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6-Mercaptopurine has been utilized for the synthesis of various fused purine analogues through different chemical reactions to yield [1,4]thiazino[4,3,2-gh]purines 2, 3, 10a,b, 14, (8-oxo-[1,4]thiazino[4,3,2-gh]purin-7(8H)-ylidene) acetate 4, [1,4]thiazepino[4,3,2-gh]purine 6, thiazolo[3,4,5-gh]purine 7, imidazo[1,5,4-gh]purin-5-amine 8, 5-methylimidazo[1,5,4-gh]purine 9, [1,2,4]triazino[4,3-i]purines 16, 18, 21, [1,2,4]triazino[4,5,6-gh]purine 20, 5-methyl-2-(7H-purin-6-yl)-1H-pyrazol-3(2H)-one 22, [1,2,4]triazolo[4,3-i]purine 23, [1,2,5]triazepino[5,4,3-gh]purine 24, and ethyl 6-(2-(ethoxycarbonyl)hydrazinyl)-9H-purine-9-carboxylate 26. Seventeen of the newly synthesized compounds were selected by the NCI, Maryland, USA, and were tested for their anticancer activity in an initial single high dose in the full NCI 60 cell line panel among which [1,4]thiazino[4,3,2-gh]purine-7,8-dione 2, 7-benzyl-[1,4]thiazino[4,3,2-gh]purine 10b, and 3-(2,4-dimethoxyphenyl)-7H-[1,2,4]triazolo[4,3-i]purine 23 were found to possess very potent anticancer activity against most of the cancer cell lines.

The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.

Aim This study evaluated the survival outcome, pattern of failure and prognostic factors in cervix uteri cancer patients. Methods We reviewed the data of 60 patients with stages IB-IVA cancer who were treated between January 2004 and December 2010. Results Most patients (n = 50; 83%) had squamous cell carcinoma. Stage IIB was the most common presentation (n = 41; 68%). Forty-seven patients (78%) received Cisplatin concurrent with radiotherapy (CRT). The 2- and 4-year overall survival (OS) was 82% and 79%, respectively. Prolongation of the overall treatment time (OAT) for greater than 56 days, advanced stage and pretreatment hemoglobin (Hb) levels (

Eighteen new 5-benzylidene-3-(4-arylpiperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-ones were designed as hybrid structures from previously reported anticonvulsant compounds, synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using the strychnine (2 mg/kg IP) potent generalized-induced seizure and pentylenetetrazole (PTZ) (60 mg/kg IP) acute clonic-induced convulsion screens in mice. All the molecules were found to be effective in at least one seizure model, compounds 10, 13, 15, 17, and 18 were active against both types of seizures induced. Compound 13 turned out to be the most active candidate within the strychnine model, having an average survival time of 6 min close to that of the positive control phenytoin, while compound 8 showed 100% protection from the induced PTZ seizures, resembling the protection of the positive control phenobarbital. Initial SAR studies for anticonvulsant activity are discussed.

Three novel series of 1,2,4-triazole derivatives were designed and synthesized as potential adenosine A2B receptor antagonists. The design of the new compounds depended on a virtual screening of a previously constructed library of compounds targeting the human adenosine A2B protein. Spectroscopic techniques including 1 H nuclear magnetic resonance (NMR) and 13 C NMR, and infrared and mass spectroscopy were used to confirm the structures of the synthesized compounds. The in vitro cytotoxicity evaluation was carried out against a human breast adenocarcinoma cell line (MDA-MB-231) using the MTT assay, and the obtained results were compared with doxorubicin as a reference anticancer agent. In addition, in silico studies to propose how the two most active compounds interact with the adenosine A2B receptor as a potential target were performed. Furthermore, a structure-activity relationship analysis was performed, and the pharmacokinetic profile to predict the oral bioavailability and other pharmacokinetic properties was also explained. Four of our designed derivatives showed promising cytotoxic effects against the selected cancer cell line. Compound 15 showed the highest activity with an IC50 value of 3.48 µM. Also, compound 20 revealed an equipotent activity with the reference cytotoxic drug, with an IC50 value of 5.95 µM. The observed IC50 values were consistent with the obtained in silico docking scores. The newly designed compounds revealed promising pharmacokinetic profiles as compared with the reference marketed drug.

