Biomedical subjects
Publications and source records attributed to M Prato.
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We report the synthesis of three novel, versatile fullerene intermediates whose main feature is the presence of an amino end group. Simple condensation reactions of these intermediates under standard conditions produce new derivatives that are useful for applications in materials science and medicinal chemistry.
Grafting of a ferrocene-containing liquid-crystalline malonate derivative to C60 led to the mixed fullerene-ferrocene material 1 which gave rise to a smectic A phase. Cholesterol was used as liquid-crystalline promoter. X-ray diffraction experiments and volumetric measurements indicated that 1 is organized in double layered structures. The corresponding supramolecular organization within the mesomorphic lamellar phase is characterized by a microsegregation of the different units (ferrocene, fullerene, and cholesterol) in distinct sublayers. In such a smectic A phase, C60 imposes the arrangement of the other molecular moieties. Photophysical studies revealed that electron transfer occurs from the donor ferrocene to the electron accepting fullerene. The formation of a long-lived radical pair, with lifetimes of the order of several hundred nanoseconds, was confirmed by time-resolved spectrometry, especially in the near infrared region, in which the radical anion of the fullerene moiety displays its characteristic fingerprint absorption.
[see structure]. A fullerene derivative containing a free amino group has been condensed with N-Fmoc-L-glutamic acid alpha-tert-butyl ester to give a C60-functionalized amino acid. The carboxylic end of this amino acid has been deprotected in acidic conditions, and the resulting acid has been used for solid-phase peptide synthesis. The final peptide, cleaved from the resin, was very soluble in water solutions and showed antimicrobial activity against two representative bacteria.
We report the isolation and characterization of bisadducts of fulleropyrrolidine derivatives. The compounds were characterized by means of a variety of spectroscopic techniques, including ES-MS, UV-vis, (1)H NMR, and (13)C NMR. The whole series of bisadducts was separated for the first time in the case of the bispyrrolidines, and the determination of their structure was obtained by NMR spectroscopy with the help of HMQC and HMBC techniques.
Photoprocesses associated with the complexation of a pyridine-functionalized C60 fullerene derivative to ruthenium- and zinc-tetraphenylporphyrins (tpp) have been studied by time-resolved optical and transient EPR spectroscopies. It has been found that upon irradiation in toluene, a highly efficient triplet-triplet energy transfer governs the deactivation of the photoexcited [Ru(tpp)], while electron transfer (ET) from the porphyrin to the fullerene prevails in polar solvents. Complexation of [Zn(tpp)] by the fullerene derivative is reversible and, following excitation of the [Zn(tpp)], gives rise to very efficient charge separation. In fluid polar solvents such as THF and benzonitrile, radical-ion pairs (RPs) are generated both by intramolecular ET inside the complex and by intermolecular ET in the uncomplexed form. Charge-separated states have lifetimes of about 10 micros in THF and several hundred of microseconds in benzonitrile at room temperature.
Recent advances in the chemistry of fullerene have allowed the synthesis of many classes of novel fullerene derivatives. Among these classes, fullerene-based amino acids and peptides are particularly interesting, both for structural studies and biological applications. In this review, we will discuss our own achievements in this rapidly growing field. In particular, the application of fulleroproline (Fpr) amino acids and peptides to medicinal chemistry and material science will be highlighted.
This review describes recent advances in the development of DNA-photocleavage agents. Major mechanisms of photosensitized DNA photocleavage are presented and the most popular categories of compounds are considered, which include metal complexes and many organic functional derivatives. DNA-targeted conjugates of photosensitizers are also described and discussed.
[structure] Two water-soluble fullerene derivatives have been computer-designed and synthesized. They may exhibit interesting anti-HIV activity owing to the presence of two ammonium groups strategically located on the spheroid surface.
The addition of nitrile oxides to [60]fullerene, leading to isoxazolinofullerenes, can be reversed using reducing agents such as Mo(CO)(6) or DIBALH. Thus, this reaction can be used, in principle, for protection/deprotection of [60]fullerene or for solubilization purposes. The tether-controlled tandem addition of nitrile oxides and azomethine ylides provides mainly cis-1 patterns. The determination of the structure of bisadducts was obtained by NMR spectroscopy with the help of HMQC, HMBC, and NOEDS techniques. The isoxazoline moiety could be removed using Mo(CO)(6) leaving a fulleropyrrolidine derivative.
Positively charged fullerene derivatives, moderately soluble in water:DMSO 9:1, have been tested using three strains of Mycobacterium spp. Some compounds inhibit the growth of Mycobacterium tuberculosis, a human clinical isolate, particularly virulent and resistant, at doses as low as 5 microg/mL.
This Account reviews our main achievements in the field of excited-state properties of fullerene derivatives. The photosensitizing and electron-acceptor features of some relevant classes of functionalized fullerene materials are highlighted, considering the impact of functionalization on fullerene characteristics. In addition, the unique optimization in terms of redox potentials, water-solubility, and singlet oxygen generation is presented for several novel fullerene-based materials.
