Synthesis and anticancer activity of multisubstituted purines and xanthines with one or two propynylthio and aminobutynylthio groups.

A synthesis of new 2,6-disubstituted and 2,6,8-trisubstituted 7-methylpurines as well as 8-substituted 3,7-dimethylxanthines containing a triple bond chain have been worked out. Purinethiones and xanthinethiones were converted into propynylthio derivatives, which were then further transformed via a Mannich reaction into aminobutynylthio derivatives (amine = pyrrolidine, piperidine, morpholine, and diethylamine). The products thus obtained represent various types of the purine and xanthine structure: 8-mono-, 2,6- and 6,8-dipropynylthio, 6- and 8-monoaminobutynylthio, 2,6- and 6,8-diaminobutynylthio derivatives. All of these compounds were tested for their anticancer activity against human glioblastoma SNB-19, human adenocarcinoma MDA-MB-231, and melanoma C-32 cell lines. The anticancer activity depends on the nature of the substituent and its localization in the purine and xanthine framework. Generally, compounds possessing two alkynylthio groups (propynylthio or aminobutynylthio) were more active than those possessing only one group. Some compounds exhibited stronger or similar anticancer activity to cisplatin. All compounds were also tested for their cytotoxic activity against normal human fibroblasts (HFF-1). The most promising anticancer compounds were found to be 2,6-dipropynylthio-7-methylpurine 4, 2-chloro-6,8-dipropynylthio-7-methylpurine 14, and 2-chloro-6,8-di(N-morpholinylbutynylthio)-7-methylpurine 15c acting selectively on glioblastoma SNB-19, melanoma C-32, and adenocarcinoma MDA-MB-231 with the IC50 = 0.07-4.08 µg/mL.

Synthesis and anticancer activity of thiosubstituted purines.

New thiopurines with the propargylthio, pyrrolidinobutynylthio, sulfenamide, and sulfonamide groups in the pyrimidine ring were synthesized. The anticancer activity of these compounds and previously obtained 2- or 6-substituted azathioprine analogs and dialkylaminoalkylthiopurines were tested in vitro against three cell lines: glioblastoma SNB-19, melanoma C-32, and human ductal breast epithelial tumor T47D. 2-Chloro-7-methyl-6-pyrrolidinobutynylthiopurine (5b) was the most potent compound against SBN-19 and C-32 cell lines with the activity similar to cisplatin (EC50 = 5.00 and 7.58 µg/ml, respectively). The dialkylaminoalkylthio derivatives (4b, 4c, 4e, and 4f) showed good activity against SBN-19 cell line (EC50 < 10 µg/ml). The azathioprine analogs (2a, 2b, and 3a) were more active than azathioprine against SBN-19 and C-32 cell lines. The sulfenamide and sulfonamide derivatives of purine were very weak active against tested cell lines. All studied thiopurines were less toxic than cisplatin.

The relationship of carotid arterial stiffness to left ventricular diastolic dysfunction in untreated hypertension.

