Membrane Conformations and Their Relation to Cytotoxicity of Asimicin and Its Analogues

Abstract

Certain plant species belonging to the family Annonaceae produce Annonaceous acetogenins, which are a unique class of long-chain fatty acid derivatives with potent cytotoxicity. Putative protein targets of the acetogenins are membrane-associated proteins, including complex I. Asimicin and its analogues constitute a class of Annonaceous acetogenins containing two tetrahydrofuran (THF) rings with hydrocarbon chains tethered to each ring; an alpha,beta-unsaturated gamma-lactone ring is terminal to one of the alkyl chains. The compounds examined in this study differ in the length of the alkyl chain between the THF rings and the lactone ring. The positions of both the THF and the lactone rings within liposomal membranes were determined by proton (1H) nuclear magnetic resonance spectroscopy. The depth of membrane penetration of acetogenins, coupled to membrane diffusion, controls the conformation of acetogenins as they diffuse to an active site. Based on 1H intermolecular nuclear Overhauser effects (NOEs), the THF rings of all acetogenins studied reside near the polar interfacial head group region of the DMPC. This was corroborated by 1H two-dimensional NOE spectroscopy and differential scanning calorimetry studies. The 1H difference NOE spectra indicated that the lactone rings of asimicin and parviflorin, the latter of which has two fewer carbons in its alkyl chain, are located below the glycerol backbone in the membrane. In contrast with asimicin and parviflorin, the lactone ring of longimicin B, an asimicin analogue with an alkyl chain four carbons shorter, resides close to the midplane in the membrane. This was corroborated by manganese-induced broadening studies. Since the THF rings are located near the center of the acetogenin molecules and the lactone ring is terminal to a long alkyl chain, these observations indicate that an asimicin-type acetogenin can be in either sickle-shaped or U-shaped conformations, depending on the length of the alkyl chain between the THF rings and the lactone ring. Interestingly, longimicin B does not exhibit significant cytotoxicity, but parviflorin is as cytotoxic as asimicin. The cytotoxicity of the asimicin-type of acetogenins would seem to be strongly related to the membrane conformation. This is the first report elucidating the conformation of Annonaceous acetogenins in membranes.

Inhibitory Activities of Three Annonaceous Acetogenins on NADH Oxidase of Chicken Liver Mitochondria

“…12,13) Besides these important structures, the factors deciding the potency of ACG included dissolubility in cells and mitochondria, the conformation of mitochondrial membrane, transportation, and the metabolism of energy conservation. 14) ACG were absorbing so much because of their potent inhibitory effects on many sorts of cells. Cancer cells had an unusual action mechanism of energy conservation such as higher respiration and energy production, and this kind of energy metabolism made it more easily inhibited by ACG than normal cells.…”

Quinone-Annonaceous Acetogenins: Synthesis and Complex I Inhibition Studies of a New Class of Natural Product Hybrids

“…Removal of the solvents and purification of the residue by column chromatography (20 g silica, CHCl 3 /MeOH 10:1) was performed to isolate unconverted bi-THF diol 17 (78 mg, 386 mmol). (all-R)-5'-(5''-Benzyloxymethyl-tetrahydrofuran-2''-yl)-tetrahydrofuran-2'-carbaldehyde (20): Oxalyl dichloride (140 mL, 1.61 mmol) was dissolved in CH 2 Cl 2 (10 mL). The solution was cooled to À 60 8C and DMSO (250 mL, 3.54 mmol) in CH 2 Cl 2 (5 mL) was added.…”

“…[20] However, it is possible to substitute this structural unit with a quinone group without loss of activity, and by a carboxylic acid with only a little loss of activity. Therefore, these structural features probably interact with complex I in a related fashion.…”

Natural and Derivatized Acetogenins Promising for the Control of <i>Spodoptera frugiperda</i> Smith

“…ACG acetylated (OAc) derivatives: squamocin (3 OAc) (11), molvizarin (3 OAc) (12) and motrilin (3 OAc) (13), and their methoxy methylated (MOM) derivatives: squamocin (MOM) (14) and motrilin (MOM) (15) (Figure 2) were synthesized and purified, and then characterized by spectroscopic techniques (Table 1 and Table 2). …”