Tamarindus indica seed ash extract for C-C coupling under added organics and volatile organic solvent-free conditions: a waste repurposing technique for Suzuki-Miyaura reaction.

A tremendous research has been appeared on Pd-catalyzed Suzuki-Miyaura cross-coupling (SMC) during the last four decades due to its high prominence in constructing biaryl motifs of several complexes as well as simple organic compounds of high biological and commercial significance. The use of organic solid waste-derived materials for SMC in benign solvents like water/aqueous media is a very good achievement in these cases. We report in this article the usability of water extract of Tamarindus indica seeds ash (WETS) as a renewable base and reaction medium for Pd(OAc)2-catalyzed SMC reaction at room temperature (RT). The WETS has been characterized using powder XRD, EDAX, SEM, and FTIR analysis. Furthermore, this process is highly environmentally beneficial by the waste repurposing to prominent chemical transformation along with the advantages such as ambient condition and avoids non-renewable chemicals like volatile organic solvents, ligands, promoters, and bases. Based on these merits and the quick reactions with high yields of products, this method can attain the interest of the scientific community in exploring the waste-derived ashes to significant chemical transformations. Tamarindus indica seed ash extract for C-C coupling under added organics and volatile organic solvent-free conditions: a waste repurposing technique for Suzuki-Miyaura reaction.

Palladium-Catalyzed [2 + 2 + 2] Annulation via Transformations of Multiple C-H Bonds: One-Pot Synthesis of Diverse Indolo[3,2- a]carbazoles.

A Pd-catalyzed novel cascade reaction has been developed for the synthesis of indolo[3,2 a]carbazoles involving multiple C-H transformation-annulations between the indoles and alkynes. The method involves molecular oxygen as the sole oxidant and is an effective and step-economic process.

Feasibility of Axillary Reverse Mapping and Clinicopathological Features Predicting ARM Node Metastasis in Breast Cancer-a Pilot Study.

The axillary reverse mapping (ARM) technique has been described as an attempt to map and preserve the upper extremity lymphatic drainage during axillary lymph node dissection (ALND) and/or SLNB. This technique is based on the hypothesis that the lymphatic pathway from the upper extremity is not involved by metastasis from primary breast cancer. The ARM node/s however, has been found, in various studies, to be involved with metastatic foci in patients with extensive axillary lymph node metastases. Therefore, the oncological safety of this procedure has not yet been determined. In this pilot study, we assessed the ARM node intraoperatively for various parameters and compared it to final HPR, to try and determine the oncologic safety of preserving the ARM node. Seventy-two breast cancer patients were screened for this prospective pilot study which was planned to recruit 20 patients. The study was initiated on May 2014, 20 patients were recruited till July 2015. Eligibility criterion was as follows: patients requiring primary axillary lymph node dissection based on a clinically positive axilla. Forty-five patients were ineligible because they had either received neoadjuvant chemotherapy or underwent previous axillary surgery or axillary radiation (exclusion criteria). Seven patients refused to give consent. ARM node identification rate was 75%. The most common location of the ARM node was lateral to the latissimus dorsi pedicle (42.10%), none of them being malignant. None of the oval or firm nodes were malignant. Tumor deposits were identified in 13%. Fine-needle aspiration cytology (FNAC) had 100% specificity, 94.4% negative predictive value, 100% positive predictive value, and 50% sensitivity. ARM is feasible using blue dye alone, with an acceptable identification rate. Location, consistency, and intraoperative FNAC of the ARM node, put together, may be reliable parameters to predict involvement of the ARM node with metastasis.

Metal catalyst free cyclization of 3-alkynyl substituted 2-(indol-3-yl)quinoxalines in TFA alone: a new synthesis of indolophenazines.

TFA alone was found to be remarkably effective for the intramolecular hydroarylation (IMHA) of alkynes when employed as a solvent in the cyclization of 3-alkynyl substituted 2-(indol-3-yl)quinoxalines. This simple and metal free cyclization method afforded a range of indolophenazines as new and potential cytotoxic agents. The use of excess TFA was found to be crucial for the success of this reaction.

A simple access to N-(un)substituted isoquinolin-1(2H)-ones: unusual formation of regioisomeric isoquinolin-1(4H)-ones.

