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1.  Phospholipase A2 Inhibitors Synthesized by Two Entomopathogenic Bacteria, Xenorhabdus nematophila and Photorhabdus temperata subsp. temperata 
Applied and Environmental Microbiology  2012;78(11):3816-3823.
The entomopathogenic bacteria Xenorhabdus nematophila and Photorhabdus temperata subsp. temperata suppress insect immune responses by inhibiting the catalytic activity of phospholipase A2 (PLA2), which results in preventing biosynthesis of immune-mediating eicosanoids. This study identified PLA2 inhibitors derived from culture broths of these two bacteria. Both X. nematophila and P. temperata subsp. temperata culture broths possessed significant PLA2-inhibitory activities. Fractionation of these bacterial metabolites in the culture broths using organic solvent and subsequent chromatography purified seven potent PLA2 inhibitors, three of which (benzylideneacetone [BZA], proline-tyrosine [PY], and acetylated phenylalanine-glycine-valine [FGV]) were reported in a previous study. Four other compounds (indole, oxindole, cis-cyclo-PY, and p-hydroxyphenyl propionic acid) were identified and shown to significantly inhibit PLA2. X. nematophila culture broth contained these seven compounds, while P. temperata subsp. temperata culture broth contained three compounds (BZA, acetylated FGV, and cis-cyclo-PY). BZA was detected in the largest amount among these PLA2 compounds in both bacterial culture broths. All seven bacterial metabolites also showed significant inhibitory activities against immune responses, such as phenoloxidase activity and hemocytic nodulation; BZA was the most potent. Finally, this study characterized these seven compounds for their insecticidal activities against the diamondback moth, Plutella xylostella. Even though these compounds showed relatively low toxicities to larvae, they significantly enhanced the pathogenicity of Bacillus thuringiensis. This study reports bacterial-origin PLA2 inhibitors, which would be applicable for developing novel insecticides.
PMCID: PMC3346408  PMID: 22447611
2.  Synthesis, Characterization and In Vitro Antitumour Activity of Di-n-Butyl, Tri-n-Butyl and Triphenyltin 3,6-Dioxaheptanoates and 3,6,9-Trioxadecanoates 
Metal-Based Drugs  1998;5(4):189-196.
A series of di- and triorganotin 3,6-dioxaheptanoates and 3,6,9-trioxadecanoates were synthesized and characterized by 1H, 13 and 117Sn NMR, electrospray mass and 119mSn Mössbauer spectroscopy, as well as elemental analysis. Their in vitro antitumour activity against seven tumoural cell lines of human origin, two breast cancers (MCF-7, EVSA-T), a colon carcinoma (WiDr), an ovarian cancer (IGROV), a melanoma (M 19 MEL), a renal cancer (A 498) and a non small cell lung cancer (H 226), is reported. They are characterized by similar inhibition doses ID50 as the analogous di- and triorganotin derivatives of 4-carboxybenzo-15-crown-5 and -18-crown-6 and in some cases by much lower ID50 values than clinically used reference compounds such as doxorubicine and methotrexate.
PMCID: PMC2365126  PMID: 18475843
3.  Incorporating bazedoxifene/conjugated estrogens into the current paradigm of menopausal therapy 
Many women experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Decreasing levels of estrogens during menopause are also associated with reduced bone density and an increased risk of osteoporosis. Combined estrogen/progestin therapy (hormone therapy) effectively treats menopausal symptoms and prevents bone loss, but has been associated with some safety and tolerability concerns. A novel menopausal therapy is the tissue selective estrogen complex, which pairs a selective estrogen receptor modulator with one or more estrogens. In preclinical studies, the tissue selective estrogen complex partnering bazedoxifene (BZA) with conjugated estrogens (CE) antagonized stimulation of breast and endometrial tissue, reduced vasomotor instability, and preserved bone mass in rat and mouse models. The specific attributes seen with BZA/CE were different from those observed with other selective estrogen receptor modulator/estrogen pairings. BZA/CE has undergone clinical evaluation in the Phase III Selective estrogens, Menopause, And Response to Therapy (SMART) trials in postmenopausal women with an intact uterus. Of the various doses of BZA/CE evaluated, BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of endometrial hyperplasia (<1%) similar to placebo, and showed significant improvements in hot flushes and vulvar/vaginal symptoms and increases in bone mineral density. BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of breast-related adverse events and demonstrated no difference from placebo in age-related changes in mammographic breast density. Both BZA/ CE doses showed a favorable tolerability profile, with no increases in uterine bleeding or breast tenderness, and had positive effects on metabolic parameters and quality of life. BZA/CE may be a promising alternative to hormone therapy for the treatment of menopausal symptoms and prevention of osteoporosis in nonhysterectomized postmenopausal women.