Demonstration of unilateral aldosterone production by adrenal venous sampling (AVS) is required to select appropriate candidates for adrenalectomy in patients with primary aldosteronism (PA). During AVS, aldosterone and cortisol levels are measured to assess successful cannulation and lateralization. In patients with aldosterone-producing adenoma (APA), concurrent autonomous cortisol secretion might confound AVS results.We retrospectively examined results in eight patients with cortisol-producing adenoma (CPA), but without PA, who underwent AVS.In all eight, cortisol was higher on the CPA side than contralateral (CL) (median 6·7-fold [range 2·4-27·2]; P = 0·012]). By cortisol criteria, CL catheter placement would have been labelled inadequate in six despite adrenal venous aldosterone levels markedly higher than peripheral (41·6-fold [7·2-510·5]; P 0·001), suggesting successful cannulation. In all eight, adrenal venous aldosterone/cortisol (A/C) ratios on the CL side were indicative of increased aldosterone production (≥2 times peripheral), but in only three patients on the CPA side (difference CL side 44·5-fold [6·0-109·0] vs CPA side 1·65-fold [1·0-23·0]; P = 0·017). A/C ratios were higher on the CL vs the CPA side in seven (20·0-fold [4·7-76·0]).These results in patients with CPA suggest that in patients with APA, concurrent autonomous unilateral cortisol hypersecretion could confound AVS accuracy by increasing cortisol levels (reducing A/C ratio) on the CPA side, while reducing levels (increasing A/C ratio and suggesting failed cannulation) on the CL side. Misclassification of PA subtype or repeat AVS could result, underscoring the importance of adequately assessing cortisol production prior to AVS and the need to consider alternatives.

Herein, we report the synthesis of novel tetrahydro-β-carbolines that induce cell death via the autophagic pathway. Five of the new compounds induced cell death in a panel of patient-derived human metastatic melanoma cells. The autophagic pathway was confirmed using LC3 autophagosome markers; the involvement of ATG7 and Beclin 1 autophagy regulating genes was confirmed using infection with short hairpin RNA (shRNA) to silence Beclin 1 and ATG7. Compound VIII (IC50 = 2.34-5.15 μM) displayed activities greater than cisplatin against a panel of patient-derived human metastatic melanoma cell lines. The structure-activity relationship (SAR) of this class and the role of the absolute stereochemistry and geometrical isomerism are evaluated.

The review summarizes published data on the behavior and reactions of acylthiosemicarbazides and their derivatives, which lead to the formation of heterocyclic systems, including methods of preparation in addition to synthesis of pyrrole, thiazole, thiadiazole, thiadiazolidine, and triazole derivatives as well as fused heterocyclic compounds. J. Heterocyclic Chem., (2012).

Starting from tadalafil as a template, a series of functionalized tetrahydro-β-carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4-methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2-methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC(50) = 3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively.

AIM: Women in Saudi Arabia develop breast cancer at a young age with high prevalence of poor prognostic features. Because of such features, it is necessary to examine prognostic factors in this population. One such factor is the prognostic role of lymph node ratio (LNR). METHODS: We performed retrospective analyses of patients with invasive non-metastatic breast cancer who underwent axillary lymph node dissection and had one or more positive axillary lymph nodes. RESULTS: Two hundred and seventeen patients were considered eligible for the analysis. The median age was 46 years. At a median follow-up of 39.8 months, the median disease-free survival (DFS) was 67.3 months (95% CI, 50.4 to 84.3 months). Neither the classification of patients based on positive lymph node (pN) staging system, nor the absolute number of pN prognosticated DFS. Conversely, age 0.20 to 0.65) LNR categories were the only variables that were independently associated with adverse DFS. Using these variables in a prognostic model allowed the classification of patients into three distinctive risk strata. The overall survival (OS) in this series was 92.5 months (95% CI, 92.1-92.6). Only ER negative tumor adversely influenced OS. CONCLUSION: Analysis of survival outcome of mostly young patients with early breast cancer identified adverse prognostic variables affecting DFS. If the utility of the derived model including LNR is proven in a larger patient population, it may replace the use of absolute number of positive axillary lymph nodes

