Marine Heterocyclic Compounds That Modulate Intracellular Calcium Signals: Chemistry and Synthesis Approaches

Abstract

Intracellular Ca²⁺ plays a pivotal role in the control of a large series of cell functions in all types of cells, from neurotransmitter release and muscle contraction to gene expression, cell proliferation and cell death. Ca²⁺ is transported through specific channels and transporters in the plasma membrane and subcellular organelles such as the endoplasmic reticulum and mitochondria. Therefore, dysregulation of intracellular Ca²⁺ homeostasis may lead to cell dysfunction and disease. Accordingly, chemical compounds from natural origin and/or synthesis targeting directly or indirectly these channels and proteins may be of interest for the treatment of cell dysfunction and disease. In this review, we show an overview of a group of marine drugs that, from the structural point of view, contain one or various heterocyclic units in their core structure, and from the biological side, they have a direct influence on the transport of calcium in the cell. The marine compounds covered in this review are divided into three groups, which correspond with their direct biological activity, such as compounds with a direct influence in the calcium channel, compounds with a direct effect on the cytoskeleton and drugs with an effect on cancer cell proliferation. For each target, we describe its bioactive properties and synthetic approaches. The wide variety of chemical structures compiled in this review and their significant medical properties may attract the attention of many different researchers.

Keywords: calcium channel; heterocycles; marine drugs; medicinal properties; total synthesis.

Figure 1

Ion channels, transport proteins and Ca²⁺ regulated functions targeted by heterocycles (+ activator, − inhibitor).

Figure 2

Viridicatol.

Scheme 1

Synthesis of viridicatol by Kamal and Babu.

Scheme 2

Kobayashi and Harayama’s synthesis of viridicatol.

Scheme 3

Synthesis of viridicatol by Mamedov’s group.

Figure 3

Structure of zooxanthellatoxin A 10 (ZT-A).

Scheme 4

Degradation of ZT-A.

Scheme 5

Obtention of spiroacetal alcohol peracetates 13 and 14 from ZT-A (10).

Scheme 6

Synthesis of spiroacetal fragments 16 and 17 from intermediate 15.

Figure 4

Structure of tetrahydropyran 18 and its acyclic derivatives 19, 20 and 21.

Scheme 7

Structural fragments 23 and 24.

Scheme 8

Synthesis of fragment 23.

Figure 5

Structures of massadine 27 and massadine chloride 28.

Scheme 9

Baran’s total synthesis of massadine 27 and massadine chloride 28.

Scheme 10

Synthesis of norbornene derivative 31 by Ugi-4-component reaction and further elaboration to CD-ring subunit 35.

Scheme 11

Synthesis of the D-ring subunit 36 of massadine proposed by Lee.

Scheme 12

Cannon’s synthesis of the CD-ring subunit 41 of massadine.

Figure 6

The crambescidin family.

Scheme 13

Moore’s synthesis of crambrescidin 359 (45).

Scheme 14

Total synthesis of crambescidin 359 (45).

Scheme 15

Overman’s synthesis of crambescidin 359 (45).

Figure 7

Structure of maitotoxin (53).

Scheme 16

Formation of the WXYZA’B’C’ ring by Oishi group.

Scheme 17

Stereoselective formation of the C’D’E’F’ ring by Oishi group.

Scheme 18

Stereoselective formation of the QRS ring by Oishi group.

Figure 8

Structure of yessotoxin.

Scheme 19

Mori’s synthesis of BCDE ring.

Scheme 20

Kadota’s synthesis of FGHI ring.

Scheme 21

Kadota’s approach to the IJK ring system of yessotoxin.

Scheme 22

Oishi’s synthesis of the ABC ring.

Scheme 23

Oishi’s synthesis of IJ ring.

Scheme 24

Oishi’s synthesis of the FGHIJ ring.

Scheme 25

Zhang and Rainier’s approach to the ABCDEF ring system of yessotoxin.

Scheme 26

Zhang and Rainier’s approach to the FGHI ring system of yessotoxin.

Figure 9

Structure of palytoxin and palytoxin carboxylic acid.

Scheme 27

Retrosynthesis of palytoxin carboxylic acid.

Scheme 28

Synthesis of fragment 105 of palytoxin carboxylic acid.

Scheme 29

Synthesis of fragment 107 of palytoxin carboxylic acid.

Scheme 30

Synthesis of fragment 108 of palytoxin carboxylic acid.

Scheme 31

Synthesis of palytoxin.

Figure 10

Structures of latrunculin A and B.

Scheme 32

Fürstner’s synthesis of latrunculin A.

Scheme 33

White’s synthesis of latrunculin A.

Scheme 34

Smith highly convergent synthesis of latrunculin A.

Scheme 35

White’s synthesis of latrunculin A.

Figure 11

Structure of mandelalide A (130).

Scheme 36

Synthesis of the tetrahydropyran unit.

Scheme 37

Synthesis of the tetrahydrofuran building block 137.

Figure 12

Structures of the patellamide family.

Scheme 38

Synthesis of patellamides B and C by Hamada and Shioiri.

Scheme 39

Schmidt’s synthesis of patellamide B.

Scheme 40

Synthesis of patellamide A by VanNieuwenhze.

Figure 13

Structures of some members of the lamellarin family.

Scheme 41

Total synthesis of lamellarin D by Chandrasekhar.

Scheme 42

Khan’s synthesis of lamellarin D trimethyl ether.

Scheme 43

Michael’s synthesis of lamellarin D trimethyl ether.