PMCID: PMC3325004  PMID: 22505832
tissue selective estrogen complex; bazedoxifene; conjugated estrogens; menopause; osteoporosis; vasomotor symptoms
4.  Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice☆ 
Molecular Metabolism  2014;3(2):177-190.
Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.
PMCID: PMC3953695  PMID: 24634829
Akt, protein kinase B; AMPKα, AMP-activated protein kinase α; AUC, area-under the curve; BAT, brown adipose tissue; BZA, bazedoxifene; CE, conjugated equine estrogens; E2, 17β-estradiol; ER, estrogen receptor; FAS, fatty acid synthase; FGF21, fibroblast growth factor 21; GIR, glucose infusion rate; H&E, hematoxylin and eosin; HFD, high-fat diet; HGP, hepatic glucose production; ITT, insulin tolerance test; Lcn2, lipocalin 2; LPL, lipoprotein lipase; NAFLD, non-alcoholic fatty liver disease; OGTT, oral glucose tolerance test; OVX, ovariectomy; PTT, pyruvate tolerance test; RBP4, retinol binding protein 4; Rd, rate of whole-body glucose disappearance; RER, respiratory exchange ratio; SERM, selective estrogen receptor modulator; TBARS, thiobarbituric acid reactive substances; TG, triacylglycerol; TSEC, tissue-selective estrogen complex; UCPs, uncoupling proteins; VO2, oxygen consumption; WAT, white adipose tissue.; Tissue-selective estrogen complexes; Bazedoxifene; Menopause; Metabolic syndrome; Insulin resistance; Type 2 diabetes
5.  Chemical synthesis of a self-complementary octanucleotide, dG-G-T-T-A-A-C-C by a modified triester method. 
Nucleic Acids Research  1978;5(8):2809-2823.
The synthesis of a self-complementary octanucleotide, d(G-G-T-T-A-A-C-C-), using a modified triester approach is described. The protected dinucleotides, d(Me2O)TribG(C1C6H4) ibG, d(Me2O)TrT(ClC6H4)T, d(Me2O)TrbzA(ClC6H4)bzA, and d(Me2O)TranC(ClC6H4)anC were synthesized by a one step triester procedure. After removal of the trityl group, the dinucleotides, dT(ClC6H4)T and danC (ClC6H4)anC were coupled to d(Me2O)TribG(ClC6H4)ibG and d(Me2O)TrbzA(ClC6H4)bzA, respectively to yield the respective tetranucleotides. The tetranucleotide, d(Me2O)TrbzA(ClC6H4)bzA(ClC6H4) and (ClC6H4)anC was detritylated and then coupled with d(Me2O)TribG(ClC6H4)ibG(ClC6H4)T(Cl6H4)T to give octanucleotide. The fully protected octanucleotide was deblocked by treatment with aqueous NH3 followed by acid and was characterized by nucleotide sequence analysis.
PMCID: PMC342209  PMID: 693321
6.  The Tissue Selective Estrogen Complex: A Promising New Menopausal Therapy 
Pharmaceuticals  2012;5(9):899-924.
Menopause is associated with health concerns including vasomotor symptoms, vulvar/vaginal atrophy (VVA), and osteoporosis. Estrogen therapy or combined estrogen-progestin therapy (EPT) are primary treatment options for menopausal symptom relief and osteoporosis prevention. Because EPT has been associated with some safety/tolerability concerns relating to undesirable effects of estrogen and progestin, alternative options are needed. The tissue selective estrogen complex (TSEC) is a novel class of agents pairing a selective estrogen receptor modulator (SERM) with 1 or more estrogens. The TSEC combines the established efficacy of estrogens on menopausal symptoms and bone with the protective effects of a SERM on the reproductive tract. The pairing of bazedoxifene (BZA) with conjugated estrogens (CE) has been evaluated in a series of phase 3 clinical trials. BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg have shown efficacy in reducing the frequency and severity of hot flushes, relieving VVA symptoms, and maintaining bone mass while protecting the endometrium and breast. These BZA/CE doses have been associated with a favorable safety/tolerability profile, with higher rates of cumulative amenorrhea and lower incidences of breast pain than those reported for EPT. Thus, BZA/CE may be a promising alternative to conventional EPT for treating non-hysterectomized, postmenopausal women.
