Tamoxifen-like metallocifens target thioredoxin system determining mitochondrial impairment leading to apoptosis in Jurkat cells

Tamoxifen-like metallocifens (TLMs) of the group-8 metals (Fe, Ru, and Os) show strong anti-proliferative activity on cancer cell lines resistant to apoptosis, owing to their unique redox properties. In contrast, the thioredoxin system, which is involved in cellular redox balance, is often overexpressed in cancer cells, especially in tumour types resistant to standard chemotherapies. Therefore, we investigated the effect of these three TLMs on the thioredoxin system and evaluated the input of the metallocene unit in comparison with structurally related organic tamoxifens. In vitro, all three TLMs became strong inhibitors of the cytosolic (TrxR1) and mitochondrial (TrxR2) isoforms of thioredoxin reductase after enzymatic oxidation with HRP/H2O2 while none of the organic analogues was effective. In Jurkat cells, TLMs inhibited mainly TrxR2, resulting in the accumulation of oxidized thioredoxin 2 and cell redox imbalance. Overproduction of ROS resulted in a strong decrease in the mitochondrial membrane potential, translocation of cytochrome c to the cytosol and activation of caspase 3, thus leading to apoptosis. None of these events occurred with organic tamoxifens. The mitochondrial fraction of cells exposed to TLMs contained a high amount of the corresponding metal, as quantified by ICP-OES. The lipophilic and cationic character associated with the singular redox properties of the TLMs could explain why they alter the mitochondrial function. These results provide new insights into the mechanism of action of tamoxifen-like metallocifens, underlying their prodrug behaviour and the pivotal role played by the metallocenic entity in their cytotoxic activity associated with the induction of apoptosis

Photoinduced Coupling of Acetylenes and Quinone in the Solid State as Preorganized Donor−Acceptor Pairs

Crystalline electron donor−acceptor (EDA) complexes of various diarylacetylenes (DA) and dichlorobenzoquinone (DB) are isolated and structurally characterized by X-ray crystallography. Deliberate excitation of either the DB acceptor at λDB = 355 nm or the 1:2 [DA, 2DB] complex at λCT = 532 nm in the solid state leads to [2 + 2] cycloaddition and identical (isomeric) mixtures of the quinone methide products. Time-resolved (ps) diffuse reflectance spectroscopy identifies the ion-radical pair [DA•+, DB•-] as the reactive intermediate derived by photoinduced electron transfer in both photochemical procedures. The effects of crystal-lattice control on the subsequent ion-radical pair dynamics are discussed in comparison with the same photocouplings of acetylenes and quinone previously carried out in solution

CYP712K4 catalyzes the C-29 oxidation of friedelin in the Maytenus ilicifolia quinone methide triterpenoid biosynthesis pathway

The native Brazilian plant Maytenus ilicifolia accumulates a set of quinone methide triterpenoids with important pharmacological properties, of which maytenin, pristimerin and celastrol accumulate exclusively in the root bark of this medicinal plant. The first committed step in the quinone methide triterpenoid biosynthesis is the cyclization of 2,3-oxidosqualene to friedelin, catalyzed by the oxidosqualene cyclase friedelin synthase (FRS). In this study, we produced heterologous friedelin by the expression of M. ilicifolia FRS in Nicotiana benthamiana leaves and in a Saccharomyces cerevisiae strain engineered using CRISPR/Cas9. Furthermore, friedelin-producing N. benthamiana leaves and S. cerevisiae cells were used for the characterization of CYP712K4, a cytochrome P450 from M. ilicifolia that catalyzes the oxidation of friedelin at the C-29 position, leading to maytenoic acid, an intermediate of the quinone methide triterpenoid biosynthesis pathway. Maytenoic acid produced in N. benthamiana leaves was purified and its structure was confirmed using high-resolution mass spectrometry and nuclear magnetic resonance analysis. The three-step oxidation of friedelin to maytenoic acid by CYP712K4 can be considered as the second step of the quinone methide triterpenoid biosynthesis pathway, and may form the basis for further discovery of the pathway and heterologous production of friedelanes and ultimately quinone methide triterpenoids

Stereoselective Synthesis of Atropisomeric Acridinium Salts by the Catalyst-Controlled Cyclization of ortho-Quinone Methide Iminiums

Quinone methides are fundamental intermediates for a wide range of reactions in which catalyst stereocontrol is often achieved by hydrogen bonding. Herein, we describe the feasibility of an intramolecular Friedel-Crafts 6π electrocyclization through ortho-quinone methide iminiums stereocontrolled by a contact ion pair. A disulfonimide catalyst activates racemic trichloroacetimidate substrates and imparts stereocontrol in the cyclization step, providing a new avenue for selective ortho-quinone methide iminium functionalization. A highly stereospecific oxidation readily transforms the enantioenriched acridanes into rotationally restricted acridiniums. Upon ion exchange, the method selectively affords atropisomeric acridinium tetrafluoroborate salts in high yields and an enantioenrichment of up to 93 : 7 e.r. We envision that ion-pairing catalysis over ortho-quinone methide iminiums enables the selective synthesis of a diversity of heterocycles and aniline derivatives with distinct stereogenic units

Arylmethylamino steroids as antiparasitic agents

In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC50 1–5?nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites

Synthesis and Chemistry of Naphthalene Annulated Trienyl Iron Complexes: Potential Anticancer DNA Alkylation Reagents

