Synthesis and characterization of a novel iNOS/Akt inhibitor Se,Se′-1,4-phenylenebis(1,2-ethanediyl)bisisoselenourea (PBISe)-against colon cancer

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 6, 2010, Pages 2038-2043

  Desai, Dhimant ^a   Madhunapantula, SubbaRao V ^a   Gowdahalli, Krishnegowda ^a   Sharma, Arati ^a   Chandagaludoreswamy, Raghavendragowda ^a   El Bayoumy, Karam ^a   Robertson, Gavin P ^a,b   Amin, Shantu ^a  

^a PENN STATE COLLEGE OF MEDICINE   (United States)

^b PENNSYLVANIA STATE UNIVERSITY   (United States)

Author keywords

Chemoprevention; Colon cancer; iNOS Akt inhibitor; PBISe

Indexed keywords

ANTINEOPLASTIC AGENT; ENZYME INHIBITOR; INDUCIBLE NITRIC OXIDE SYNTHASE; PROTEIN KINASE B INHIBITOR; S,S' 1,4 PHENYLENE BIS(1,2 ETHANEDIYL)BIS ISOTHIOUREA; SE,SE' 1,4 PHENYLENEBIS(1,2 ETHANEDIYL)BISISOSELENOUREA; SELENIUM; SULFUR; UNCLASSIFIED DRUG;

ARTICLE; CANCER CELL CULTURE; COLON ADENOCARCINOMA; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENCY; DRUG SYNTHESIS; HUMAN; HUMAN CELL;

COLONIC NEOPLASMS; ENZYME INHIBITORS; HUMANS; NITRIC OXIDE SYNTHASE TYPE II; ORGANOSELENIUM COMPOUNDS; PROTO-ONCOGENE PROTEINS C-AKT; UREA;

EID: 77549085001     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.09.071     Document Type: Article

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53. 3 using a Bruker 500 MHz instruments. The chemical shifts are reported in ppm downfield from TMS. MS were run on 4000 Q trap hybrid triple quadrupole/linear ion trap instrument (Applied Biosystems/MDS Sciex) at the proteomic facility in Penn State Cancer Institute at Penn State College of Medicine, Hershey, PA. High-resolution MS were determined at the Instrument Center, University of Buffalo, Buffalo, NY. Thin-layer chromatography (TLC) was on aluminum-supported, pre-coated silica gel plates (EM Industries, Gibbstown, NJ). All starting materials and reagents were obtained from Aldrich Chemical Co. (Milwaukee, WI) and used without further purification.
54. Methyl 1,4-phenylenediacetic acid (5), 1,4-phenylene diethanol (6), and 1,4-di(2-bromoethyl)benzene (7) were prepared as reported by E. P. Garvey, J. A. Oplinger, G. J. Tanoury, P. A. Sherman, M. Fowler, S. Marshall, M. F. Harmon, J. E. Paith, E. S. Furfine, J. Biol. Chem., 1994, 269, 26669.
55. +1, 100), 266 (40), 207 (30), 142 (70), 131 (100), 104 (10), 77 (30).
56. 2; found: 378.9935.
57. +, 100), 181 (80), 159 (10), 105 (10).
58. Cell lines and culture conditions: colon adenocarcinoma cell line (Caco-2; ATCC No. HTB-37, HT-29; ATCC No. HTB-38, HCT-116; ATCC No. CCL-247, and SW-480; CCL-228) were grown in Advanced DMEM (2 Mm) supplemented with 10% heat treated (56 °C for 30 min) FBS (Hyclone, Logan, UT) and L-glutamine or RPMI-1640 containing 10% FBS. Lung adenocarcinoma (A549; ATCC No. CCL-185), fibrosarcoma (HT-1080; ATCC No. CCL-121), prostate adenocarcinoma (PC-3; ATCC No. CRL-1435), ovarian adenocarcinoma (NIH: OVCAR-3; ATCC No. HTB-161), and a breast adenocarcinoma cell line (MDA-MB-231; ATCC No. HTB-26) were grown in DMEM supplemented with 10% FBS. The human vertical growth phase (VGP) melanoma cell line WM115 was maintained in Tu2% medium lacking calcium chloride, but supplemented with 2% heat treated (56 °C for 30 min) FBS and l-glutamine as described previously.
59. 50 values were calculated by treating with increasing concentrations of PBIT, PEIT, PEISe (10-100 μM) or PBISe (1.6-50 μM) for 72 h and the number of viable cells quantified using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) (Promega, WI).
60. 50 value for each compound was determined from at least three independent experiments and represented with a standard error (Fig. 2).
61. 60 growth inhibitory effects on normal fibroblast cells (FF2441), and cultured cancer cells from human vertical growth phase (VGP) melanoma (WM115), Lung adenocarcinoma (A549), fibrosarcoma (HT-1080), prostate adenocarcinoma (PC-3), ovarian carcinoma (OVCAR-3), and breast adenocarcinoma (MDA-MB-231) were tested with increasing concentrations of PBIT (10-100 μM) or PBISe (1-40 μM) (Table 2, Fig. 3).
62. 6) were plated in 60 mm culture dishes in advanced DMEM containing 10% heat treated FBS. Twelve hours later, growing cells were conditioned (∼12 h) with phenol-red free DMEM containing 0.5% FBS and then treated with increasing concentrations of PBIT (40 μM) or PBISe (2 μM) dissolved in phenol-red free DMEM (2 mL) containing 0.5% FBS for 72 h. Culture supernatants were collected, centrifuged (500g) and total nitrite (nitrate + nitrite) measured by incubating 80 μL supernatant with enzyme cofactor mixture (10 μL) and nitrate reductase (10 μL) for 2 h. The addition of Griess reagent-I and II (50 μL each) produced characteristic color that was measured at 540 nm using a SPECTRAmax M2 plate reader (Molecular Devices, Sunnyvale, CA). A nitrate standard curve (5-35 μM) was simultaneously prepared and total nitrite present in samples was measured.
63. Western blot analysis: cell lysates were harvested by addition of lyses buffer containing 50 mM HEPES (pH 7.5), 150 mM NaCl, 10 mM EDTA, 10% glycerol, 1% Triton X-100, 1 mM sodium orthovanadate, 0.1 mM sodium molybdate, 1 mM phenylmethylsulfonyl fluoride, 20 μg/mL aprotinin, and 5 μg/mL leupeptin. Whole cell lysates were centrifuged (≥10,000g) for 10 min at 4 °C to remove cell debris. Protein concentrations were quantitated using the BCA assay (Pierce; Rockford, IL), and 30 μg of lysate loaded per lane onto NuPAGE Gels (Life Technologies, Inc. Carlsbad, CA). Following electrophoresis, samples were transferred to polyvinylidene difluoride (PVDF) membrane (Pall Corporation, Pensacola, FL) and the blots probed with antibodies according to each supplier's recommendations: antibodies to PRAS40 and phosphorylated PRAS40 from Invitrogen (Invitrogen Corporation, Carlsbad, CA); antibodies to cyclin D1, p27, and Erk2 from Santa Cruz Biotechnology (Santa Cruz, CA); and antibodies to Akt3, phosphorylated-Akt (Ser473), phosphorylated-Erk 1/2, and cleaved PARP from Cell Signaling Technology (Danvers, MA). Secondary antibodies conjugated with horseradish peroxidase were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Immunoblots were developed using the enhanced chemiluminescence (ECL) detection system (Pierce Biotechnology, Rockford, IL) (Fig. 5).