Synthesis of Novel Benazepril-Derived Trizole Compounds Assisted by Ultrasound: In Vitro and In Silico Analysis for Potential Anticancer Properties.

Benazepril-based novel trizole derivatives are being explored as potential anticancer agents, designed with an N-substituted 1,2,3-triazole moiety linked to Benazepril's N-1 position via a methylene bridge. An ultrasound irradiated CuAAC method was used to prepare all these compounds and evaluated their anti-proliferative activities against cancer and drug-resistant cell lines. While some of these compounds demonstrated anti-proliferative activity towards leukemic cancer cell line K562, two of them displayed complete inhibitory activity. Interestingly, the compounds 5n and 5o showed potent activity against imatinib-resistant cell lines suggesting their promise to overcome cancer drug resistance. Furthermore, molecular docking analysis revealed that compounds 5n and 5o have higher predicted sensitivity towards ACE protein when compared to benazepril and lisinopril indicating their value as potential drug lead molecules. This research introduces a distinctive approach by employing ultrasound to facilitate CuAAC reactions in medicinal chemistry.

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.

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.

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.

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.

Significant pulmonary toxicity associated with interferon and ribavirin therapy for hepatitis C.

OBJECTIVE: The aim of this study was to analyze the clinical presentation and outcomes of significant pulmonary toxicity associated with interferon and ribavirin. METHODS: We conducted a retrospective review of patients enrolled in four clinical trials at three sites, two academic medical centers and one community practice, and reviewed the literature. RESULTS: Four patients, while on therapy with interferon a and ribavirin for chronic hepatitis C, developed significant pulmonary signs and symptoms. Further workup, which included lung biopsy in three, revealed bronchiolitis obliterans organizing pneumonia in two, and interstitial pneumonitis in two other cases. There were no other predisposing factors for lung disease identified. Resolution of symptoms occurred in all patients upon discontinuation of interferon and ribavirin, with or without corticosteroid therapy. One of the patients developed pulmonary complications while on a clinical trial of pegylated interferon and represents the first reported case associated with the use of long-acting interferon in chronic hepatitis C infection. CONCLUSIONS: A spectrum of significant pulmonary toxicity, including bronchiolitis obliterans organizing pneumonia and interstitial pneumonitis, can occur with interferon or pegylated interferon in combination with ribavirin. Though pulmonary toxicity of interferon is well known, these cases represent the first cases reported in the literature with combination therapy. It is likely that pulmonary toxicity may not be investigated in patients on combination therapy because of the frequent pulmonary symptoms with ribavirin. Though usually reversible, at least one case has required long-term steroids with inadequate resolution. Though pulmonary toxicity is rare, symptoms which are more than mild or progressive in nature should likely be investigated.

Successful sequential liver and stem cell transplantation for hepatic failure due to primary AL amyloidosis.

We report on a patient with primary AL amyloidosis who presented with progressive liver failure secondary to hepatic infiltration in the absence of significant extrahepatic involvement. Orthotopic liver transplantation was performed successfully. After an uneventful postoperative course, the patient developed evidence of significant recurrent amyloidosis requiring treatment. He then underwent stem cell transplantation 10 and 14 months after liver transplantation. After 28 months of follow-up posttransplantation, the patient continues to do well, with no clinical evidence of recurrent disease. This is the first reported patient with primary amyloidosis to undergo sequential liver and stem cell transplantation leading to resolution of the disease and only the second to undergo successful liver transplantation for this disorder.