Here we report a series of potent anti-HCV agents bearing a symmetrical benzidine l-prolinamide backbone with different capping groups including alkyl/aryl carbamates of natural and unnatural valine and leucine amino acids. All compounds were investigated for their inhibitory activity in an HCV replicon assay on genotype 1b. The novel compounds share some chemical and clinical attributes of commercially available NS5A inhibitors. Compounds 5 and 6 with unnatural capping residue and ethyl and isobutyl carbamates showed EC50 values in the picomolar range with a low toxicity profile and selectivity indices of several orders of magnitude. These findings enlarge the chemical space from which NS5A inhibitors may be discovered by adopting unnatural amino acids, amino acids other than valine and carbamates other than methyl as the capping groups.

Novel cycloalkene-fused thienopyrimidine analogues with enhanced phosphodiesterase 5 (PDE5) inhibitory properties are presented. The structure of the reported scaffold was modulated through variation of the terminal cycloalkene ring size, as well as by varying the substituents at position 4 through the attachment of different groups including aniline, benzylamine, cyclohexylethylamine, methyl/acetyl/aryl piperazines, and aryl hydrazones. Compound 15Y with a benzylamine substituent and cycloheptene as terminal ring showed the highest PDE5 inhibitory activity with an IC50 value as low as 190 nM and with good selectivity versus PDE7 and PDE9.

(1,3-Dioxo-2,3-dihydro-1H-inden-2-ylidene)propanedinitrile (1, in ethyl acetate solution), 3-(dicyano-methylene)-2-indolone (2, in ethanol/piperidine solution) and 7,7′,8,8′-tetracyanoquinodimethane (3, in pyridine solution) act on substituted acylthiosemicarbazides 4a-d, forming the derivatives of oxoindeno-pyrrolylidenehydrazide (5a-d and 7a-d), thiazoloindolylidenehydrazide (12a-d), pyrroloindolylidene-hydrazide (13a-d) and spiro[pyrrolylidene-4,1′(cyclohexa-2′,5′-dienylidene)]propanedinitrile (18a-d). Rationales for these conversiones involving the nucleophilic addition on dicyanomethylene carbon atom are presented.

1-Acylthiosemicarbazides 9a-d reacted with ethenetetracarbonitrile (TCNE, 2) in ethyl acetate with formation of N′-(4-amino-5,6-dicyano-2H-1,3-thiazin-2-ylidene) substituted hydrazide 10a-d, N′-(5-amino-3,4-dicyano-2H-pyrrol-2-ylidene)-2-substituted hydrazide 11a-d and 2-substituted imidazo[2,1-b][1,3,4]-oxadiazole-5,6-dicarbonitrile 12a-d. Rationales for the conversions observed are presented.

This review deals with synthesis, reactions and their applications of pyrano triazolo pyrimidines. The main purpose of this review is present a survey of literatures on the reactivity of amino imino derivatives and carboxylic acid derivatives. Some of these reactions have been applied successfully to the synthesis of biological important compounds.

Reactions of N,N′-disubstituted hydrazine-1,2-carbothioamides 8a-c and substituted N,N″-ethane-1,2-diylbis(thioureas) 9a-c with 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil, 10a) and 2,3,5,6-tetrabromo-1,4-benzoquinone (bromanil, 10b) to form N,N′-disubstituted 1,3,4-thiadiazole-2,5-diamines 11a-c, substituted 3-amino-6,7-dichloro-2,3-dihydro-1H-4,2,1-benzothiadiazine-5,8-diones 12a-c, 2,3,7,8-tetrahalothianthrene-1,4,6,9-tetrones 13a,b, substituted 5,6,8-trihalo-7-oxo-3,7-dihydroquinoxaline-2H-carbothioamides 14a-c, 15a-c and 7-substituted imino-1,3,6-thiadiazepane-2-thiones 16a-c are reported.

