Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents

Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets. \ua9 2012 Elsevier Masson SAS. All rights reserved

Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents

Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets.This research was supported by a grant from MIUR, Rome (PRIN), University of Bologna (RFO) and Polo Scientifico-Didattico di Rimini (to V.T.). We thank the National Cancer Institute (Bethesda, MD) for the anticancer assays. MICINN (Spanish Government) is acknowledged for grant BIO2010-16351 (to J.F.D.). Lizzia Raffaghello is a recipient of MFAG Grant. Giovanna Bianchi is a recipient of a FIRC fellowship

Cyclic shear tests on RC precast beam-to-column connections retrofitted with a three-hinged steel device

Recent European earthquakes demonstrated that the seismic response of RC precast structures can be significantly influenced by the connection systems. Moreover, during past seismic events, many failures of the beam-to-column connections occurred due to their inadequate strength under seismic loads. The seismic safety of these connections has a crucial role in the overall seismic capacity of existing precast structures. A new connection system is employed as a retrofitting solution for a damaged beam-to-column connection and its cyclic shear performance is investigated by means of two cyclic shear tests on two different configurations. In both the experimental tests, the results demonstrate an efficient behavior of the retrofitted connections under horizontal cyclic loads. The comparison between the performance of the investigated connection and the response of a typical beam-to-column dowel connection allows to discuss the main critical features of the dowel connection system

Self-Appropriation between Social Mourning and Individuation: a Qualitative Study on Psychosocial Transition among Jehovah\u2019s Witnesses

Loss and its associated grief are important elements of many adverse life events. The focus of this study is centred on a particular form of mourning: the affliction derived from the social identity loss caused by the disaffiliation with a religious sect. In postmodern society, this phenomenon needs to be better evaluated because it may be causing severe distress in an increasing number of people. The literature describes the stress caused by switching from one religious group to another, but less analysis has been done on the potential deleterious effects of the loss of social identity because of the breaking down of relationships with people within the original group. Following the grounded theory approach, 14 former Jehovah\u2019s Witnesses were interviewed with interpretative phenomenological analysis. Three main profiles emerged\u2014born into the faith, converts to the faith, and inactive members\u2014with different difficulties deriving from the loss of social identity and the relational network. The inquiry was focused on the effects of the identification versus individuation processes and also addressed the role of death anxiety. Results confirmed on the one hand a high level of distress that often caused death anxiety, alcoholism, panic attacks, and depression, as described in the literature. On the other hand, the importance of the individuation process emerged, following theologian Paul Tillich\u2019s concept of \u201ccourage of self-affirmation\u201d and Bernard Lonergan\u2019s \u201cself-appropriation,\u201d whose development occurs in three phases: de-identification and loss, grieving and crisis, and the work of grief and complete self-affirmation or self-appropriation. The usefulness of communicating these specific themes to a broad audience by enhancing community education through widespread spiritual counseling is also addressed