ABSTRACT
Ten acetogenins, one of them new, were isolated from leaves and twigs of a Bolivian collection of Annona montana. The new compound that we named tucupentol (1) is a mono-tetrahydrofuran-pentahydroxy-acetogenin. The inhibitory potency of tucupentol (1) on the mitochondrial complex I was evaluated, and this activity was compared with that of the known acetogenins, annonacin-A, cis-annonacin-10-one, aromin, and gigantetronenin, also isolated from this plant material. The mentioned acetogenins acted as selective inhibitors of mitochondrial complex I in the 0.8-5.4-nM range.
Subject(s)
Acetogenins/isolation & purification , Acetogenins/pharmacology , Annona/chemistry , Electron Transport Complex I/antagonists & inhibitors , Furans/isolation & purification , Furans/pharmacology , Animals , Bolivia , Cattle , Inhibitory Concentration 50 , Mitochondria, Heart/drug effects , Nuclear Magnetic Resonance, Biomolecular , Plant Leaves/chemistry , Plant Stems/chemistryABSTRACT
We describe herein the isolation and semisynthesis of four acetogenin derivatives (1-4) as well as their ability to inhibit the mitochondrial respiratory chain and several tumor cell lines. In addition, four nanoseconds (ns) of MD simulation of compound 4, in a fully hydrated POPC bilayer, is reported.
Subject(s)
Antineoplastic Agents, Phytogenic/biosynthesis , Fatty Alcohols/metabolism , Lactones/metabolism , Acetogenins , Annona/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Computer Simulation , Electron Transport/drug effects , Fatty Alcohols/pharmacology , Furans/pharmacology , Humans , Hydrogen Bonding , Indicators and Reagents , Lactones/pharmacology , Lipid Bilayers , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Phosphatidylcholines/chemistry , Seeds/chemistryABSTRACT
The antitumoral activity of a series of acetylated bis-tetrahydrofuranic acetogenins with a threo/trans/threo/trans/erythro relative configuration was characterized by four new natural and two semisynthetic, 15,24,30-trioxygenated acetogenins that were found to inhibit mitochondrial complex I enzyme as well as growth of several tumor cell lines. Placement of acetyl groups along the alkyl chain modulated the potency of the bis-tetrahydrofuranic acetogenins and could be important for future utilization of these compounds as chemotherapeutic agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Electron Transport Complex I/antagonists & inhibitors , Fatty Alcohols/chemical synthesis , Fatty Alcohols/pharmacology , Growth Inhibitors/chemical synthesis , Growth Inhibitors/pharmacology , Lactones/chemical synthesis , Lactones/pharmacology , Acetogenins , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Electron Transport Complex I/metabolism , Fatty Alcohols/chemistry , Growth Inhibitors/chemistry , Humans , Lactones/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Neoplasms/enzymology , Neoplasms/pathology , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
Annonaceous acetogenins are known to be cytotoxic against tumor cell lines by virtue of their inhibition of mitochondrial complex I. We decided to conclude part of our recent revisions of the different structure-activity relationships (SARs) found within these compounds with a detailed description of the cytotoxic activity, and correlations with the inhibition of the target enzyme, of the broadest subclass of this family of natural products, the bis-tetrahydrofuranic acetogenins (bis-THF ACGs) of threo/trans/threo/trans/erythro relative configuration. Five naturally occurring ACGs and more than 10 semisynthetic analogs were tested against the MCF-7 (breast), A-549 (lung), HepG2 (liver), HT-29 (colon), MES-SA (ovary), and a multidrug-resistant (MDR-MES-SA/Dx5) cell lines using the MTr cytotoxicity assay to determine if the mitochondrial complex I inhibition correlated with the in vitro antitumor potency of the most common ACGs. Results indicated that a previously observed trend for other subclasses of ACGs between the ED50 of the cytotoxicity assay and the polarity of compounds was not present in this set and that there were several specific interactions that enhanced the antitumor activity. For example, some of the guanacone derivatives prepared were two orders of magnitude more potent than the parent compound for specific cell lines.