BACKGROUND: In patients with acute exacerbations of chronic obstructive pulmonary disease, mechanical ventilation is often needed. The rate of weaning failure is high in these patients, and prolonged mechanical ventilation increases intubation-associated complications. OBJECTIVE: To determine whether noninvasive ventilation improves the outcome of weaning from invasive mechanical ventilation. DESIGN: Multicenter, randomized trial. SETTING: Three respiratory intensive care units. PATIENTS: Intubated patients with chronic obstructive pulmonary disease and acute hypercapnic respiratory failure. INTERVENTION: A T-piece weaning trial was attempted 48 hours after intubation. If this failed, two methods of weaning were compared: 1) extubation and application of noninvasive pressure support ventilation by face mask and 2) invasive pressure support ventilation by an endotracheal tube. MEASUREMENTS: Arterial blood gases, duration of mechanical ventilation, time in the intensive care unit, occurrence of nosocomial pneumonia, and survival at 60 days. RESULTS: At admission, all patients had severe hypercapnic respiratory failure (mean pH, 7.18+/-0.06; mean PaCO2, 94.2+/-24.2 mm Hg), sensory impairment, and similar clinical characteristics. At 60 days, 22 of 25 patients (88%) who were ventilated noninvasively were successfully weaned compared with 17 of 25 patients (68%) who were ventilated invasively. The mean duration of mechanical ventilation was 16.6+/-11.8 days for the invasive ventilation group and 10.2+/-6.8 days for the noninvasive ventilation group (P = 0.021). Among patients who received noninvasive ventilation, the probability of survival and weaning during ventilation was higher (P = 0.002) and time in the intensive care unit was shorter (15.1+/-5.4 days compared with 24.0+/-13.7 days for patients who received invasive ventilation; P = 0.005). Survival rates at 60 days differed (92% for patients who received noninvasive ventilation and 72% for patients who received invasive ventilation; P = 0.009). None of the patients weaned noninvasively developed nosocomial pneumonia, whereas 7 patients weaned invasively did. CONCLUSIONS: Noninvasive pressure support ventilation during weaning reduces weaning time, shortens the time in the intensive care unit, decreases the incidence of nosocomial pneumonia, and improves 60-day survival rates.
The 1H NMR study of fulleroproline derivative Ac-Fpr-OtBu and its Pro analogue Ac-L-Pro-OtBu over a range of temperatures in toluene-d8 solution has enabled the comparison of their equilibrium and activation parameters for the trans/cis interconversion around the amide partial double bond.
We have recently described the preparation of Fpr (C60-based fulleroproline). In this paper the synthesis and a conformational characterization of heterochiral di- and tripeptides containing this new alpha-amino acid are reported. A folded structure, induced by the -L-Fpr-D-Ala-sequence in chloroform solution and detected by Fourier transform infrared absorption and 1H nuclear magnetic resonance, has been compared with the known propensity of the cognate -L-Pro-D-Ala-sequence to adopt a beta II-turn conformation, which has also been confirmed in this work. The beta II-turn structure is retained in the crystal state by the Pro-peptides, as shown by the X-ray diffraction structures of Ibu-L-Pro-D-Ala-NHtBu and Z-L-Pro-D-Ala-L-Ala-OtBu.
The highly hydrophobic C60 (buckminsterfullerene) was water solubilized by covalently linking the synthon 1,2-dihydro-1,2-methanofullerene [60]-61-carboxylic acid to the alpha-amino group of the hydrophilic 4-8 sequence of peptide T, known to display potent human monocyte chemotaxis. The resulting compound, characterized by a variety of analytical techniques, including a UV spectrum in aqueous solution, exhibits remarkable chemotactic potency, comparable to that of the parent pentapeptide. Furthermore, this fullerene-peptide conjugate inhibits, albeit weakly, HIV-1 protease.
Esophageal motility was studied in 26 children with gastroesophageal reflux. In 11 patients (group A), esophagitis was severe; in the remaining 15 (group B), either mild or no microscopic changes were found. Lower esophageal sphincter pressure and amplitude, as well as velocity and duration of esophageal pressure waves, were manometrically measured. All patients underwent a 12-week intensive antacid course. Manometric tracings, blindly read, were compared with those of 16 age-matched children with emesis without proven reflux (group C). Among the variables analyzed, amplitude of the motor waves was significantly lower in patients with severe esophagitis than in group B and C patients (P less than 0.01). Nonspecific motor defects (simultaneous, broad-based, double-peaked waves) were more commonly present in group A. At the end of therapy, symptoms had either disappeared or significantly improved. Endoscopic and histologic studies showed disappearance of the severe inflammatory changes. Manometry, repeated in patients with cured severe esophagitis, showed normalization of the amplitude and significant decrease of the nonspecific motility abnormalities. We conclude that severe gastroesophageal reflux disease in children causes esophageal motor dysfunction, resulting from esophageal inflammation. The occurrence of esophageal motility disorders only in patients with severe esophagitis and its disappearance after therapy may account for the favorable course of reflux disease in infancy.
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