Are Two Riboses Better Than One? The Case of the Recognition and Activation of Adenosine Receptors

Traditionally, molecular recognition between the orthosteric site of adenosine receptors and their endogenous ligand occurs with a 1 : 1 stoichiometry. Inspired by previous mechanistic insights derived from supervised molecular dynamics (SuMD) simulations, which suggested an alternative 2 : 1 binding stoichiometry, we synthesized BRA1, a bis-ribosyl adenosine derivative, tested its ability to bind to and activate members of the adenosine receptor family, and rationalized its activity through molecular modeling

Cationic porphyrin-\u200bruthenium(II) conjugates as potential selective stabilizers of G-\u200bquadruplex

Porphyrins and metalloporphyrins have been extensively investigated as potential anticancer drugs working as DNA binding agents as well as photosensitizer in the photodynamic therapy (PDT)\u200b. Conjugation of the macrocycle with organo-\u200bmetallic complexes have been considered a powerful tool to implement the soly. of the porphyrin and to provide addnl. cytotoxic properties. Here, we prepd. six four-\u200bfold sym. cationic porphyrin-\u200bruthenium(II) conjugates which differ one from each other's for the nature of the linker, the substituents on the Ru(II) fragments and the total pos. charge and we investigated their interaction with DNA templates different from the B form. Our data suggested that the tested conjugated are not selective toward the G-\u200bquadruplex form of the human telomeric sequence. Indeed, unfolded DNA efficiently works as matrix for the cationic conjugates. Nevertheless, they are extremely efficient in cleaving the macromol. upon irradn., irresp. of its structural arrangement

Ruthenium Anticancer Compounds: Challenges and Expectations

Two ruthenium compounds, namely [ImH]trans-[RuCl4(Im)(dmso-S)] (NAMI-A, Im = imidazole) and [IndH] trans-[RuCl4(Ind)2] (KP1019, Ind = indazole) have already completed phase I clinical trials as anticancer agents. They both have properties different from platinum anticancer drugs: for example, NAMI-A is selectively active against metastases of solid tumors. They show that in the field of anticancer metal drugs a new approach, based on targeted therapies, is possible. After a concise history of ruthenium anticancer compounds, this contribution will focus on ruthenium-dmso complexes and, in particular, on NAMI-A. Particular emphasis is given on the challenges that are inherent to this field: how to develop new anticancer ruthenium compounds and how to select new active compounds that manifest their anticancer activity through non-conventional mechanisms

Intramolecular ring opening of epoxides by bis-activated carbanions. The influence of ring size on reactivity and selectivity

A quantitative study on the effect of ring size in the intramolecular ring opening of epoxides by carbanions is described. Two series of substrates were examined a,a-bis-sulfonyl w-epoxides 1 and a-cyano-a-sulfonyl w-epoxides 2; in each series the carbanion is tethered to the epoxide by a chain of variable length from one to four methylene groups. The nucleophile can attack either electrophilic position of the oxirane ring, or both; exo ring opening of cyano sulfonyl epoxides 2 is followed by a second cyclization leading eventually to bicyclic, fused y-lactones. Both series of epoxides show the same trend of reactivity as a function of ring size, in the formation of three- to seven-membered rings, with reactivity maxima corresponding to the formation of cyclopropane and cyclopentane derivatives. Unlike 8 N 2 ring closure of w-halogeno carbanions, cyclization to a five-membered ring is the fastest process in this case. The ratio kdk5 between formation of three- and five-membered rings drops from over 100, in the SN2 cyclization of w-iodo bis-sulfones, to less than 0.5, in the cyclization of w-epoxy bis-sulfones 1. The difference is discussed in terms of trajectory of approach of the carbanion to the nucleophilic center. Cyclization of cyano sulfonyl epoxide 2a, in which the nucleophilic center and the epoxide are spaced by a single methylene group, is diastereoselective and leads to a bicyclic product with a cis fusion between the y-lactone and the cyclopropane ring

