Iatrogenic Rhabdomyolisis and Guillain-Barre’ Syndrome: a Dangerous Association.

Guillan-Barré Syndrome (GBS) is an acute, symmetrical polyneuropathy with a clinical manifestation of flaccid paralysis with areflexia and variable sensory disturbance. GBS has an incidence of 1-2 cases/100.000 inhabitants for year. The pathological spectrum of GBS includes Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Acute Motor Axonal Neuropathy (AMAN) and Acute Motor Sensory Axonal Neuropathy (AMSAN). We report a case of an 81-year-old man with GBS (subtype AMSAN), secondary to a previous Micoplasma Pneumoniae infection, who presented with an elevation of Creatin Kinase (CK) serum levels, and worsened by a co-administration of statins and clarithromycin. By our knowledge there are few cases in the literature in which the association of these drugs contributed to worsening GBS

Antibody drug conjugates (ADCs) charged with HDAC inhibitor for targeted epigenetic modulation

We describe here two novel antibody-drug conjugates loaded with the HDAC inhibitor ST7612AA1 (IC50equal to 0.07 μM on NCI-H460 cells), a thiol-based molecule with a moderate toxicity in vivo. Two payloads were prepared using cleavable and non-cleavable linkers. After anchoring to cetuximab through amide bond with lysines, the resulting HDAC inhibitor-antibody conjugates showed ability to recognize EGFR and efficient internalization in tumor cells. Both ADCs induced sensible increment of histones 3 and 4 and alpha-tubulin acetylation. Animal models of human solid tumors showed high anti-tumor efficacy of the conjugates without the toxicity generally observed with traditional ADCs delivering highly potent cytotoxic drugs. These compounds, the first ADCs charged with not highly cytotoxic warheads, are potentially suitable for epigenetic modulation, extending the ADC strategy to the targeted delivery of HDAC inhibitors with many possible therapeutic applications beyond cancer

Water-Based Synthesis and Enhanced CO2 Capture Performance of Perfluorinated Cerium-Based Metal–Organic Frameworks with UiO-66 and MIL-140 Topology

Reaction of cerium ammonium nitrate and tetrafluoroterephthalic acid in water afforded two new metal–organic frameworks with UiO-66 [F4_UiO-66(Ce)] and MIL-140 [F4_MIL-140A(Ce)] topologies. The two compounds can be obtained in the same experimental conditions, just by varying the amount of acetic acid used as crystallization modulator in the synthesis. Both F4_UiO-66(Ce) and F4_MIL-140A(Ce) feature pores with size <8 Å, which classifies them as ultramicroporous. Combination of X-ray photoelectron spectroscopy and magnetic susceptibility measurements revealed that both compounds contain a small amount of Ce(III), which is preferentially accumulated near the surface of the crystallites. The CO2 sorption properties of F4_UiO-66(Ce) and F4_MIL-140A(Ce) were investigated, finding that they perform better than their Zr-based analogues. F4_MIL-140A(Ce) displays an unusual S-shaped isotherm with steep uptake increase at pressure <0.2 bar at 298 K. This makes F4_MIL-140A(Ce) exceptionally selective for CO2 over N2: the calculated selectivity, according to the ideal adsorbed solution theory for a 0.15:0.85 mixture at 1 bar and 293 K, is higher than 1900, among the highest ever reported for metal–organic frameworks. The calculated isosteric heat of CO2 adsorption is in the range of 38–40 kJ mol–1, indicating a strong physisorptive character

Antibody drug conjugates with hydroxamic acid cargos for histone deacetylase (HDAC) inhibition.

