Biomedical subjects
Publications and source records attributed to P Diana.
The synthesis of a series of new antitumour agents, the benzothiazole substituted quinol ethers and esters, is reported via the hypervalent iodine mediated oxidation of hydroxylated 2-phenylbenzothiazoles. The products were found to be active in vitro against human colon and breast cancer cell lines with IC50 values in the nanomolar range.
The title compounds, that hold the deaza skeleton of temozolomide, exhibited potent in vitro antiproliferative activity. An evaluation of such a biological activity indicates that the mode of action of these compounds differs from that of temozolomide and is also mechanistically unrelated to that of any known antitumor drug.
Derivatives of the new ring system indolo[1,2-c]benzo[1,2,3]triazine 5 were synthesized by diazotization of substituted 2-(2-aminophenyl)indoles followed by an intramolecular coupling reaction of the diazonium group with the indole nitrogen. To obtain the indolobenzotriazine system it was necessary to protect the 3 position of the indole nucleus to avoid cyclization into the indolo[3,2-c]cinnoline system 4. Indolobenzotriazines 5a-g were evaluated in vitro for antitumor activity against a panel of leukemia-, lymphoma-, carcinoma-, and neuroblastoma-derived cell lines. Some compounds inhibited the proliferation of T and B cell lines at submicromolar concentrations, whereas their activity against solid tumor cell lines was in the micromolar range. When evaluated for their antifungal potential 5a,d inhibited some of the fungi tested, although at concentrations very close to those inhibiting the proliferation of human cells. On the contrary, all indolobenzotriazines proved fairly potent and selective inhibitors of Streptococcus and Staphylococcus. In particular 5b,c,g were up to 80 times more potent than the reference drug streptomycin and inhibited the growth of the above Gram-positive bacteria at concentrations far lower than those cytotoxic for animal cells.
A series of indolo[3,2-c]cinnoline derivatives was prepared and tested to evaluate their biological activity. Most of them inhibited the proliferation of leukemia, lymphoma and solid tumor-derived cell lines at micromolar concentrations, whereas none of the compounds were active against HIV-1. With the exception of 7g, all title compounds showed antibacterial activity against gram-positive bacteria, being up to 200 times more potent than the reference drug streptomycin. Some of the indolo[3,2-c]cinnolines were also endowed with good antifungal activity, particularly against Criptococcus neoformans.
The new of 1-(2-hydroxyethoxy)methylindole derivatives 3a-i were prepared in good yields. None of them showed any significant anti-HIV activity and therefore the benzocondensation between the 2 and 3 positions of the pyrrole ring definitely reduced the weak activity found in the analogues 1a-c.
Acyclic glycosidopyrroles of type 1, synthesized in good overall yields, were evaluated for anti-viral activity. Compound 10i was found to inhibit the HIV-1 replication at concentrations that were very close to those cytotoxic for MT-4 cells. Compounds 10a,f,i inhibited both strains HSV-1 and HSV-2 at concentrations slightly below those cytotoxic for Vero cells. However for this series of glycosidopyrroles some relationship between calculated log P values and the observed cytotoxicity was found.
Acyclic glycosidopyrroles of type 3 were synthetized in good overall yields, according to the Scheme. When evaluated for antiviral activity against DNA and RNA viruses, only compound in which R1 = R2 = Ph, R3 = NH2 was found to inhibit the HIV-1 replication at concentrations that were not cytotoxic for MT-4 cells.
The series of 1-(1,3-dihydroxy-2-propoxy)methylpyrroles 2a-o were prepared in good overall yields according to Scheme I. When evaluated for antiviral activity against HIV-1, only compounds of the triphenyl series (R3 = NH2, N3, Br) were found to inhibit the HIV-1 replication at concentrations that were very not cytotoxic for MT-4 cells, with selectivity index 1.5-9.3. None of these compounds showed antibacterial or antifungal activity.
The title compounds were synthesised in preparative yields by diazotization of the corresponding 2-aminopyrroles. In preliminary screening tests as antileukemic agents they showed modest activity against the murine and human leukemic cell lines FLC and K562S and their multidrug-resistant daunorubicin selected sublines.
3-Diazopyrroles, a class of compounds particularly interesting from a chemical and biological point of view, were assayed for their ability to induce gene mutations employing back mutation (his+ reversion) test in the philamentous bacterium Streptomyces coelicolor at various time during life cycle. Our results suggest that in evaluating the mutagenicity and toxicity of chemicals in Streptomyces system it is important to consider factors such as growth phase. Furthermore in this series of diazopyrroles a relationship between toxicity, mutagenicity and chemical structure was found. The observed mutagenic activity can be the molecular basis for the appearance of antitumor activity.
Pyrrolo-, pyrazolo- and triazolo-phenanthridines were synthetized by using a Pschorrtype cyclization reaction or an intramolecular cyclization of arylnitrenium ions. By using these synthetic methods several azolo-phenanthridines, variously functionalized either in the azolo ring and in the phenanthridine moiety, were prepared. The title compounds, tested against murine leukemia cell lines, sensible and multidrug resistant, showed moderate activity with IC50 in the range 5-50 microM.
