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The investigational anticancer agents laulimalide and peloruside are known to exert an antimitotic effect on cells by binding to β-tubulin. The binding affinities of derivatives of laulimalide and peloruside to all known isoforms of human β-tubulin were calculated using molecular mechanical, molecular dynamical, and quantum mechanical methods. Several of the derivatives are predicted to have improved β-tubulin binding affinities compared to the parent structures. These results can form the starting point for developing laulimalide or peloruside derivatives with greater specificity for the particular β-tubulin isoforms, which are overexpressed in certain tumours. Key words: peloruside, laulimalide, molecular mechanics, molecular dynamics, tubulin, cancer. Resume : Le laulimalide et le peloruside sont des agents anticancereux de recherches qui sont connus pour exercer un effet antimitotique sur les cellules par fixation a la β-tubuline. Faisant appel a des methodes de mecanique moleculaire, de dynamique moleculaire et de mecanique quantique, on a calcule d'une faon theorique les affinites de fixation des derives du laulimalide et du peloruside avec toutes les formes connues de la β-tubuline humaine. Il a ete possible de predire que plusieurs des derives ont des affinites ameliorees de fixation de la β-tubuline lorsque comparees aces des structures parentes. Ces resultats peuvent servir de point de depart pour developper des derives du laulimalide ou du peloruside qui auraient des specificites superieures par des isoformes particulieres de β-tubulines qui seraient surexprimees dans certaines tumeurs. [Traduit par la Redaction] Mots-cles: peloruside, laulimalide, mecanique moleculaire, dynamique moleculaire, tubuline, cancer., Introduction Approximately 647 000 deaths from cancer occurred in North America in 2011. (1,2) An estimated 1774 500 new cases of cancer were diagnosed in North America over the past [...]

Density functional theory (DFT) calculations for M--([C.sub.10][H.sub.12][N.sub.2][O.sub.8.sup.4-]) and M--[([H.sub.2]O).sub.6], where M = [Na.sup.+], [K.sup.+], [Rb.sup.+], [Mg.sup.2+], [Ca.sup.2+], and [Sr.sup.2+], and ([C.sub.10][H.sub.12][N.sub.2][O.sub.8.sup.4-]) = [EDTA.sup.4-], were carried out at both all-electron and pseudopotential levels. Results from these four methods were compared, and it was found that the ions bind to [EDTA.sup.4-] with selectivity of [Mg.sup.2+] > [Ca.sup.2+] > [Sr.sup.2+] > [Na.sup.+] > [K.sup.+] > [Rb.sup.+.] Key words: ethylenediamine tetraacetic acid (EDTA), alkali metal ions, alkaline earth metal ions, binding affinity. Faisant appel a la theorie de la fonctionnelle de la densite et operant aux niveaux de tous les electrons ainsi que du pseudopotentiel, on a effectue des calculs sur les cations M--([C.sub.10][H.sub.12][N.sub.2][O.sub.8.sup.4-])] et M--[([H.sub.2]O).sub.6] dans lesquels M = [Na.sup.+], [K.sup.+], [Rb.sup.+], [Mg.sup.2+], [Ca.sup.2+], et [Sr.sup.2+] et [C.sub.10][H.sub.12][N.sub.2][O.sub.8.sup.4-] = [EDTA.sup.4-]. Les resultats obtenus avec ces methodes ont ete compares entre eux et on a trouve que les ions se lient avec [EDTA.sup.4-] avec la selectivite suivante : [Mg.sup.2+] > [Ca.sup.2+] > [Sr.sup.2+] > [Na.sup.+] > [K.sup.+] > [Rb.sup.+]. Mots-cles : acide ethylenediaminetetraacetique, ions de metaux alcalins, ions de metaux alcalinoterreux, affinite de fixation. [Traduit par la Redaction], Introduction Ethylenediamine tetraacetic acid ([H.sub.4]EDTA) is a polyprotic acid that has been widely used, together with its associated anion ethylenediamine tetraacetate ([EDTA.sup.4-]), since the pioneering work on [H.sub.4]EDTA was done [...]

Modern cancer therapies, mainly ionizing radiation and certain classes of chemotherapies target DNA. Although these treatments disrupt the genome, their rationale is clear. They prevent cancer cells from dividing and proliferating. Nevertheless, cancer cells can survive by over-activating a wide range of DNA repair pathways to remove the induced damage. In this context, DNA repair is considered as a vital target to improve cancer therapy and reduce the resistance to many DNA damaging agent currently in use as standard of care treatments. Here, we focus on two important DNA repair pathways, namely base excision repair (BER) and nucleotide excision repair (NER). Specifically, our focus will be on two protein targets that are linked to the hallmark relapse or drug resistance phenomena. These are Excision Repair Cross-Complementation Group 1 (ERCC1), and DNA polymerase beta (pol β). The former is a key player in NER, while the latter is the error-prone polymerase of BER. Our objective is to list all known inhibitors for the two targets and provide an overview of the great efforts that were made for their discovery. While for the DNA pol β case, more than sixty inhibitors were identified, on the ERCC1 side, very few inhibitors have been discovered. It is hoped that the application of this review will assist in the discovery of novel, potent and specific drug candidates aimed at improving existing cancer therapies including ionizing radiation, bleomycin, monofunctional alkylating agents and cisplatin.