Irvalec Inserts into the Plasma Membrane Causing Rapid Loss of Integrity and Necrotic Cell Death in Tumor Cells

Abstract

Irvalec is a marine-derived antitumor agent currently undergoing phase II clinical trials. In vitro, Irvalec induces a rapid loss of membrane integrity in tumor cells, accompanied of a significant Ca2+ influx, perturbations of membrane conductivity, severe swelling and the formation of giant membranous vesicles. All these effects are not observed in Irvalec-resistant cells, or are significantly delayed by pretreating the cells with Zn2+. Using fluorescent derivatives of Irvalec it was demonstrated that the compound rapidly interacts with the plasma membrane of tumor cells promoting lipid bilayer restructuration. Also, FRET experiments demonstrated that Irvalec molecules localize in the cell membrane close enough to each other as to suggest that the compound could self-organize, forming supramolecular structures that likely trigger cell death by necrosis through the disruption of membrane integrity.

A Small Molecule with Anticancer and Antimetastatic Activities Induces Rapid Mitochondrial-Associated Necrosis in Breast Cancer

“…Natural product toxins such as the kahalalides induce rapid cell death, but likely oligomerize directly to form pores in cellular membranes (Molina-Guijarro et al, 2011). Honokiol is a small molecule lignan isolated from tree bark found to induce mitochondrial dysfunction and necrosis (Li et al, 2007).…”

The first total synthesis of the cyclodepsipeptide pipecolidepsin A

“…Finally, the membrane permeabilization assays and the morphological changes observed by phase contrast microscopy indicated that pipecolidepsin A induced a lytic process that leads to rapid necrotic cell death. Given that the cellular effects observed with pipecolidepsin A are quite similar to those detected with the structurally related compound Irvalec 37 , it is likely that these compounds share a common mechanism of action, directly interacting with the plasma membrane of tumour cells. Interestingly, the cyclodepsipeptide lacking the diol (DADHOHA) moiety did not show any cytotoxicity, thereby highlighting the relevance of the linear peptidic arm and pointing out the importance of the distinctive head-to-side-chain scaffold in the biological activity of these natural products.…”

Crystal structure of 2-ethyl-1-tert-butyl-2-((4-fluorophenyl)(tert-butoxycarbonylamino)methyl)-3-oxo-pyrrolidine-1,2-dicarboxylate, C24H33FN2O7

“…Oxopyrrolidine molecules with a proline backbone have been considered for a wide range of applications such as ACE inhibitors, antibacterial, antitumor properties and applications in asymmetric catalysis [1][2][3]. The asymmetric synthesis of pyrrolidine derivatives for both biological and catalytic purposes has received signi cant attention.…”