A ligand/additive/Pd-free Cu-mediated coupling/cyclization strategy afforded the first practical, one-pot and general approach towards synthesis of N-(un)substituted isoquinolin-1(2H)-ones. Both the catalyst and the solvent used are recyclable. The use of the Cu reagent in excess led to the unusual formation of regioisomeric and uncommon isoquinolin-1(4H)-ones.

Montmorillonite K-10 catalyzed green synthesis of 2,6-unsubstituted dihydropyridines as potential inhibitors of PDE4.

Montmorillonite K-10 mediated MCR of anilines, arylaldehydes and ethyl-3,3-diethoxypropionate in water afforded 2,6-unsubstituted dihydropyridines depending on the nature of anilines employed. A variety of dihydropyridines were prepared by using this green methodology in good yields and montmorillonite K-10 was found to be an inexpensive and reusable catalyst. The structure elaboration of a representative compound was carried out under Heck conditions. Some of the compounds synthesized showed significant inhibition of PDE4B when tested in vitro. Docking studies indicated that one of the ester moieties of these compounds played a key role in their interactions with the PDE4B protein.

Novel imidazophenoxazine-4-sulfonamides: their synthesis and evaluation as potential inhibitors of PDE4.

A number of novel imidazophenoxazine-4-sulfonamides have been designed as potential inhibitors of PDE4. All these compounds were readily prepared via an elegant multi-step method involving the initial construction of 1-nitro-10H-phenoxazine ring and then fused imidazole ring as key steps. Some of these compounds showed promising PDE4B and D inhibition when tested in vitro and good interactions with these proteins in silico. Three of these compounds showed dose dependent inhibition of PDE4B with IC50 value of 3.31 ± 0.62, 1.23 ± 0.18 and 0.53 ± 0.18 µM.

A new approach to construct a fused 2-ylidene chromene ring: highly regioselective synthesis of novel chromeno quinoxalines.

Regioselective construction of a fused 2-ylidene chromene ring was achieved for the first time by using AlCl(3)-induced C-C bond formation followed by Pd/C-Cu mediate coupling-cyclization strategy. A number of chromeno[4,3-b]quinoxaline derivatives were prepared by using this strategy. Single crystal X-ray diffraction study of a representative compound e.g. 6-(2,2-dimethylpropylidene)-4-methyl-6H-chromeno[4,3-b]quinoxalin-3-ol confirmed the presence of an exocyclic C-C double bond with Z-geometry. The crystal structure analysis and hydrogen bonding patterns of the same compound along with its structure elaboration via propargylation followed by Sonogashira coupling of the resulting terminal alkyne is presented. A probable mechanism for the formation of 2-ylidene chromene ring is discussed. Some of the compounds synthesized showed anticancer properties when tested in vitro.

Solvent effect on copper-catalyzed azide-alkyne cycloaddition (CuAAC): synthesis of novel triazolyl substituted quinolines as potential anticancer agents.

A regioselective route to novel mono triazolyl substituted quinolines has been developed via copper-catalyzed azide-alkyne cycloaddition (CuAAC) of 2,4-diazidoquinoline with terminal alkynes in DMF. The reaction provided bis triazolyl substituted quinolines when performed in water in the presence of Et(3)N. A number of the compounds synthesized showed promising anti-proliferative properties when tested in vitro especially against breast cancer cells.

Conformationally restricted novel pyrazole derivatives: synthesis of 1,8-disubstituted 5,5-dimethyl-4,5-dihydro-1H-benzo[g]indazoles as a new class of PDE4 inhibitors.

A number of novel 1,8-disubstituted 5,5-dimethyl-4,5-dihydro-1H-benzo[g]indazoles based on a conformationally restricted pyrazole framework have been designed as potential inhibitors of PDE4. All these compounds were readily prepared by using simple chemistry strategy. The in vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized along with the X-ray single crystal data of a representative compound is presented.

C-C bond formation at C-2 of a quinoline ring: synthesis of 2-(1H-indol-3-yl)quinoline-3-carbonitrile derivatives as a new class of PDE4 inhibitors.

A number of 2-(1H-indol-3-yl)quinoline-3-carbonitrile derivatives were synthesized via AlCl(3)-mediated C-C bond forming reaction between 2-chloroquinoline-3-carbonitrile and various indoles. The methodology does not require any N-protection of the indoles employed and provided the corresponding products in good yields. The molecular structure of a representative compound was established unambiguously by single crystal X-ray diffraction and structural elaboration of a compound synthesized has been demonstrated. Many of these compounds synthesized showed PDE4 inhibitory properties in vitro. A brief structure-activity relationship studies within the series along with docking results of a representative compound (EC(50) ∼0.89 µM) is presented.

