François Dufrasne

Cardiotonic Steroids-Mediated Targeting of the Na+/K+-ATPase to Combat Chemoresistant Cancers.

A large proportion of cancer patients fail to respond to conventional chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli and/or the acquisition of a multidrug resistant (MDR) phenotype during chronic chemotherapy. A new angle in chemotherapeutics against these cancer types associated with dismal prognoses would be the targeting of specific ion channels and pumps over expressed by cancer cells as compared to normal cells. Several reports suggest that the alpha subunits of the Na(+)/K(+)-ATPase (referred as sodium pump from now on) could be such targets, using cardiotonic steroids (CS) including cardenolides and bufadienolides. A significant proportion of non-small-cell-lung cancers (NSCLCs), glioblastomas (GBMs), melanomas and kidney cancers overexpresses the alpha-1 subunit of the sodium pump as compared to corresponding normal tissues, while colon cancers overexpress the alpha-3 subunit. Thus, a deeper knowledge of the structure-activity relationship (SAR), in terms of CS-mediated anticancer effects, to the sodium pump alpha subunits might enable the identification of potent anticancer agents with limited cardiotoxicity. The current review provides an in depth SAR analysis with respect to cardenolide- versus bufadienolide-mediated anticancer effects. Moreover, pharmacological data from in vitro and in vivo experiments, as well as pre-clinical and clinical trials regarding cardenolides to combat cancers associated with dismal prognoses are presented.

Structure-Based Design, Synthesis, and Pharmacological Evaluation of 3-(Aminoalkyl)-5-fluoroindoles as Myeloperoxidase Inhibitors

Oxidized low-density lipoproteins (LDLs) accumulate in the vascular wall and promote local inflammation, which contributes to the progression of the atheromatous plaque. The key role of myeloperoxidase (MPO) in this process is related to its ability to modify APO B-100 in the intima and at the surface of endothelial cells. A series of 3-(aminoalkyl)-5-fluoroindole analogues was designed and synthesized by exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor. In vitro assays were used to study the effects of these compounds on the inhibition of MPO-mediated taurine chlorination and oxidation of LDLs. The kinetics of the interaction between the MPO redox intermediates, Compounds I and II, and these inhibitors was also investigated. The most potent molecules possessed a 4- or 5-carbon aminoalkyl side chain and no substituent on the amino group. The mode of binding of these analogues and the mechanism of inhibition is discussed with respect to the structure of MPO and its halogenation and peroxidase cycles.

DYRK1A Kinase Inhibitors with Emphasis on Cancer

Various types of cancers (including gliomas, melanomas, and esophageal, pancreas and non-small-cell lung cancers) display intrinsic resistance to pro-apoptotic stimuli, such as conventional chemotherapy and radiotherapy, and/or the activation of a multidrug resistance phenotype, which are major barriers to effective treatment and lead to poor patient prognosis. The DYRK1A kinase is directly implicated in the resistance of cancer cells to pro-apoptotic stimuli and drives several pathways that enhance proliferation, migration, and the reduction of cell death, leading to very aggressive biological behavior in cancer cell populations. The DYRK1A kinase is also implicated in neurological diseases and in neoangiogenic processes. Thus, the DYRK1A kinase is of great interest for both cancer and neuroscience research. During the last decade, numerous compounds that inhibit DYRK1A have been synthesized. The present review discusses the available molecules known to interfere with DYRK1A activity and the implications of DYRK1A in cancer and other diseases and serves as a rational analysis for researchers who aim to improve the anti-DYRK1A activity of currently available compounds.

Simple di- and trivanillates exhibit cytostatic properties toward cancer cells resistant to pro-apoptotic stimuli

A series of 33 novel divanillates and trivanillates were synthesized and found to possess promising cytostatic rather than cytotoxic properties. Several compounds under study decreased by >50% the activity of Aurora A, B, and C, and WEE1 kinase activity at concentrations <10% of their IC(50) growth inhibitory ones, accounting, at least partly, for their cytostatic effects in cancer cells and to a lesser extent in normal cells. Compounds 6b and 13c represent interesting starting points for the development of cytostatic agents to combat cancers, which are naturally resistant to pro-apoptotic stimuli, including metastatic malignancies.

