Some Chemical Aspects of Tetrahydro-1-thiopyran-4-one Derivatives

3,5-Diarylmethylene-2,6-diphenyltetrahydrothiopyran-4-thiones, 2, reacted with two or four moles of bromine to form 3-aryimethylene 5-bromoarylmethylene- 2,6-dipheny1tetrahydrothiopyran- -4-thione, 3, and 3-arylmethylene-5-bromoarylmethylene-2,6-dibromo- 2,6-diphenyltetrahydrothiopyran-4-thione, 5, respectively. Compound 2a reacted with amines giving 2,6-diphenyl-5-iminophenylmethyl- 3-phenylmethylenetetrahydrothiopyran-4-thiones, 6. Diphenydiazomethane and 9-diazofluorene converted 2a into 4-diphenylethylene- 2,6-dipheny1-3,5 diphenylmethylenetetrahydrothiopyran, 7, and 2,6-diphenyl-3,5-diphenylmethylene-4-(9-fluorenylidene) tetrahydrothiopyran, 8, respectively. Compounds 2 with copper-bronze afforded 3,3\u27,5,5\u27-tetraarylmethylene-2,2\u27 ,6,6\u27-tetraphenyl-Lr-thio- 4,4\u27 dipyranylidenes

The correlation between increasing Body Mass Index and the incidence of local recurrence and distant metastasis in breast cancer patients

OBJECTIVE: Patients with breast cancer (BC) who are obese or overweight at the time of diagnosis have a low survival rate and a high death rate. We aimed to investigate if having a higher body mass index (BMI) at diagnosis raised the risk of local recurrence (LR) and distant metastasis. PATIENTS AND METHODS: Patients were divided into three categories based on their BMI. The patient's BMI was determined by dividing his weight in kilograms by his height in square meters (kg/m2). The WHO defines normal weight as 18.5 ≤ BMI < 25 kg/m2, overweight as 25 ≤ BMI < 30 kg/m2, and obesity as BMI ≥ 30 kg/m2. RESULTS: The mean BMI was 30.27±6.06 kg/m2. Out of 250 patients, 60 (24.0%), 73 (29.2%) and 117 (46.8%) patients had normal, overweight and obese BMI respectively. No significant difference between BMI and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) was found, but there was an association between tumor (T) stage and lymph vascular invasion (LVI) (p<0.05). Obese patients had poorer disease-free survival (DFS) and overall survival (OS) than normal and overweight categories (35.38 ±1.72 vs. 42.38 ± 2.79 and 37.82 ± 2.27 months) (39.65±1.65 vs.45.70 ± 2.53 and 44.31 ± 2.04 months) (p<0.001). LR occurs more prevalent in over-weight and obese patients than normal (p<0.03) but there is no significant difference for distant metastasis. CONCLUSIONS: There is a strong negative association between increased BMI and BC prognosis and patient survival; controlling of this phenomenon may improve the response to treatment and survival, therefore health awareness programs should be implemented

New Paracyclophanylthiazoles with Anti-Leukemia Activity: Design, Synthesis, Molecular Docking, and Mechanistic Studies

A new series of methyl 2-(2-(4′-[2.2]paracyclophanyl)-hydrazinylidene)-3-substituted-4-oxothiazolidin-5-ylidene)acetates 3a–f were synthesized from the reaction of paracyclophanyl-acylthiosemicarbazides 2a–f with dimethyl acetylenedicarboxylate. Based upon nuclear magnetic resonance (NMR), infrared (IR), and mass spectra (HRMS), the structure of the obtained products was elucidated. X-ray structure analysis was also used as unambiguous tool to elucidate the structure of the products. The target compounds 3a–f were screened against 60 cancer cell lines. They displayed anticancer activity against a leukemia subpanel, namely, RPMI-8226 and SR cell lines. The activity of compound 3a was found as the most cytotoxic potency against 60 cancer cell lines. Consequently, it was selected for further five doses analysis according to National Cancer Institute (NCI) protocol. The cytotoxic effect showed selectivity ratios ranging between 0.63 and 1.28 and between 0.58 and 5.89 at the GI50 and total growth inhibition (TGI) levels, respectively. Accordingly, compound 3a underwent further mechanistic study against the most sensitive leukemia RPMI-8226 and SR cell lines. It showed antiproliferation with IC50 = 1.61 ± 0.04 and 1.11 ± 0.03 µM against RPMI-8226 and SR cell lines, respectively. It also revealed a remarkable tubulin inhibitory activity, compared to colchicine with IC50 = 4.97 µM/mL. Caspase-3, BAX, and Bcl-2 assays for 3a using annexin V-FITC staining revealed significant pro-apoptotic activity. Furthermore, multidrug-resistant leukemia SR cells were used to show better resistance indices (1.285 ng/mL, 1.15-fold) than the reference. Docking studies with β-tubulin indicate that most of the tested compounds illustrated good binding at the colchicine binding site of the enzyme, especially for compound 3a, which made several interactions better than that of the reference colchicine