Background and objective The clinical problem of a neck mass in general and tuberculous lymph nodes in the neck in particular may present a diagnostic dilemma. This retrospective study was conducted to highlight clinical presentation, management, and outcome. Patients and methods All patients (n = 59) diagnosed with tuberculosis of the cervical lymph node in Irbid governorate during the period 1996 through 2000 were reviewed for standard criteria, in addition to diagnostic and therapeutic modalities. Results Medical records were reviewed and relevant data were included; all age groups were equally involved with a female/male ratio of 2:1. Most of the patients presented with a neck mass to the outpatient surgical clinic. The diagnosis was made mainly based on the clinical picture and results of the Mantoux test, Ziehl-Neelsen staining, and culture of bacilli. Fine needle aspiration cytology and histologic examination of incisional or excisional specimens are the main objective diagnostic tools. All patients were treated with antituberculous drugs under directly observed therapy short-course regimen with 83% cure rate. Conclusion Tuberculosis of the cervical lymph nodes responds well to antituberculous drugs and the surgical role is limited to guidance in fine needle aspiration, incision and drainage, and incisional and limited excisional biopsy. Major excisional procedures are not without complications and should be avoided.

Microwave and thermal heterocyclization of N,N′-disubstituted hydrazinecarbothioamide 1a,b and substituted thioureidoethylthioureas 2a–c as well as 1-phenyl-3[2-(3-phenylthio-ureido)phenyl]thiourea 6 are reported. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:535–541, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10188

The synthesis of some new analogs of quinolin-4-one and 1,7-naphthyridin-4-one is described. The prepared compounds were tested for their in vitro antitumor and cdc2 kinase or cdc25 phosphatase inhibitory activity. Compound ethyl 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][2,3-b]pyrido-1,4-thiazine-6-carboxylate (6b) showed antitumor activity against CNS SNB-75, breast T-47D, and lung NCI-H522 cancer cell lines with GI50 values of 8.3, 17.6, and 22.7 microM, respectively. Meanwhile, the compounds ethyl 4-oxo-8-phenylthio-1H,4H-quinoline-3-carboxylate (11a) and 4-oxo-8-phenylthio-1H,4H-1,7-naphthyridine-3-carboxylic acid (12b) have proved to be cdc25 phosphatase inhibitors at IC50 values of 11 and 5 microM, respectively.

Several derivatives of 5-substituted 2-bromoindolo[3,2-b]quinoxaline were synthesized and characterized. The synthesized compounds were evaluated for their antitumor activity using the National Cancer Institute-in vitro-disease oriented antitumor screen and two biochemical mechanism-based screens (cdc2 kinase and cdc25 phosphatase). Compound 19 showed broad spectrum antitumor activity with full panel (MG-MID) GI50. TGI, and LC50 of 14.2, 31.6- and 66.2 microM, respectively. In addition it inhibited cdc2 kinase and cdc25 phosphatase with IC50's of 70 and 25 microM, respectively. Thus, compound 19 represents a model for compounds with potential antitumor activity and cdc25 phosphatase inhibitory properties.

Two series of 3-cyano-2(1H)-oxopyridine and 3-cyano-2(1H)-iminopyridine derivatives carrying various aryl substituents at position 4 and (4-((7-chloro or trifluoromethylquinol-4-yl)amino)phenyl) substituent at position 6 were synthesized and evaluated for their antitumor activity. Compounds 3f and 6d showed high selectivity towards leukemia cell lines with full panel median growth inhibition GI50 average sensitivity towards all cell lines (MG-MID) at 7.9 and 19.7 microM and leukemia subpanel GI50 average sensitivity towards leukemia cell lines (MG-MID) at 1.74 and 2.9 microM, respectively, also they exhibited full panel total growth inhibition TGI (MG-MID) at 34.8 and 59.0 microM and leukemia subpanel TGI (MG-MID) at 5.3 and 13.5 microM, respectively.