Marine Invertebrate Metabolites with Anticancer Activities: Solutions to the "Supply Problem"

Abstract

Marine invertebrates provide a rich source of metabolites with anticancer activities and several marine-derived agents have been approved for the treatment of cancer. However, the limited supply of promising anticancer metabolites from their natural sources is a major hurdle to their preclinical and clinical development. Thus, the lack of a sustainable large-scale supply has been an important challenge facing chemists and biologists involved in marine-based drug discovery. In the current review we describe the main strategies aimed to overcome the supply problem. These include: marine invertebrate aquaculture, invertebrate and symbiont cell culture, culture-independent strategies, total chemical synthesis, semi-synthesis, and a number of hybrid strategies. We provide examples illustrating the application of these strategies for the supply of marine invertebrate-derived anticancer agents. Finally, we encourage the scientific community to develop scalable methods to obtain selected metabolites, which in the authors' opinion should be pursued due to their most promising anticancer activities.

Keywords: discodermolide; eribulin; frondoside A; monanchocidin A; mycalamide A; phenylmethylene hydantoin; spongistatin 1; stelletin A; trabectedin.

Figure 1

Structures of spongouridine (1), spongothymidine (2) and didemnin B (3).

Figure 2

Structures of cytarabine (4), trabectedin (5), halichondrin B (6), eribulin (7), monomethylauristatin E (8) and dolastatin 10 (9).

Figure 3

Structures of bryostatin 1 (10), kahalalide F (11), eleutherobin (12), avarol (13), and manzamine A (14).

Figure 4

Structures of onnamide A (15), theopederin A (16) and irciniastatin A (17), aplidine (18), patellamide A (19) and C (20), discodermolide (21).

Figure 5

Total synthesis of Halaven^® starting from building blocks 22 and 24.

Figure 6

Retrosynthetic scheme illustrating the convergent approach in Corey’s synthesis of trabectedin.

Figure 7

Synthesis of the building block C.

Figure 8

Synthesis of the building block D.

Figure 9

Linking building blocks C and D and further manipulations to prepare for the incorporation of fragments A and B.

Figure 10

Incorporation of fragments A and B and completion of the synthesis of trabectedin.

Figure 11

Semisynthesis of trabectedin from cyanosafracin B.

Figure 12

Structures of mycalamide A (58), spongistatin 1 (59), stelletin A (60), monanchocidin A (61), phenylmethylene hydantoin (62), and frondoside A (63).