Spectrophotometric and Thermal Studies of the Reaction of Iodine with Nickel(II) Acetylacetonate

The reaction of iodine (acceptor) and nickel(II) acetylacetonate (donor) was studied photometrically in different solvents such as chloroform, dichloromethane and carbon tetrachloride at room temperature. The results indicate the formation of a 1: 1 charge-transfer complex in each solvent and the iodine complex is formulated as the triiodide species [Ni(acac)2]2I+.I3-, based on the characteristic electronic absorptions of the I3- ion at 361 and 285 nm, as well as on the far infrared absorption bands characteristic of the I3- ion with C2v symmetry. These bands are observed at 132, 101 and 84 cm-1 and are assigned to na(I-I), ns(I-I) and d(I3-), respectively. The values of the equilibrium constant (K), absorptivity (e) and oscillator strength (f) of the iodine complex are shown to be strongly dependent on the type of solvent used. The important role played by the solvent is suggested to be mainly due to the interaction of the ionic complex with the solvent. The proposed structure of the new solid triiodide charge-transfer complex reported in this study is further supported by thermal and mid-infrared measurements. (South African Journal of Chemistry: 2003 56: 10-14

Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation:A step towards the next generation p53 activators

Despite the achieved progress in developing efficient MDM2-p53 protein-protein interaction inhibitors (MDM2 inhibitors), the acquired resistance of tumor cells to such p53 activators posed an argument about the druggability of the pathway. Combination studies disclosed that concomitant inhibition of MDM2 and BCL2 functions can sensitize the tumor cells and synergistically induce apoptosis. Herein, we employed a rapid combinatorial approach to generate a novel series of hybrid spirooxindole-based MDM2 inhibitors (5a-s) endowed with BCL2 signaling attenuation. The adducts were designed to mimic the thematic features of the chemically stable potent spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-ones MDM2 inhibitors while installing a pyrrole ring on the core via a carbonyl spacer inspired by the natural product marinopyrrole A that efficiently inhibits BCL2 family functions by various mechanisms. NCI 60 cell-line panel screening revealed their promising broad-spectrum antiproliferative activities. The NCI-selected derivatives were screened for cytotoxic activities against normal fibroblasts, MDA-MB 231, HepG-2, and Caco-2 cells via MTT assay, subjected to mechanistic apoptosis studies for assessment of p53, BCL2, p21, and caspase 3/7 status, then evaluated for potential MDM2 inhibition utilizing MST assay. The most balanced potent and safe derivatives; 5i and 5q were more active than 5-fluorouracil, exhibited low μM range MDM2 binding (KD =1.32 and 1.72 μM, respectively), induced apoptosis-dependent anticancer activities up to 50%, activated p53 by 47-63%, downregulated the BCL2 gene to 59.8%, and reduced its protein level (13.75%) in the treated cancer cells. Further downstream p53 signaling studies revealed > 2 folds p21 upregulation and > 3 folds caspase 3/7 activation. Docking simulations displayed that the active MDM2 inhibitors resided well into the p53 binding sites of MDM2, and shared key interactions with the co-crystalized inhibitor posed by the indolinone scaffold (5i, 5p, and 5q), the halogen substituents (5r), or the installed spiro ring (5s). Finally, in silico ADMET profiling predicted acceptable drug-like properties with full accordance to Lipinski's, Veber's, and Muegge's bioavailability parameters for 5i and a single violation for 5q

Design, Synthesis, Chemical and Biochemical Insights Into Novel Hybrid Spirooxindole-Based p53-MDM2 Inhibitors With Potential Bcl2 Signaling Attenuation

The tumor resistance to p53 activators posed a clinical challenge. Combination studies disclosed that concomitant administration of Bcl2 inhibitors can sensitize the tumor cells and induce apoptosis. In this study, we utilized a rapid synthetic route to synthesize two novel hybrid spirooxindole-based p53-MDM2 inhibitors endowed with Bcl2 signaling attenuation. The adducts mimic the thematic features of the chemically stable potent spiro [3H-indole-3,2′-pyrrolidin]-2(1H)-ones p53-MDM2 inhibitors, while installing a pyrrole ring via a carbonyl spacer inspired by the natural marine or synthetic products that efficiently inhibit Bcl2 family functions. A chemical insight into the two synthesized spirooxindoles including single crystal x-ray diffraction analysis unambiguously confirmed their structures. The synthesized spirooxindoles 2a and 2b were preliminarily tested for cytotoxic activities against normal cells, MDA-MB 231, HepG-2, and Caco-2 via MTT assay. 2b was superior to 5-fluorouracil. Mechanistically, 2b induced apoptosis-dependent anticancer effect (43%) higher than that of 5-fluorouracil (34.95%) in three studied cancer cell lines, activated p53 (47%), downregulated the Bcl2 gene (1.25-fold), and upregulated p21 (2-fold) in the treated cancer cells. Docking simulations declared the possible binding modes of the synthesized compounds within MDM2