New Paracyclophanylthiazoles with Anti-Leukemia Activity: Design, Synthesis, Molecular Docking, and Mechanistic Studies

A new series of methyl 2-(2-(4′-[2.2]paracyclophanyl)-hydrazinylidene)-3-substituted-4-oxothiazolidin-5-ylidene)acetates 3a–f were synthesized from the reaction of paracyclophanyl-acylthiosemicarbazides 2a–f with dimethyl acetylenedicarboxylate. Based upon nuclear magnetic resonance (NMR), infrared (IR), and mass spectra (HRMS), the structure of the obtained products was elucidated. X-ray structure analysis was also used as unambiguous tool to elucidate the structure of the products. The target compounds 3a–f were screened against 60 cancer cell lines. They displayed anticancer activity against a leukemia subpanel, namely, RPMI-8226 and SR cell lines. The activity of compound 3a was found as the most cytotoxic potency against 60 cancer cell lines. Consequently, it was selected for further five doses analysis according to National Cancer Institute (NCI) protocol. The cytotoxic effect showed selectivity ratios ranging between 0.63 and 1.28 and between 0.58 and 5.89 at the GI50 and total growth inhibition (TGI) levels, respectively. Accordingly, compound 3a underwent further mechanistic study against the most sensitive leukemia RPMI-8226 and SR cell lines. It showed antiproliferation with IC50 = 1.61 ± 0.04 and 1.11 ± 0.03 µM against RPMI-8226 and SR cell lines, respectively. It also revealed a remarkable tubulin inhibitory activity, compared to colchicine with IC50 = 4.97 µM/mL. Caspase-3, BAX, and Bcl-2 assays for 3a using annexin V-FITC staining revealed significant pro-apoptotic activity. Furthermore, multidrug-resistant leukemia SR cells were used to show better resistance indices (1.285 ng/mL, 1.15-fold) than the reference. Docking studies with β-tubulin indicate that most of the tested compounds illustrated good binding at the colchicine binding site of the enzyme, especially for compound 3a, which made several interactions better than that of the reference colchicine

Design, Synthesis, and Molecular Docking of Paracyclophanyl-Thiazole Hybrids as Novel CDK1 Inhibitors and Apoptosis Inducing Anti-Melanoma Agents