Glycogen Synthase Kinase 3β Involvement in Neuroinflammation and Neurodegenerative Diseases

Background: GSK-3 beta activity has been strictly related to neuroinflammation and neurodegeneration. Alzheimer's disease is the most studied neurodegenerative disease, but GSK-3 beta seems to be involved in almost all neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, and the autoimmune disease multiple sclerosis.Objective: This review aims to help researchers both working on this research topic or not to have a comprehensive overview of GSK-3 beta in the context of neuroinflammation and neurodegeneration.Methods: Literature has been searched using PubMed and SciFinder databases by inserting specific keywords. A total of more than 500 articles have been discussed.Results: First of all, the structure and regulation of the kinase were briefly discussed, and then, specific GSK-3 beta implications in neuroinflammation and neurodegenerative diseases were illustrated with the help of figures, to conclude with a comprehensive overview on the most important GSK-3 beta and multitarget inhibitors. The structure and IC50 values at the target kinase have been reported for all the discussed compounds.Conclusion: GSK-3 beta is involved in several signaling pathways in neurons, glial cells and immune cells. The fine regulation and interconnection of all these pathways are at the base of the rationale use of GSK-3 beta inhibitors in neuroinflammation and neurodegeneration. Some compounds are now under clinical trials. Despite this, the compounds' pharmacodynamic and ADME/Tox profiles were often not fully characterized which is deleterious in such a complex system

DNA Targeting by Cationic Porphyrin-\u200bRuthenium(II) Conjugates

Porphyrins and metalloporphyrins are investigated extensively as potential anticancer drugs. They work as DNA binding agents as well as photosensitizers in photodynamic therapy. Conjugation of the macrocycle with organometallic complexes is a powerful tool to implement the water soly. of the adducts and to provide distinct cytotoxic properties. Herein, six fourfold-\u200bsym. cationic porphyrin-\u200bruthenium(II) conjugates (P1-\u200bP6) are considered, which differ from one another by the substituents on the RuII fragments, the linkage of the metal fragments to the porphyrin, and the total pos. charge. Their interaction with DNA sequences arranged in different conformations is investigated. The data suggest that the tested conjugates discriminate poorly between different DNA structures. Indeed, unfolded DNA works efficiently as a template for the cationic conjugates. Nevertheless, they are extremely efficient in cleaving the macromol. upon irradn., regardless of its structural arrangement

New half sandwich-type Ru(II) coordination compounds characterized by the fac-Ru(dmso-S)3 fragment: influence of the face-capping group on the chemical behavior and in vitro anticancer activity.

The Ru(II) complex fac-[RuCl(dmso-S)3(dmso-O)2][PF6] (P2) was found to be an excellent precursor for the facile preparation in high yield of half sandwich-type compounds of the general formula fac-[RuCl(dmso-S)3(N)2][PF6] (e.g. (N)2 = 1,2-diaminoethane (en, 4), trans-1,2-diaminocyclohexane (dach, 5), or 2 NH3 (6)). Neutral half sandwich-type compounds of the general formula fac-[RuCl(dmso-S)3(N\u2013O)] where N\u2013O is an anionic chelating ligand (e.g. N\u2013O = picolinate (pic, 7)) are best prepared from the universal Ru(II)-dmso precursor cis-[RuCl2(dmso)4] (P1). These complexes, that were fully characterized in solution and in the solid state, are structurally similar to the anticancer organometallic compounds [Ru(h6-arene)(chel)Cl][PF6]n but, in place of a face-capping arene, have the fac-Ru(dmso-S)3 fragment. In contrast to what observed for the corresponding arene compounds, that rapidly hydrolyze the Cl ligand upon dissolution in water, compounds 4\u20136 are very stable and inert in aqueous solution. Probably their inertness is the reason why they showed no significant cytotoxicity against the MDA-MB-231 cancer cell lin