PMCID: PMC3816651  PMID: 24280697
hormone therapy; tissue selective estrogen complex (TSEC); bazedoxifene; conjugated estrogens; menopause
7.  Tissue Selective Estrogen Complexes (TSECs) Differentially Modulate Markers of Proliferation and Differentiation in Endometrial Cells 
Reproductive Sciences  2013;20(2):129-137.
Selective estrogen receptor modulators (SERMs) have tissue-specific estrogen receptor (ER) modulating properties. Combining an SERM with one or more estrogens to form a tissue selective estrogen complex (TSEC) can provide an improved blend of tissue-specific ER agonist and antagonist effects. While both estrogens and SERMs affect the uterine endometrium, not all TSECs reverse the endometrial effects of estrogens preventing endometrial proliferation and hyperplasia. Their action in uterine cells is not completely understood. HOXA 10, leukemia inhibitory factor (LIF), progesterone receptor (PR), and EMX2 are genes known to regulate endometrial proliferation and differentiation. The expression of these genes was used to assess endometrial effects of SERMs and TSECs. We evaluated the effects of raloxifene (RAL), tamoxifen (TAM), lasofoxifene (LAS), bazedoxifene acetate (BZA), and progesterone (P) alone and in combination with estradiol (E2) in Ishikawa cells. Increased HOXA10, LIF, PR, and EMX2 messenger RNA (mRNA) expression was noted in E2-treated cells compared with vehicle-treated controls. All TSECs maintained E2-induced PR expression and all except TAM prevented estrogen-induced LIF expression. The TSEC containing BZA uniquely decreased HOXA10 expression and increased EMX2 expression. The TSECs alter endometrial cell proliferation by selective modulation of estrogen responsive genes, maintaining the antiproliferative effects mediated by PR and inhibiting LIF. The differential effect of TSECs on endometrial gene expression suggests a mechanism by which they manifest differential effects on endometrial safety against the risk of estrogen-induced endometrial hyperplasia.
PMCID: PMC3826278  PMID: 23171676
TSECS; SERMS; HOXA10; leukemia inhibitory factor (LIF); progesterone receptor; EMX2; ishikawa
8.  Communication: Synthesis of a Novel Triphenyltin(IV) Derivative of 2- Mercaptonicotinic Acid with Potent Cytotoxicity in vitro  
A novel triphenyltin(IV) derivative of 2-mercaptonicotinic acid (H2mna) of formula {[(C6H5)3Sn]2(mna).[(CH3)2CO]} (1) has been synthesized and characterized by elemental analysis and 1H, 13C-NMR, and FT-IR spectroscopic techniques. The crystal structure of complex (1) has been determined by single crystal X-ray diffraction analysis at 173(1) K. Compound (1) contains two triphenyltin moieties linked by a doubly de-protonated 2,mercaptonicotinic acid (H>2mna). It is an example of a pentacoordinated Ph3SnXY system with an axial-equatorial arrangement of the phenyl groups at Sn(1). Compound (1), exhibits potent, in vitro, cytotoxicity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (PAH, benzo[a]pyrene) carcinogenesis.
PMCID: PMC2267064  PMID: 18365056
9.  Synthesis, Characterization and In Vitro Antibacterial Studies of Organotin(IV) Complexes with 2-Hydroxyacetophenone-2-methylphenylthiosemicarbazone (H2dampt) 
Five new organotin(IV) complexes of 2-hydroxyacetophenone-2-methylphenylthiosemicarbazone [H2dampt, (1)] with formula [RSnCln-1(dampt)] (where R = Me, n = 2 (2); R = Bu, n = 2 (3); R = Ph, n = 2 (4); R = Me2, n = 1 (5); R = Ph2, n = 1 (6)) have been synthesized by direct reaction of H2dampt (1) with organotin(IV) chloride(s) in absolute methanol. The ligand (1) and its organotin(IV) complexes (2–6) were characterized by CHN analyses, molar conductivity, UV-Vis, FT-IR, 1H, 13C, and 119Sn NMR spectral studies. H2dampt (1) is newly synthesized and has been structurally characterized by X-ray crystallography. Spectroscopic data suggested that H2dampt (1) is coordinated to the tin(IV) atom through the thiolate-S, azomethine-N, and phenoxide-O atoms; the coordination number of tin is five. The in vitro antibacterial activity has been evaluated against Staphylococcus aureus, Enterobacter aerogenes, Escherichia coli, and Salmonella typhi. The screening results have shown that the organotin(IV) complexes (2–6) have better antibacterial activities and have potential as drugs. Furthermore, it has been shown that diphenyltin(IV) derivative (6) exhibits significantly better activity than the other organotin(IV) derivatives (2–5).