<b>Synthesis, characterization and antimicrobial activity of some nitrilotriacetic acid−V(III), −Sn(II), −Sm(II) and −Sm(III) complexes</b>

Four new complexes [V(NTA)(H2O) 2]&#149;H2O (1), H[Sn(NTA)] (2), H[Sm(NTA)]&#149;H2O (3), and [Sm(NTA)(H2O) 2]&#149;H2O (4) were obtained during the reactions of metal salts (VCl3, SnCl2&#149;2H2O, SnCl4, Sm(NO3)2&#149;6H2O and SmCl3&#149;6H2O) with nitrilotriacetic acid, H3NTA. The infrared and 1H-NMR spectra of the solid complexes have been obtained and assigned. Thermogravimetric analyses were also carried out. The data obtained agree with the proposed structures and show that the complexes decomposed to the corresponding metal oxide. The ligand and their metal complexes were screened for their antimicrobial activities by the agar-well diffusion technique using DMSO as a solvent against the following bacterial species: Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa and antifungal activity against Aspergillus niger, Aspergillus flavus, Saccharomyces cerevisiae and Candida albicans. The obtained results were compared with some types of known antibiotics. The minimum inhibitory concentration (MIC) values were calculated at 30 °C for 24−48 h. The activity data show that the complexes are more potent antimicrobials than the parent ligand

Preparation, spectroscopic and structural studies on charge-transfer complexes of 2,9-dimethyl-1,10-phenanthroline with some electron acceptors

Charge-transfer (CT) complexes formed in the reactions of 2,9-dimethyl-1,10-phenanthroline (Me2phen) with some acceptors such as chloranil (Chl), picric acid (HPA) and chloranilic acid (H2CA) have been studied in the defined solvent at room temperature. Based on elemental analysis and infrared spectra of the solid CT-complexes along with the photometric titration curves for the reactions, obtained data indicate the formation of 1:1 charge-transfer complexes [(Me2phen)(Chl)] (1), [(Me2phenH)(PA)] (2) and [(Me2phenH)(HCA)] (3), respectively, was proposed. In the three complexes, infrared and 1H NMR spectroscopic data indicate a charge-transfer interaction and as far as complexes 2 and 3 are concerned this interaction is associated with a hydrogen bonding. The formation constants for the complexes (KC) were shown to be dependent upon the nature of the electron acceptors used. The X-ray structure of complex 3 indicate the formation of dimeric units [Me2phenH]2[(HCA)2] in which the two anions (HCA)− are connected by two O–HO hydrogen bonds whereas the cations and anions are joined together by strong three-center (bifurcated) N–HO hydrogen bonds. Furthermore, the cations are arranged in a π–π stacking

Corrigendum to “Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators”

We have replaced the original Fig. 3 with a revised version, and we sincerely apologize for the inconvenience caused by our oversight. There was a mistaken duplication of the image of compound 5i against the MDA-MB 231 cells with the image for compound 5q against HepG-2 cells. Furthermore, the untreated control images were also changed with higher resolution ones. In the revised Fig. 3, we have corrected this error and provided the accurate representation.</p

Corrigendum to “Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators”

We have replaced the original Fig. 3 with a revised version, and we sincerely apologize for the inconvenience caused by our oversight. There was a mistaken duplication of the image of compound 5i against the MDA-MB 231 cells with the image for compound 5q against HepG-2 cells. Furthermore, the untreated control images were also changed with higher resolution ones. In the revised Fig. 3, we have corrected this error and provided the accurate representation.</p

Corrigendum to “Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators”

We have replaced the original Fig. 3 with a revised version, and we sincerely apologize for the inconvenience caused by our oversight. There was a mistaken duplication of the image of compound 5i against the MDA-MB 231 cells with the image for compound 5q against HepG-2 cells. Furthermore, the untreated control images were also changed with higher resolution ones. In the revised Fig. 3, we have corrected this error and provided the accurate representation.</p

Corrigendum to “Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators”

We have replaced the original Fig. 3 with a revised version, and we sincerely apologize for the inconvenience caused by our oversight. There was a mistaken duplication of the image of compound 5i against the MDA-MB 231 cells with the image for compound 5q against HepG-2 cells. Furthermore, the untreated control images were also changed with higher resolution ones. In the revised Fig. 3, we have corrected this error and provided the accurate representation.</p

Corrigendum to “Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators”

We have replaced the original Fig. 3 with a revised version, and we sincerely apologize for the inconvenience caused by our oversight. There was a mistaken duplication of the image of compound 5i against the MDA-MB 231 cells with the image for compound 5q against HepG-2 cells. Furthermore, the untreated control images were also changed with higher resolution ones. In the revised Fig. 3, we have corrected this error and provided the accurate representation.</p