BACKGROUND: Interest in the role of arterial stiffness in the pathomechanism of left ventricular (LV) diastolic dysfunction has grown in recent years. AIM: To examine the relationship between local carotid arterial stiffness parameters assessed by the ultrasonic high-resolution echo-tracking (eT) method and LV diastolic function indices in patients with untreated hypertension (H). METHODS: The study group consisted of 173 subjects, 78 male and 95 female, 113 of them with untreated H, mean age 55.7 ± 10.4 years, and 60 age-matched controls. Using 2D echo, conventional and tissue Doppler echocardiography, LV systolic and diastolic function and left ventricular hypertrophy (LVH) indices were assessed. Hypertensives were divided into two groups: those with diastolic dysfunction (HDD+: with relaxation abnormalities, n = 55 and with pseudonormalisation pattern, n = 12); and those without diastolic dysfunction (HDD-, n = 46). Using carotid arteries ultrasound, intima media thickness (IMT) and eT arterial stiffness parameters were evaluated, as also were ß - beta, Ep - epsilon, AC - arterial compliance, PWVß - one-point pulse wave velocity and AI - augmentation index. RESULTS: Linear regression analysis revealed significant correlations between arterial stiffness indices and diastolic function parameters in the study groups: the ratio of early to late transmitral pulse Doppler velocities - E/A - correlated to Ep,ß, AC and PWVß (r = -0.30, r = -0.25, r = 0.26, r = -0.30, respectively, p < 0.05); early diastolic mitral annular velocity - e' - correlated to Ep, ß and PWVß (r = -0.22, r = -0.26, r = -0.25, respectively, p < 0.05); the ratio of early to late diastolic mitral annular velocities - e'/a' - was correlated with ß and PWVß (r = -0.28, r = -0.28, respectively, p < 0.05). HDD+ did not present echocardiographic LVH. Using ROC curve analysis, we identified optimal cut-off values of different parameters in the determination of diastolic dysfunction occurrence. Univariable analysis revealed the following significant variables in determining LV diastolic dysfunction: ß > 9.2 (OR 2.65, p = 0.026), Ep > 118 kPa (OR 3.53, p = 0.040), PWVß > 6.2 m/s (OR 3.92, p = 0.002), AI > 7.8 (OR 2.62, p = 0.049), age > 54 (OR 4.76, p < 0.001), diabetes presence (OR 2.78, p = 0.013), IMT > 0.51 mm (OR 4.49, p < 0.001), diastolic blood pressure < 70 mm Hg (OR 3.38, p = 0.047), pulse pressure > 64 (OR 2,90, p = 0.031) and ejection fraction < 76 (OR 3.38, p = 0.019). However, at multivariate analysis, only age (OR = 2.43, p = 0.073), IMT (OR = 4.56, p = 0.002) and PWVß (OR = 2.18; p = 0.091) were independently associated with diastolic dysfunction occurrence. CONCLUSIONS: Carotid IMT as a marker of subclinical atherosclerosis and PWVß as an index of carotid arterial stiffness are, besides age, independently associated with LV early diastolic dysfunction occurrence in untreated middle-aged hypertensives.

Polish queer lesbianism: sexual identity without a lesbian community.

The article investigates the state of Polish lesbianism. It presents the history of lesbian groups, lesbian culture, and community in Poland. It puts social and political activism of lesbians in the context of the growing feminist movement and strong nationalism in Poland. Showing the important role of the Internet communication and the way in which queer philosophy is understood in this country, it investigates sexual identity formation and the process through which lesbian communities develop in Poland. The analysis of Polish lesbianism confirms the constructionists' theory that sexual identity formation highly depends on cultural and political circumstances.

2,6-Dimethoxy-7,9-dimethylpurinium iodide hemihydrate.

In the title compound, C(9)H(13)N(4)O(2)(+) x I(-) x 0.5 H(2)O, the non-H atoms of the ionic components lie on a mirror plane in Cmca, with the O atom of the partial water molecule lying on a twofold rotation axis. Whereas one of the methoxy methyl groups is directed away from the adjacent N-methyl group, the other methoxy methyl group is directed towards its adjacent N-methyl group. The conformation of the methoxy methyl groups provides an explanation for the outcomes of intramolecular thermal rearrangements of 2,6-dialkoxy-7,9-dimethylpurinium salts.

Early predictors of adverse left ventricular remodelling after myocardial infarction treated by primary angioplasty.

BACKGROUND: Progressive left ventricular dilatation (PLVD) occurs after myocardial infarction (MI), and this may take place in the area of primary percutaneous coronary intervention (PCI). The factors predicting PLVD after primary PCI still need to be clarified. The aim of the study was to assess the prevalence and to define the baseline clinical and echocardiographic predictors of PLVD in patients with STEMI treated by primary PCI. METHODS: Of the 90 patients initially selected for the study 88 (29 women and 59 men, mean age 67.1 +/- 5.6 years) with first ST-elevation myocardial infarction (STEMI) treated with primary PCI were examined. Echocardiographic examination was performed in all patients at discharge (M1) and after 6 months (M2). The following factors influencing PLVD were evaluated: type of infarct-related artery (IRA), infarct size expressed as wall motion score index (WMSI) >/= 1.5, left ventricular end-diastolic volume index (LVEDVI) >/= 80 ml/m(2), ejection fraction (EF) /= 125 g/m(2) and coronary risk factors. RESULTS: The overall prevalence of PLVD (according to the criterion of 20% LVEDVI increase from M1 to M2) was 24%. Univariate regression analysis revealed that the following were the significant baseline M1 predictors of adverse PLVD: left anterior descending as IRA (relative risk: rr = 2.3, p < 0.05), WMSI >/= 1.5 (rr = 4.29, p < 0.005), EF /= 1.5. CONCLUSIONS: Both regional and global left ventricular systolic dysfunction indices as well as severe left ventricular diastolic abnormalities but not left ventricular dilatation at discharge are significant predictors of adverse cardiac remodelling after STEMI in patients treated with primary PCI. However the only independent determinant of PLVD was WMSI >/= 1.5 expressing the infarct size. (Cardiol J 2007; 14: 238-245).