The bioconjugation of hydroxamic acids to antibodies has been made possible through a non-cleavable linker based on the p-mercaptobenzyl alcohol structure that releases hydroxamates in the cells

Synthesis and evaluation of new Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold

Abstract: Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates, gave a new family of 1,4,5-trisubstitued triazole carboxylic acid derivatives that showed high affinity towards Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring, were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstitued triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18; SST0287CL1) was selected for further investigation as the most promising drug candidate

A theoretical approach to the factorization of the effects governing the barrier for internal rotation around the C(sp(2))-C(sp(3)) bond into alpha-substituted toluenes

The effects governing the barrier for internal rotation in a number of alpha-substituted toluenes C6H5CH2X (X = Cl, F, CH3, C(CH3)(3), CF3, CCl3) and alpha,alpha-disubstituted toluenes C6H5CHX2 (X = Cl, Fl were interpreted using a model which factorizes the energy barrier into three components, namely, a) hyperconjugation, b) electrostatic effects and c) van der Waals interactions. The potential energy profiles for internal rotation of the CH2X and CHX2 rotors were calculated at molecular orbital MO ab initio level with a 6-31G* basis set and analysed by means of a truncated Fourier series in the V-2 and V-4 terms. The hyperconjugative contributions were estimated employing natural bond orbitals (NBO) derived from the 6-31G* wave functions in a scheme of acceptor-donor intramolecular interactions. The donor and acceptor hyperconjugative contributions, with respect to the pi system of the benzene ring, of each bond constituting the CH2X and CHX2 rotors were found to contribute additively to the hyperconjugative effect of the whole rotating group. Electrostatic effects and van der Waals interactions were tentatively estimated with empirical formulas. The separate contributions of these effects were compared, albeit at a qualitative level, with the total molecular energy and their relative weight discussed. The rotational barriers of benzylchloride and benzalchloride are mainly controlled by hyperconjugative effects. In benzylfluoride and benzalfluoride, the hyperconjugative effects are active to the same extent as in chlorine derivatives but the barrier is mainly controlled by electrostatic effects. In the compounds with bulky X groups (X = C(CH3)(3), CF3 and CCl3), hyperconjugation plays a less important role than van der Waals interactions and electrostatic effects, and the relative weight of these effects differs for the substituents examined

CONFORMATIONAL PROPERTIES OF PEROXYACIDS, PEROXYESTERS AND OF STRUCTURALLY RELATED RADICALS - A THEORETICAL AB-INITIO MO APPROACH

The geometrical features relative to the lowest conformational minimum, and absolute and relative energy contents of a number of peroxyacids RC(O)OOH (R = H, CH3, CF3, C6H5) and methyl esters (R = H, CH3, CF3) have been calculated at the ab initio MO level with the 6-31G* basis set. For the peroxyacids with R = H and CH3, the most stable conformation obtained from this calculation is of cis type (referring to internal rotation around the O-O bond) and agrees with that found experimentally. This conformation is the most stable one also for the other peroxyacids examined and for the peroxyesters. Poor agreement is, however, found between calculated and experimental geometrical parameters relative to the O-O and O-H bond lengths, and to the OOC and OOH bond angles. Comparison of calculated structural features of peroxyacids with those of the corresponding acids shows that stabilization of the planar cis conformation of the former compounds is due to intramolecular hydrogen bonding. This property influences the energy difference between cis and trans forms, DELTAE, which, for the same R, is larger in the peroxyacid than in the peroxyester. The DELTAE values increase approximately with the bulk of R. The energy content, conformational features and geometrical parameters of the more stable conformation have been analysed within the same theoretical approach for the radicals RC(O)O, RC(O)OO and C(O)OOR'(R' = H, CH3), formally derived from homolytic bond dissociation of the peroxyacids and peroxyesters examined. The sigma(RC(O)O and C(O)OOR') and pi (RC(O)OO) characters, atom spin densities and relative stabilities of the conformers of these radicals are discussed

A theoretical study of the effects governing the internal rotation process in allyl derivatives