AlCl3 induced (hetero)arylation of 2,3-dichloroquinoxaline: a one-pot synthesis of mono/disubstituted quinoxalines as potential antitubercular agents.

A direct and single-step method has been developed for the synthesis of mono and 2,3-disubstituted quinoxalines by using a AlCl(3) induced (hetero)arylation of 2,3-dichloroquinoxaline. Both symmetrical and unsymmetrical 2,3-disubstituted quinoxalines can be prepared conveniently by using this method under appropriate reaction conditions. The reaction proceeds via C-C bond formation and can be utilized for the preparation of a variety of quinoxaline derivatives from readily available starting materials and reagents. The molecular structure of a representative compound was confirmed by single crystal X-ray diffraction study. Some of the compounds synthesized were tested for chorismate mutase inhibitory properties in vitro and one compound showed promising activity representing one of the few examples of chorismate mutase inhibition by a heteroarene based small molecule.

Yb(OTf)3 catalyzed new cascade reaction: a facile assembly of fused quinazolinones.

A one-pot Yb(III)-mediated cascade reaction has been developed leading to small molecules based on a novel structural motif, i.e. quinazolin-4-one moiety fused with an isoquinoline ring, for potential inhibition of TNF-α.

C-C (alkynylation) vs C-O (ether) bond formation under Pd/C-Cu catalysis: synthesis and pharmacological evaluation of 4-alkynylthieno[2,3-d]pyrimidines.

The Pd/C-CuI-PPh(3) catalytic system facilitated C-C bond formation between 4-chlorothieno[2,3-d]pyrimidines and terminal alkynes in methanol with high selectivity without generating any significant side products arising from C-O bond formation between the chloro compounds and methanol. A variety of novel 4-alkynylthieno[2,3- d]pyrimidines were prepared via alkynylation of 4-chlorothieno[2,3-d]pyrimidines in good to excellent yields. Some of the compounds synthesized were tested for cytotoxic activity in vitro.

Novel pyrazole-3-carboxamide derivatives as cannabinoid-1 (CB1) antagonists: journey from non-polar to polar amides.

The synthesis and biological evaluation of novel pyrazole-3-carboxamide derivatives as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced. In general, a range of modifications were well tolerated. Several molecules with high polar surface area were also identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is exemplified with a lead compound from this series.

Severe falciparum malaria simulating fulminant hepatic failure.

OBJECTIVE: To identify clinical and laboratory features of patients with malarial hepatitis simulating fulminant hepatic failure (MHsFHF) and distinguish it from viral FHF. PATIENTS AND METHODS: At a tertiary care unit in Bangalore, India, we compared clinical and laboratory characteristics of 25 patients with MHsFHF with those of 25 patients with viral FHF from November 1996 to January 2000. RESULTS: No statistically significant differences were seen in duration of jaundice, altered consciousness, and the interval between onset of jaundice and altered consciousness between the 2 groups. Hepatomegaly and splenomegaly were present in 72% and 48% of patients with MHsFHF and in 12% and 0% of patients with viral FHF (P<.001), respectively. The MHsFHF group had a significantly lower hemoglobin level (9.3 g/dL vs 12.9 g/dL), total leukocyte count (9.1 x 10(9)/L vs 18 x 10(9)/L), platelet count (44.8 x 10(9)/L vs 218.6 x 10(9)/L), and transaminases (alanine aminotransferase, 86.2 U/L vs 1230.0 U/L; aspartate aminotransferase, 131.9 U/L vs 720.0 U/L) (P<.001). Thrombocytopenia and elevated serum urea nitrogen were universal in patients with MHsFHF. Prothrombin time was abnormal in all patients with viral FHF and in only 1 patient with MHsFHF. Of patients with MHsFHF, 24% died; of patients with viral FHF, 76% died (P=.02). CONCLUSIONS: In endemic areas, severe malaria should be considered in the differential diagnosis of FHF. Hepatomegaly and normal prothrombin time in the setting of FHF are suggestive of malaria, and a peripheral blood smear should be obtained for diagnostic confirmation.

Clinical implications of quantification of mesorectal tumor invasion by endoscopic ultrasound: All T3 rectal cancers are not equal.