Indolo[3,2-c]cinnolines of type 5, variously substituted either in the indole and in the cinnoline moieties, were prepared in good overall yields, by intramolecular cyclization of indolo derivatives 4. Compounds 5a-d showed a good cytotoxic activity against FLC and K562 leukemic cell lines, both sensitive and multi-drug resistant.
To assess the potential effects of coronary artery bypass surgery on left ventricular diastolic filling, 12 patients, aged 65 +/- 11 years, were studied by serial transesophageal Doppler echocardiograms. Doppler measures of mitral inflow velocity were made before, immediately after, 4 h after, and 20 h after cardiopulmonary bypass (CPB). Left atrial pressure was directly measured and controlled at 10 +/- 2 mm Hg for each study period. Mitral maximal early inflow velocity (E)/maximal atrial velocity (A) ratios and atrial filling fractions were calculated as indexes of diastolic function from maximal E and A velocities and their time velocity integrals, respectively. Data sets were available for serial comparison in 11 patients and were also compared with an age-matched control group of normal values. The results of E/A ratios were as follows: control group--1.4 +/- 0.2; before CPB--1.7 +/- 0.6; immediately after CPB--1.0 +/- 0.2 (p < 0.05 vs control group, before CPB, and 20 h after CPB values); 4 h after CPB--0.8 +/- 0.2 (p < 0.05 vs control group, before CPB, and 20 h after CPB values); and 20 h after CPB--1.3 +/- 0.4. Atrial filling fractions were as follows: control group--0.29 +/- 0.05; before CPB--0.25 +/- 0.06; immediately after CPB--0.43 +/- 0.07 (p < 0.05 vs control group, before CPB, and 20 h after CPB values); 4 h after CPB, 0.46 +/- 0.07 (p < 0.05 vs control group, before CPB, and 20 h after CPB values); and 20 h after CPB--0.35 +/- 0.06. Alterations in Doppler indexes of left ventricular filling occurred immediately after CPB and persisted 4 h after CPB. These indexes returned to baseline values by 20 h after CPB. This suggests reversible diastolic dysfunction in patients after coronary artery bypass surgery.
Isoflurane may precipitate ischemia in patients with coronary artery disease, presumably via "coronary steal." We sought to examine whether myocardial ischemia is more common in patients with coronary artery disease receiving isoflurane (0.7%) than in a control group receiving enflurane (0.9%). Thirty-eight patients scheduled for coronary artery bypass surgery were randomly assigned one anesthetic and monitored for ischemia. All patients had ejection fractions of at least 45%. Extraneous causes of ischemia were controlled as much as possible: arterial blood pressure was maintained within 20% of baseline (primarily with phenylephrine), heart rate was maintained below 80 bpm, effects from endotracheal intubation were monitored, and measurements were made before incision. Electrocardiogram, transthoracic echocardiography, and coronary sinus lactate measurement were used to detect ischemia. Measurements were made after insertion of vascular catheters, after intubation, and after 20 min of breathing the inhaled anesthetic. During the awake period and after induction of anesthesia with fentanyl (25 micrograms/kg), there was no significant difference detected between the two groups in incidence of ischemia: 20% in the enflurane group and 22% in the isoflurane group (P = 0.38). After 20 min of receiving the inhaled anesthetic, the incidence of ischemia in the isoflurane group increased to 50%, whereas the incidence in the enflurane group was unchanged at 20% (P = 0.02). These results show that, even with strict control of hemodynamics, isoflurane is associated with more myocardial ischemia than is enflurane.
Some 3-triazenopyrroles were prepared by coupling 3-diazopyrroles and secondary amines. In preliminary in vitro screening tests derivatives 3 showed to be cytotoxic and exhibited mutagenic effects.
A new prototype transesophageal transducer with continuous-wave Doppler and pulsed Doppler capabilities was evaluated to calculate intraoperative cardiac output from the main pulmonary artery. Fifteen consecutive patients undergoing elective coronary artery bypass surgery were studied. The main pulmonary artery diameter above the pulmonic valve was measured with the single horizontal plane transesophageal transducer. The pulmonary artery cross-sectional area was calculated from its diameter using the formula: Area = 1/4 pi (diameter)2. Continuous-wave Doppler and pulsed Doppler spectra were recorded from the main pulmonary artery and their flow velocity integrals were then multiplied by pulmonary artery area and heart rate to yield cardiac output. The main pulmonary artery diameter could not be confidently measured in 2 of 15 patients (13%). In the remaining 13 patients, Doppler cardiac output measurements were correlated with simultaneous thermodilution measurements. The closest correlation with thermodilution cardiac output was with the continuous-wave Doppler cardiac output method: R = 0.91, SEE = 0.2 L/min, and y = 1.1x . 0.2 (p less than 0.001). The correlation of thermodilution with pulsed Doppler cardiac output was R = 0.83, SEE = 0.5 L/min, and and y = 0.86 + 1.0 (p less than 0.001). Transesophageal continuous-wave Doppler is a new technique that may be used in selected patients for accurate determination of intraoperative cardiac output.
3-Diazo-2-phenylpyrroles 3a-g showed antimicrobial activity against Gram-positive bacteria, whereas against Gram-negative strains the inhibitory activity is limited to derivatives 3a and 3c. The substituents at 4 and 5 positions strongly influence the inhibitory activity, but the presence of the diazo group is crucial for appearance of activity.
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