Total molecular energy as a function of internal rotation around the C(sp(2))-C(sp(3)) bond, referred to as the C-C bond, in the molecules CH2=CHCY3, CH2=CHCH2Y, with Y = H, F, Cl, CH3, and CH2=CHCHY3, with Y = F, Cl, was calculated at the ab initio MO level, with the 6-31G* basis set. The molecular geometry was fully relaxed at fixed rotational angles phi. The potential energy profiles V(phi) were obtained with a truncated Fourier series and the V-n terms (n = 1-3) are derived and discussed. The C-C bond distances change on rotation and the highest values of the increment Delta d are found in the rotational maxima. For the molecules with the CY3 top the changes in Delta d are linearly related to the changes in total molecular energy Delta E-TOT, but with different slopes in the different molecules. The slopes seem to depend on the absolute length of the C-C bond, and while the Delta d behaviour within a molecule seems mostly dictated by hyperconjugative effects, the absolute length d is most probably determined by through-space effects. The elongation Delta d is due, in the majority of the molecules examined, to a decrease in attractive interactions (barrier of attractive type: in the rotational maxim., although in 3,3,3-trichloropropene and cis-1,3,3,3-tetrachloropropene the barrier is mostly of the repulsive type (increase in repulsive interactions). This kind of correlation is less statisfactory for tops of lower symmetry: in the molecules with the CH2Y top it would appear that the gauche-skew barrier is of the repulsive type, and the trans-skew barrier of the attractive type. The rotational behaviour of the total energy was also analyzed according to a model of factorization in energy components ascribed to different effects, identified in the first instance as hyperconjugative and through-space effects. The hyperconjugative effect of the groups examined, Delta E-x, calculated with the Natural Bond Orbital (NBO) approach, is similar to that found for the corresponding benzyl derivatives, yet slightly stronger. The rotational pattern of Delta E-x mirrors that of Delta E-TOT, even though it seems necessary to take into account the presence of other effects to explain peculiar differences between these patterns. The through-space effect was further factorized in the contribution of van der Waals, Delta E-vdW, and electrostatic, Delta E-el., interactions. For the calculation of Delta E-d from atomic charges different approaches were employed (Mulliken NBO, CHELPG), yet none afforded a Delta E-el. contribution quantitatively in agreement with the other factors. A qualitative description of the through-space effect of the groups considered is nevertheless attempted in order to suggest a combination of effects exerted by the susbtituents examined on the vinyl moiety, stemming from the theoretical treatment of these molecules

THERMOCHEMICAL PROPERTIES AND HOMOLYTIC BOND-CLEAVAGE OF ORGANIC PEROXYACIDS AND PEROXYESTERS - AN EMPIRICAL-APPROACH BASED ON AB-INITIO MO CALCULATIONS

Heats of formation DELTAH(f)-degrees of a number of peroxyacids RC(O)OOH, peroxyesters RC(O)OOR' and of the radicals RC(O), RC(O)O, RC(O)OO and C(O)OOR', related to possible routes of their thermal decomposition, were estimated by employing empirical approaches. R and R' are a wide set of alkyl and aryl groups. The approaches were based on isodesmic reactions, atom equivalent, group additivity and molecular mechanics (MM2) calculations. Isodesmic reactions and atom equivalent schemes were employed with HF/6-31G* ab initio total molecular energies. The MM2 calculations were applied to peroxyacids and peroxyesters and the values of DELTAH(f)-degrees obtained were corrected by a constant quantity because they appeared systematically in excess with respect to those obtained by the other approaches. In atom equivalent and group additivity methods, new parameters were evaluated in order to be able to calculate the heats of formation of these molecules. Values of DELTAH(f)-degrees obtained from the different approaches turn out to be consistent within +/-2 kcal mol-1. For the RC(O) radicals with R = H, CH3, C6H5 and CF3, a comparison with values reported in the literature is possible and agreement can be considered satisfactory. For the RC(O)O radicals with R = H, CH3, C6H5, the DELTAH(f)-degrees values estimated in this work from isodesmic reactions and atom equivalent approaches are 7-10 kcal mol-1 higher than those reported in the literature. This difference appears to be due to improper evaluation of the total molecular energy with HF/6-31G* ab initio calculations for this radical, owing to symmetry breaking in SCF methods. With the heats of formation calculated for peroxyacids, peroxyesters and for the radicals structurally related to these molecules, homolytic dissociation energies for the various bonds were derived and discussed as a function of the structural features of the R and R' groups. Possible routes for the thermal decomposition of the peroxyesters were examined