Anticancer properties of lamellarins

Abstract

In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids.

Figure 1

Selected examples of pyrrole marine alkaloids.

Figure 2

Selected examples of natural lamellarins.

Figure 3

Selected examples of synthetic lamellarin derivatives. The pentacyclic A–E unit and/or the appended aryl group F are modified or truncated. The central pyrrole ring C is preserved whereas the lactone D ring is often removed or opened.

Figure 4

Polypharmacological action of lamellarin D. The drug affects several targets (stresses), leading to different cellular effects (responses) in cancer cells.

Figure 5

Apoptosis induced by lamellarin D (open bars) and camptothecin (black bars) in murine leukemia cells sensitive (P388) or resistant (P388CPT5) to camptothecin. Apoptosis was measured by cytometry, via the evaluation of the sub-G1 cell population.

Figure 6

Illustration of the polypharmacological activity of lamellarin D and drug design orientations to synthesize analogues with a more selective mechanism of action.