BACKGROUND: Depth of invasion beyond the muscularis propria (MP) by T3 rectal cancer can vary. The purpose of the present paper was to determine if depth of invasion beyond MP, as assessed by preoperative endoscopic ultrasound (EUS), can predict tumor recurrence in patients with T3 rectal tumors. METHODS: Patients with T3NxM0 rectal cancer, as determined by EUS, who underwent surgical resection (without preoperative neoadjuvant therapy) were reviewed by two blinded endosonographers. Tumors were classified as minimally invasive T3 (invasion 2 mm). RESULTS: Forty-two patients with T3 rectal tumors underwent surgical resection without receiving preoperative neoadjuvant therapy, of whom 14 had minimally invasive T3 and 28 had advanced T3 disease, as determined by preoperative EUS. Median follow up was 19 months. Tumor recurrence rates in minimally invasive and advanced T3 tumors were 14.3% and 39.3%, respectively, P = 0.02 (log-rank test). Adjusting for nodal status and postoperative adjuvant therapy administration, Cox proportional hazards model demonstrated advanced T3 disease (by EUS) to predict tumor recurrence, hazard ratio, 2.28 (95% confidence interval: 1.17-5.81), P = 0.01. CONCLUSIONS: All T3 rectal tumors are not equal, with minimally invasive disease carrying a more favorable prognosis. By discriminating minimally invasive from advanced T3 disease, preoperative EUS provides important prognostic information. Further subclassification of T3 tumors, based on preoperative EUS staging, should be considered to enhance selection of patients for neoadjuvant therapy.

Assessment of clinical impact of endoscopic ultrasound on esophageal cancer.

BACKGROUND AND AIM: Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) is the most accurate imaging modality for locoregional staging of esophageal cancer. It remains unclear whether this technology impacts on the outcome of patients with this malignancy. The aim of the present study was to assess the impact of EUS FNA by comparing the clinical outcomes of patients with esophageal cancer before and after the introduction of this staging modality in our institution. METHODS: Outcomes of patients with de novo non-metastatic esophageal cancer seen in 1998 without EUS FNA evaluation (non-EUS control group) were compared to patients evaluated in 2000 with EUS FNA (EUS group). RESULTS: Outcomes of 60 (non-EUS control group) and 107 (EUS group) patients with non-metastatic esophageal cancer were compared. Preoperative neoadjuvant therapy was administered to 35 patients in the EUS group, all of whom had advanced disease. Cox proportional hazards demonstrated EUS FNA to be associated with reduced recurrence risk (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43-0.87), P = 0.004, and reduced mortality (HR: 0.66; 95% CI: 0.47-0.90), P = 0.008. CONCLUSIONS: The EUS staging of esophageal cancer leads to appropriate use of preoperative neoadjuvant therapy in patients with advanced disease. Use of EUS is associated with a recurrence-free survival advantage and overall survival advantage in patients, thus supporting its routine use in esophageal cancer staging.

Ethnic differences in the prevalence of cryptogenic cirrhosis.

OBJECTIVES: Nonalcoholic steatohepatitis (NASH) associated with obesity and type 2 diabetes mellitus (DM) is postulated to be the cause of most cases of cryptogenic cirrhosis (CC). While ethnic differences in the prevalence of obesity and DM in the United States are well documented, there is little information regarding prevalence of CC or NASH among different U.S. ethnic groups. This study was performed to assess the demographic characteristics of patients with CC at a U.S. county hospital with a racially and ethnically diverse patient population. METHODS: Medical records and pathology databases were reviewed to identify patients at Parkland Memorial Hospital, Dallas County, Texas from 1990 to 2001 with CC or cirrhosis attributed to NASH. RESULTS: Forty-one patients (12 men, 29 women) were found to meet these criteria. Of these, 68% were obese (BMI > or = 30) and/or had type 2 DM and 74% of liver biopsies revealed one or more features of NASH. Of patients with CC 68% were Hispanic while only 7% were African American, despite the fact that Hispanics comprised < 26% and African Americans > 40% of adult medicine patients. Prevalence of CC among Hispanic and African American patients was 3.1-fold higher and 3.9-fold lower, respectively, than among European American patients despite similar prevalence of DM among Hispanics and African Americans. CONCLUSION: These findings support the hypothesis that NASH associated with obesity and DM is responsible for the majority of cases of CC among Hispanics and European Americans. However, the current findings also indicate that this form of cirrhosis is unexpectedly rare among African Americans.