Iron complex chemistry that opens a new door to the medicinal and pharmaceutical worlds is the aim of this research. Specifically, ortho-quinone methide moieties are intermediates in several antitumor drugs and have been identified as bioreductive alkylators of DNA. In our research, a class of iron compounds has been targeted to resemble these quinone methides. It is hoped that these new compounds could be modified to provide a window of opportunity toward the discovery of a selective mode of drug delivery. We have focused our efforts on generating a reactive transition metal complexed 5-membered ring analog of o-quinone methide based on our earlier reports of CpFe(CO)2 (butadienyl) complexes. In this vein, we have elaborated this chemistry by preparing and reacting a lithionaphthalene allene with CpFe(CO)2I. which gave the desired naphthalene annulated sigma complex. This complex thermally rearranged to the desired naphthalene annulated 5-membered ring quinone methide analog. Upon photolysis, this complex successfully mimicked its antecedent and alkylated alcohols. Thus, we here report our initial study of the preparation and chemistry of a transition metal complexed 5-membered ring quinone methide analog. Its reactions with alcohols have accomplished the first step toward the ultimate goal of selectively alkylating DNA

Reactivity of the Quinone Methide of Butylated hydroxytoluene in Solution

BHT is a common antioxidant in pharmaceutical formulations and when oxidized it forms a quinone methide (QM). QM is a highly reactive electrophilic species which can undergo nucleophilic addition. This research investigated the kinetic reactivity of QM with water at various pH values and in the presence of sodium chloride and phosphate, acetate, and TAPS buffers. The presence of HCl, HClO4, NaOH, NaCl, and phosphate buffers resulted in simple first order kinetics for disappearance of QM and the formation of a single product (OH-adduct); the reaction was subject to strong acid/base catalysis. The presence of acetate and TAPS buffers resulted in complicated kinetics suggesting the formation of an additional product in equilibrium with QM. These results indicate adduct formation with other nucleophilic excipients is likely which has implications for both the drug product impurity profile and specifications. Due to these considerations BHT should be used with caution

Biochemistry of 1, 2-Dehydro-N-Acetyldopamine Derivatives

Dehydrodopa/dopamine derivatives form an important group of biomolecules participating in sclerotization of all arthropod cuticles, gluing and cementing mussels and related organisms to solid surfaces, and defense reactions of countless marine and invertebrate organisms. Yet very little information is available on the biochemistry of these highly reactive and unstable molecules. To understand their physiological role, I conducted a thorough biochemical study on three representative compounds that cover the entire plethora of dehydrodopa/dopamine derivatives. Employing diode array UV-visible spectroscopy, HPLC, liquid chromatography-mass spectrometry, and electrospray ionization tandem mass spectrometry, I investigated the oxidation chemistry of 1,2-dehydro-N-acetyldopamine (dehydro NADA), 1,2-dehydro-N-acetyldopa and 1,2-dehydro-N-acetyldopa methyl ester. Tyrosinase converted dehydro NADA to a reactive quinone methide that formed oligomeric products with the parent compound. The sister enzyme laccase, produced semiquinone radicals that exhibited a novel coupling reaction producing just dimers. Nonenzymatic oxidation of dehydro NADA also produced semiquinone radicals that formed oligomeric products. Moreover, nonenzymatic oxidation resulted in the production of superoxide anions that could function in defense reactions. The nonenzymatic oxidation studies on dehydro NADA at mild alkaline conditions revealed the mechanisms of defense reactions and tunic formation in a vast array of tunicates. Oxidative transformations of 1,2-dehydro-N-acetyldopa indicated a new route for the biosynthesis of a vast array of bioactive marine molecules possessing dihydroxycoumarin skeleton. In addition, it revealed new transformations of coumarins to oligomeric products via highly reactive quinone methide intermediates. Biochemical studies on 1,2-dehydro-N-acetyldopa methyl ester revealed a new Diels Alder type condensation of its quinone with the parent compound. This reaction shed light on the mode of gluing of mussels and other bivalves to solid surfaces as well as the hardening reactions occurring in their periostracum. I also examined the oxidation chemistry of dehydro NADA with a model nucleophile, N-acetylcysteine and discovered yet another new addition reaction of dehydro NADA that has tremendous biological significance. Finally, I investigated the mechanism of dehydro NADA binding to insect cuticle using labeled compounds and established that they could uniquely produce ketocatecholic compound, arterenone upon hydrolysis. The biochemical significances of all these new reactions are discussed in the dissertation

Enantioselective multicomponent organoboron reactions of ortho-quinone methide intermediates catalyzed by chiral biphenols

Ortho-quinone methides are reactive intermediates with wide ranging applications in organic synthesis. However, their propensity to rearomatize renders them transitory and reactive, which has made their implementation in organic synthesis challenging. An asymmetric and organocatalytic multicomponent reaction platform was developed to address this challenge by accessing ortho-quinone methide intermediates in situ through a Friedel-Crafts hydroxy-alkylation condensation of phenols, aldehydes, and boronates. This approach provided a practical and general method to access to chiral di- and triaryl methane products in high yields and enantioselectivities from commercially available starting materials. An unanticipated cyclization pathway was discovered while exploring the scope of the reaction that afforded 2,4-diarylchroman products from an electron rich styrenyl boronate. Reaction conditions were optimized to select for the cyclization pathway, which afforded chroman products with high levels of enantio- and diastereoselectivity. The myristinin natural products are DNA polymerase-β inhibitors and DNA-damaging agents that contain a privileged chroman scaffold within their core. The multicomponent cyclization strategy was applied towards the synthesis of the myristinin natural products without success. To circumvent issues with reactivity, the multicomponent reaction platform was extended to an intermolecular cycloaddition of in situ generated ortho-quinone methides from phenols, aldehydes, and styrenes to provide 2,4-diarylchromans. The core of myristinins B/C was synthesized using the multicomponent cycloaddition strategy providing high yield and diastereoselectivity with remarkable step economy. An enantioselective version of the multicomponent cycloaddition reaction was developed utilizing triisopropyl borate Lewis acid and a chiral biphenol.2018-06-21T00:00:00