Subject(s)
Antineoplastic Agents, Phytogenic , Electron Transport Complex I/antagonists & inhibitors , Fatty Alcohols , Furans , Lactones , Mitochondria/drug effects , Acetogenins , Animals , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Cattle , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Fatty Alcohols/chemical synthesis , Fatty Alcohols/chemistry , Fatty Alcohols/pharmacology , Furans/chemical synthesis , Furans/chemistry , Furans/pharmacology , Humans , Lactones/chemical synthesis , Lactones/chemistry , Lactones/pharmacology , Mitochondria/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A new beta-hydroxy-gamma-methyl-gamma-lactone bistetrahydrofuranic acetogenin, tucumanin, with the infrequent symmetrical threo/trans/threo/trans/threo relative configuration at the tetrahydrofuran rings was isolated from Annona cherimolia (Annonaceae) seeds. The inhibitory potency on the mitochondrial complex I of acetogenins with this relative configuration (tucumanin and asimicin)was compared with that shown by the corresponding pairs with an asymmetrical threo/trans/threo/trans/erythro relative configuration (laherradurin/rolliniastatin-2, and itrabin/molvizarin). All these compounds act as selective inhibitors of mitochondrial complex I in the 0.18 - 1.55 nM range.
Subject(s)
Annona , Electron Transport Complex I/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Furans/pharmacology , Lactones/pharmacology , Phytotherapy , Plant Extracts/pharmacology , Electron Transport Complex I/metabolism , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/therapeutic use , Furans/administration & dosage , Furans/therapeutic use , Humans , Inhibitory Concentration 50 , Lactones/administration & dosage , Lactones/therapeutic use , Mitochondria, Heart/drug effects , Mitochondria, Heart/enzymology , Plant Extracts/administration & dosage , Plant Extracts/therapeutic use , SeedsABSTRACT
Four bisbenzyltetrahydroisoquinoline alkaloids (-)-medelline, (+)-antioquine, (+)-aromoline, and (+)-obamegine were isolated from the fruits of Xylopia columbiana. These compounds, the previously isolated alkaloids (+)-thaligrisine and (+)-isotetrandrine, as well as their O-acetylated derivatives were assayed on submitochondrial particles from beef heart as inhibitors of the mammalian respiratory chain. The results revealed that these alkaloids act as selective inhibitors of mitochondrial complex I in a 0.15 - 4.71 microM range. O-Acetylation, which increases their lipophilicity, considerably increased the inhibitory potency.
Subject(s)
Annonaceae , Benzylisoquinolines/pharmacology , Enzyme Inhibitors/pharmacology , NADH, NADPH Oxidoreductases/drug effects , Phytotherapy , Plant Extracts/pharmacology , Animals , Benzylisoquinolines/administration & dosage , Benzylisoquinolines/therapeutic use , Cattle , Electron Transport/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/therapeutic use , Inhibitory Concentration 50 , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , NADH, NADPH Oxidoreductases/antagonists & inhibitors , NADH, NADPH Oxidoreductases/biosynthesis , Plant Extracts/administration & dosage , Plant Extracts/therapeutic useABSTRACT
Modifications in the terminal alpha,beta-unsaturated gamma-methyl-gamma-lactone moiety or in the alkyl chain that links this terminal gamma-lactone with the alpha,alpha'-dihydroxylated THF system of the natural mono-tetrahydrofuranic acetogenins, annonacin and annonacinone, led to the preparation of eight semisynthetic derivatives. Their inhibitory effects on mitochondrial complex I is discussed and compared with that of the classical complex I inhibitor, rotenone.
Subject(s)
Electron Transport Complex I/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Fatty Alcohols/chemical synthesis , Fatty Alcohols/pharmacology , Lactones/chemical synthesis , Lactones/pharmacology , Acetogenins , Furans/chemical synthesis , Furans/pharmacology , Kinetics , Multienzyme Complexes/antagonists & inhibitors , NADH, NADPH Oxidoreductases/antagonists & inhibitorsABSTRACT
In this study we evaluated a mono-tetrahydrofuranic subgroup of natural acetogenins that had shown in previous enzyme inhibition studies different potency trends compared with the bis-tetrahydrofuranic acetogenin subgroup. The compounds were tested against colon, breast, lung, liver, and ovarian tumor cell lines. A drug-resistant ovarian cell line was also included in the panel. In general the compounds were more potent than doxorubicin. The goal was to determine how well the mitochondrial complex I inhibition correlates with the in vitro antitumor potency of these natural mono-tetrahydrofuranic acetogenins and of some derivatives. The results indicate that both the reduction of the terminal gamma-lactone after its translactonization and the introduction of an hydroxylimine group in the alkyl chain, near the mono-tetrahydrofuranic moiety, increased the antitumor activity, even against the doxorubicin-resistant cell line.
