Site-occupancy factors in the Debye scattering equation : a theoretical discussion on significance and correctness

The Debye scattering equation (DSE) [Debye (1915). Ann. Phys. 351, 809-823] is widely used for analyzing total scattering data of nanocrystalline materials in reciprocal space. In its modified form (MDSE) [Cervellino et al. (2010). J. Appl. Cryst. 43, 1543-1547], it includes contributions from uncorrelated thermal agitation terms and, for defective crystalline nanoparticles (NPs), average site-occupancy factors (s.o.f.'s). The s.o.f.'s were introduced heuristically and no theoretical demonstration was provided. This paper presents in detail such a demonstration, corrects a glitch present in the original MDSE, and discusses the s.o.f.'s physical significance. Three new MDSE expressions are given that refer to distinct defective NP ensembles characterized by: (i) vacant sites with uncorrelated constant site-occupancy probability; (ii) vacant sites with a fixed number of randomly distributed atoms; (iii) self-excluding (disordered) positional sites. For all these cases, beneficial aspects and shortcomings of introducing s.o.f.'s as free refinable parameters are demonstrated. The theoretical analysis is supported by numerical simulations performed by comparing the corrected MDSE profiles and the ones based on atomistic modeling of a large number of NPs, satisfying the structural conditions described in (i)-(iii)

Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/cyclooxygenase-1 selectivity.

he important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3- acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain

Synthesis and biological evaluation of fluorinated 1,5-diarylpyrrole-3-alkoxyethyl ether derivatives as selective COX-2 inhibitors endowed with anti-inflammatory activity

A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and the potential anti-inflammatory and antinociceptive activities of these compounds were evaluated in vivo. The compounds displayed a very good activity against both carrageenan-induced hyperalgesia and oedema in the rat paw test. Therefore, in a very preliminary test, compounds (8a,b) showed antiproliferative activity in the HaCaT (aneuploid immortal keratinocyte from adult human skin) cell models. On these basis, our research continued with the synthesis of fluorinated derivatives (8c,d, 9b-d, and 10b-d) with the aim of improving the pharmacokinetic profile of the previous active compounds. Substitution of a hydrogen atom by a fluorine atom may change the conformational preferences of the molecules due to stereoelectronic effects and also fluorine atom may be able to exert the metabolic obstruction reducing the "first-pass effect". Compound 10b exhibited a prominent in vivo anti-inflammatory and antinociceptive activities, in addition its antiproliferative power in an in vitro model of human skin cancer is herein described

Synthesis and biological evaluation of fluorinated 1,5-diarylpyrrole-3-alkoxyethyl ether derivatives as selective COX-2 inhibitors endowed with anti-inflammatory activity

A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and the potential anti-inflammatory and antinociceptive activities of these compounds were evaluated in vivo. The compounds displayed a very good activity against both carrageenan-induced hyperalgesia and oedema in the rat paw test. Therefore, in a very preliminary test, compounds (8a,b) showed antiproliferative activity in the HaCaT (aneuploid immortal keratinocyte from adult human skin) cell models. On these basis, our research continued with the synthesis of fluorinated derivatives (8c,d, 9b-d, and 10b-d) with the aim of improving the pharmacokinetic profile of the previous active compounds. Substitution of a hydrogen atom by a fluorine atom may change the conformational preferences of the molecules due to stereoelectronic effects and also fluorine atom may be able to exert the metabolic obstruction reducing the "first-pass effect". Compound 10b exhibited a prominent in vivo anti-inflammatory and antinociceptive activities, in addition its antiproliferative power in an in vitro model of human skin cancer is herein described

Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction

Cardiomyocyte proliferation stops at birth when the heart is no longer exposed to maternal blood and, likewise, to regulatory T cells (Tregs) that are expanded to promote maternal tolerance towards the fetus. Here, we report a role of Tregs in promoting cardiomyocyte proliferation. Treg-conditioned medium promotes cardiomyocyte proliferation, similar to the serum from pregnant animals. Proliferative cardiomyocytes are detected in the heart of pregnant mothers, and Treg depletion during pregnancy decreases both maternal and fetal cardiomyocyte proliferation. Treg depletion after myocardial infarction results in depressed cardiac function, massive inflammation, and scarce collagen deposition. In contrast, Treg injection reduces infarct size, preserves contractility, and increases the number of proliferating cardiomyocytes. The overexpression of six factors secreted by Tregs (Cst7, Tnfsf11, Il33, Fgl2, Matn2, and Igf2) reproduces the therapeutic effect. In conclusion, Tregs promote fetal and maternal cardiomyocyte proliferation in a paracrine manner and improve the outcome of myocardial infarction

Improving the solubility of a new class of antiinflammatory pharmacodynamic hybrids, that release nitric oxide and inhibit cycloxygenase-2 isoenzyme

The development of a novel class of pharmacodynamic hybrids that inhibits COX-2 isoform is reported. These molecules display enhanced nitric oxide releasing properties due to the presence of an ionisable moiety. The in vivo analgesic/anti-inflammatory activity was maintained in relation to the parent compounds

Enhancing the pharmacodynamic profile of a class of selective COX-2 inhibiting nitric oxide donors

We report herein the development, synthesis, physicochemical and pharmacological characterization of a novel class of pharmacodynamic hybrids that selectively inhibit cyclooxygenase-2 (COX-2) isoform and present suitable nitric oxide releasing properties. The replacement of the ester moiety with the amide group gave access to in vivo more stable and active derivatives that highlighted outstanding pharmacological properties. In particular, the glycine derivative proved to be extremely active in suppressing hyperalgesia and edema. © 2013 Elsevier Ltd. All rights reserved

Novel ester and acid derivatives of the 1,5-diarylpyrrole scaffold as anti-inflammatory and analgesic agents. Synthesis and in vitro and in vivo biological evaluation.

A new generation of selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More recent clinical findings highlighted how the cardiovascular toxicity of coxibs could be mitigated by an appropriate COX-1 versus COX-2 selectivity. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, selective for COX-2. Here, we describe the synthesis of new1,5-diarylpyrroles along with their inhibitory effects in vitro, ex vivo, and in vivo toward COX isoenzymes and their analgesic activity. Isopropyl-2-methyl-5-[4- (methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole-3-acetate (10a), a representative member of the series, was selected for pharmacokinetic and metabolic studies