported with disulfide connectivity, which is highlighted by the same color of bonding partners.

Figure 30

Structures of carteriosulfonic acids A–C (144–146) and the semisynthetic derivative 147.

Figure 31

Structures of natural manzamine derivatives 148–151.

Figure 32

Structure of (Z)-5-(4-hydroxybenzylidene)hydantoin (167).

Figure 33

Structures of palinurin (168) and of ircinin-1 and ircinin-2 (169 and 170).

Figure 34

Structure of meridianins 170–176 and iso-meridianins 177 and 178.

Figure 35

Structure of nelliellosides A and B (179 and 180) and the halenaquinol sulphate (compound 181).

Figure 36

Structure of hymenialdisine (182), spongiacidin B (183), and leucettamine B (184).

Figure 37

Structures of polyandrocarpamines A and B (185 and 186), clathridine (187), and clathridimine (188).

Figure 38

Structures of polybrominated diphenyl ethers (compounds 189–191) and alkaloids 192–195.

Figure 39

Structure of rubrolides 196–203.

Figure 40

Structures of spongiacidins 204–210.

Figure 41

Structures of psammaplin A (211), compounds 212–214, gracilioethers B and C (215–216), and plakilactone C (217).

Figure 42

Structures of compounds 218–222.

Figure 43

Structure of (−)-muqubilin A (223).

Figure 44

Graphical description of the main classes of MNPs and MNP-derived compounds involved in T2DM and its complications.

Figure 45

Numerical representation of the reported MNPs and their semisynthetic derivatives involved in T2DM and related complications. (A) Relative percentage of bioactive MNPs and MNP-derived compounds with respect to the selected targets. (B) Histogram of MNPs active on a specific target, categorized by the most representative invertebrates.