The relation between stereochemistry and biological activity of platinum(II) complexes chelated with chiral diamine ligands : An intricate problem+

The origin of activity differences between stereoisomers of anticancer platinum(II) complexes chelated with chiral diamine ligands has been almost exclusively explained by diastereoselective interactions with DNA. Although this model has been widely accepted in vitro and in vivo experiments showed some conflicting results, leading to the conclusion that other biomolecules might be responsible for this stereoselectivity as well. These compounds, called bionucleophiles, are in most instances amino acids or proteins present in biological fluids. As these chiral molecules are very reactive towards the platinum complexes, they may contribute to stereoselectivity, but also to resistance and toxicity. This review gives a general survey of chiral platinum(II) complexes and their interactions with DNA. The bionucleophiles which have been identified and the consequences of their reaction with platinum(II) complexes are discussed. Analytical techniques used to investigate interactions between established and potential chiral platinum drugs and bionucleophiles are presented.

1H-nuclear magnetic resonance determination of the enantiomeric purity of aliphatic primary amines, β-aminoalcohols, β-diamines and α-amino-acids with 1R-(−)-myrtenal: scope and limitations

Abstract 1R-(−)-myrtenal was tested as a chiral derivatising agent for the determination of the enantiomeric purity of aliphatic primary amines, β-aminoalcohols, β-diamines and α-amino-acids. Derivatisation procedure consists in mixing one equivalent each of the amine and 1R-(−)-myrtenal directly into the nuclear magnetic resonance (NMR) tube before addition of the appropriate deuterated solvent and, for α-amino-acids, one equivalent of NaOH was added to neutralise the acidic function. Diastereoisomeric imines were completely formed after 12 h and analysed by 1H-NMR except for N-methyl β-diamines for which imidazolidines were obtained. The method gave satisfactory results only for α- and β-arylalkylamines for which CDCl3 could be advantageously replaced by C6D6 or pyridine-d5 in order to increase the difference between the chemical shifts. The main advantage of the procedure is its simplicity as it does not involve steps such as activation, heating, solvent evaporation and isolation of the product. Its limitations are the limited series of compounds susceptible to be analysed and the small difference between the chemical shifts of the diastereoisomeric imines obtained.

Design, synthesis, and structure-activity relationship studies of novel 3-alkylindole derivatives as selective and highly potent myeloperoxidase inhibitors.

Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed.

Na+/K+-ATPase and cancer.

The sodium pump, Na(+)/K(+)-ATPase, could be an important target for the development of anticancer drugs as it serves as a versatile signal transducer, plays a key role in cell adhesion and has abnormal expression and activity that are implicated in the development and progression of different cancers. Several publications have reported differing expression of Na(+)/K(+)-ATPase α- and β-subunits in malignant tissues compared with their normal tissue counterparts, thus offering a powerful diagnostic tool. A growing number of patent applications claim the invention or discovery of Na(+)/K(+)-ATPase inhibitors (e.g., cardiac glycosides) to be used to effectively treat certain cancers that are refractory to conventional chemotherapy or radiotherapy. The aims of this review are to provide an overview of the most significant patents that highlight Na(+)/K(+)-ATPase as a valuable target in anticancer therapy and which report on novel Na(+)/K(+)-ATPase inhibitors and ligands designed as potential anticancer agents.

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

Synthesis and Cytotoxicity of Enantiomerically Pure [1,2‐Diamino‐1‐(4‐fluorophenyl)‐3‐methylbutane]platinum(II) Complexes

A series of leaving group derivatives of enantiomerically pure [1,2‐diamino‐1‐(4‐fluorophenyl)‐3‐methylbutane]platinum(II) complexes were synthesized and tested for cytotoxicity. The enantiomeric purity was determined by 1H NMR spectroscopy on the final diamines after derivation with (1R)‐myrtenal. For coordination to platinum, the diamines were reacted with K2PtI4. The treatment of diiodoplatinum(II) complexes (4F‐Ph/iProp‐PtI2) with Ag2SO4 resulted in the sulfatoplatinum(II) complexes (4F‐Ph/iProp‐PtSO4), which can be easily transformed to dichloroplatinum(II) complexes (4F‐Ph/iProp‐PtCl2) with 2 n HCl. The importance of the leaving groups and the configuration at the diamine ligand on the antiproliferative effects was evaluated on the hormone‐dependent MCF‐7 and the hormone‐independent MDA‐MB 231 breast cancer cell lines as well as the LNCaP/FGC prostate cancer cell line. (R,R)‐4F‐Ph/iProp‐PtCl2 was identified as the most active platinum(II) complex. The 3‐methyl group increased antiproliferative effects relative to the [1,2‐diamino‐1‐(4‐fluorophenyl)butane]platinum(II) complexes described in an earlier study.