Three new series of paracyclophanyl-dihydronaphtho[2,3-d]thiazoles and paracyclophanyl-thiazolium bromides were designed, synthesized, and characterized by their spectroscopic data, along with X-ray analysis. One-dose assay results of anticancer activity indicated that 3a–e had the highest ability to inhibit the proliferation of different cancer cell lines. Moreover, the hybrids 3c–e were selected for five-dose analyses to demonstrate a broad spectrum of antitumor activity without apparent selectivity. Interestingly, series I compounds (Z)-N-substituted-4,9-dihydronaphtho[2,3-d]thiazol-3(2H)-yl)-4′-[2.2]paracyclophanylamide) that are carrying 1,4-dihydronaphthoquinone were more active as antiproliferative agents than their naphthalene-containing congeners (series II: substituted 2-(4′-[2.2]paracyclophanyl)hydrazinyl)-4-(naphth-2-yl)-thiazol-3-ium bromide hybrids) and (series III: 3-(4′-[2.2]paracyclophanyl)amido-2-(cyclopropylamino)-4-(naphth-2-yl)thiazol-3-ium bromide) toward the SK-MEL-5 melanoma cell line. Further antiproliferation investigations of 3c and 3e on the healthy, normal unaffected SK-MEL-5 cell line indicated their relative safety. Compound 3c showed an inhibition of eight isoforms of cyclin-dependent kinases (CDK); however, it exhibited the lowest IC50 of 54.8 nM on CDK1 in comparison to Dinaciclib as a reference. Additionally, compound 3c revealed a remarkable downregulation of phospho-Tyr15 with a level (7.45 pg/mL) close to the reference. 3c mainly showed cell cycle arrest in the pre-G1 and G2/M phases upon analysis of the SK-MEL-5 cell line. The sequential caspase-3 assay for 3c indicated a remarkable overexpression level. Finally, a molecular docking study was adopted to elucidate the binding mode and interactions of the target compounds with CDK1

Design, Synthesis, and Molecular Docking of Paracyclophanyl-Thiazole Hybrids as Novel CDK1 Inhibitors and Apoptosis Inducing Anti-Melanoma Agents

Three new series of paracyclophanyl-dihydronaphtho[2,3-d]thiazoles and paracyclophanyl-thiazolium bromides were designed, synthesized, and characterized by their spectroscopic data, along with X-ray analysis. One-dose assay results of anticancer activity indicated that 3a–e had the highest ability to inhibit the proliferation of different cancer cell lines. Moreover, the hybrids 3c–e were selected for five-dose analyses to demonstrate a broad spectrum of antitumor activity without apparent selectivity. Interestingly, series I compounds (Z)-N-substituted-4,9-dihydronaphtho[2,3-d]thiazol-3(2H)-yl)-4′-[2.2]paracyclophanylamide) that are carrying 1,4-dihydronaphthoquinone were more active as antiproliferative agents than their naphthalene-containing congeners (series II: substituted 2-(4′-[2.2]paracyclophanyl)hydrazinyl)-4-(naphth-2-yl)-thiazol-3-ium bromide hybrids) and (series III: 3-(4′-[2.2]paracyclophanyl)amido-2-(cyclopropylamino)-4-(naphth-2-yl)thiazol-3-ium bromide) toward the SK-MEL-5 melanoma cell line. Further antiproliferation investigations of 3c and 3e on the healthy, normal unaffected SK-MEL-5 cell line indicated their relative safety. Compound 3c showed an inhibition of eight isoforms of cyclin-dependent kinases (CDK); however, it exhibited the lowest IC50 of 54.8 nM on CDK1 in comparison to Dinaciclib as a reference. Additionally, compound 3c revealed a remarkable downregulation of phospho-Tyr15 with a level (7.45 pg/mL) close to the reference. 3c mainly showed cell cycle arrest in the pre-G1 and G2/M phases upon analysis of the SK-MEL-5 cell line. The sequential caspase-3 assay for 3c indicated a remarkable overexpression level. Finally, a molecular docking study was adopted to elucidate the binding mode and interactions of the target compounds with CDK1

New homogeneous and alternating Mn(II)-azido 1D systems

Abstract Reaction of sodium azide with manganese(II) and 4-amino-1,2,4-triazol or 3-chloropyridine leads to the 1D systems [Mn(N 3 ) 2 (4-amtr) 2 ] n (1) or {[Mn(N 3 ) 2 (3-Clpy) 2 ] AE 1/2(3-Clpy)} n (2), respectively. Compound 1 crystallises in the C2/m (monoclinic) group and consists of chains of Mn(II) cations bridged by double l 1,3 -azido bridges in trans arrangement. Compound 2 crystallises in the I2/a (monoclinic) group and in this case the 1D system shows alternating double l 1,1 and l 1,3 bridges. Magnetic properties follow the expected antiferromagnetic (compound 1) and alternating ferro-antiferromagnetic (compound 2) behaviour