Synthesis, physicochemical properties and biological activity of 2,6-disubstituted 7-methylpurines and the 7,9-dialkyl analogues.

The preparation of several derivatives of 2,6-disubstituted-7-methylpurines and the 7,9-dialkyl analogues possessing a potential cytotoxic or cytostatic activity has been described. These compounds were tested for biological activity using a method for the determination of the toxic effects of chemical compounds on the growth of green alga Chlorella vulgaris, Beijerinck 1890. The effective concentration (EC50) was calculated.

[Prognostic value of a model using restricted left ventricular filling for prediction of developing heart failure after myocardial infarction]. / Prognostyczna wartosc modelu restrykcji napelniania lewej komory w przewidywaniu rozwoju póznej niewydolnosci serca po zawale miesnia serca.

UNLABELLED: The prognostic significance of restrictive pattern (RP) of mitral flow in myocardial infarction (MI) has yet not been defined. The aim of the study was to assess the relationship of a RP in MI patients at discharge with the development of left ventricular (LV) dilatation and clinical symptoms of heart failure (HF) after one year. METHODS: 2D and Doppler Echocardiography was performed on 88 patients (mean age 53.8 +/- 11) at discharge after their first MI and then one year after that MI. Patients were classified according to Doppler examination at discharge into 2 groups: Group I-RP (n = 9) with peak E to A ratio E/A > or = 2 or E/A > or = 1.5 and deceleration time DT < or = 140 ms, Group II--non-restrictive pattern nRP (n = 79). In predicting the development of HF the following variables were analysed using Cox proportional hazard model: MI location and extension (Inf, Ant, non-Q, Q-wave), reperfusion defined by non-invasive features (R/+/, R/-/), Killip-Kimball class (K-K), end-diastolic volume index (EDVI), end-systolic volume index (ESVI), ejection fraction (EF), wall motion score index (WMSI) and restrictive pattern of mitral flow presence (RP). RESULTS: HF developed in 23 patients: 8 pts were in RP-group (89%), while 15 pts were in nRP-group (19%) (rr = 4.68 p < or = 0.001). In the univariate Cox analysis, the following variables were associated with higher incidence of HF: Q-MI (rr = 5.66 p < or = 0.05), R- (rr = 4.96 p < or = 0.001), K-K > or = II (rr = 3.13 p < or = 0.01), EDVI > or = 80 ml/m2 (rr = 5.85 p < or = 0.001), ESVI > or = 40 ml/m2 (rr = 4.07 p < or = 0.001), WMSI > or = 1.4 (rr = 2.79 p < or = 0.01) and RP (rr = 4.6 p < or = 0.001). However, the multivariate Cox analysis revealed only three significant independent predictors of HF: EDVI > or = 80 ml/m2 (rr = 6.27 p < or = 0.001), R- (rr = 4.74 p < or = 0.01) and RP (rr = 3.2 p < or = 0.05). The cumulative predictive power of RP in connection with the selected parameters (RP + K-K > or = II, RP + EF < or = 45%, RP + WMSI > or = 1.4) was higher for RP + K-K > or = II (rr = 4.61 p < or = 0.001) and especially for RP + WMSI > or = 1.4 (rr = 5.06 p < or = 0.001). CONCLUSION: The restrictive pattern of LV filling in MI pts at discharge is an independent predictor of heart failure development. The assessment of both diastolic and systolic LV functions parameters increases prediction power.