PMCID: PMC3352140  PMID: 22611347
10.  Interaction of 5′-Guanosine Monophosphate with Organotin(IV) Moieties: Synthesis, Structural Characterization, and Anti-Inflammatory Activity 
ISRN organic chemistry  2012;2012:873035.
Reaction(s) of 5′-guanosine monophosphate (5′GMP) with di- and triorganotin(IV) chloride(s) led to formation of organotin(IV) derivatives of general formulae, [R2Sn(5′-GMP)·H2O]n and [(R′3Sn)2(5′-GMP)·H2O]n, where R = Me, n-Bu, and Ph; R′ = Me, i-Pr, n-Bu, and Ph; (5′-GMP)2− = 5′-guanosine monophosphate. An attempt has been made to prove the structures of the resulting derivatives on the basis of FT-IR, multinuclear 1H, 13C, and 119Sn NMR and 119Sn Mössbauer spectroscopic studies. These investigations suggest that both di- and triorganotin(IV)-5′-guanosine monophosphates are polymeric in which (5′-GMP)2− is bonded through phosphate group resulting in a distorted trigonal bipyramidal geometry around tin. The ribose conformation in all of the derivatives is C3′-endo, except diphenyltin(IV) and tri-i-propyltin(IV) derivatives where it is C2′-endo. All of the studied derivatives exhibited mild-to-moderate anti-inflammatory activity (~15.64–20.63% inhibition) at 40 mg kg−1 dose and LD50 values > 400 mg kg−1 in albino rats.
PMCID: PMC3767334  PMID: 24052853
11.  Spectral Studies and Bactericidal, Fungicidal, Insecticidal and Parasitological Activities of Organotin(IV) Complexes of Thio Schiff Bases Having no Donor Atoms 
Metal-Based Drugs  1995;2(6):297-309.
Twelve new organotin(IV) complexes of the type RnSnLm [where n = 3, m = 1, R = CH3 or C6H5; n = 2, m = 2, R = C6H5 or C4H9 ; L = anion of Schiff bases derived from the condensation of 2-amino-5-(o-anisyl)-l,3,4-thiadiazole with salicylaldehyde (HL-1), 2- hydroxynaphthaldehyde (HL-2) and 2-hydroxyacetophenone (HL-3)] have been synthesized and characterized by elemental analysis, molar conductances, electronic, infrared, far-infrared, 1H NMR and 119Sn Mössbauer spectral studies. Thermal studies of two complexes, viz., Ph3Sn (L-1) and Ph2Sn(L-2)2 have been carried out in the temperature range 25-1000∘C using TG, DTG and DTA techniques. All these complexes decompose gradually with the formation of SnO2 as an end product. In vitro antimicrobial activity of the Schiff bases and their complexes has also been determined against Streptococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus Penicillin resistance (2500 units), Candida albicans, Cryptococcus neoformans, Sporotrichum schenckii, Trichophyton mentagrophytes and Aspergillus fumigatus. The Schiff bases (HL-1), (HL-2) and the organotin(IV) compounds have also been tested against various important herbicidal, fungicidal, insecticidal species and also for parasitological activity against freeliving nematode.
PMCID: PMC2364992  PMID: 18472781
12.  Insecticidal Effects of Organotin(IV) Compounds on Plutella Xylostella (L.) Larvae. II. Inhibitory Potencies Against Acetylcholinesterase and Evidence for Synergism in Tests With Bacillus Thuringiensis(BER.) and Malathion 
Metal-Based Drugs  1994;1(1):1-17.
Features of pesticide synergism and acetylcholinesterase (AChE) inhibition (in vitro) were studied using a selected range of organotin compounds against the early 4th instar larvae of a highly resistant strain of the diamondback moth (DBM), Plutella xylostella, a major universal pest of cruciferous vegetables.
Fourteen triorganotin compounds were evaluated for their ability to enhance the toxicity of the microbial insecticide, Bacillus thuringiensis (BT) and of the commercial insecticide, Malathion to Plutella xylostella larvae. Supplemental synergism was observed with triphenyl- and tricyclopentyltin hydroxides in combinations with Bacillus thuringiensis. Increased synergism was observed with an increase in the number of cyclopentyl groups on tin in the mixed series, Cypn Ph3-n SnX, where X = OH, and 1-(1,2,4-triazolyl). The combination of (p-chlorophenyl)diphenyltin N,N-dimethyldithiocarbamate at LD10 and LD25 concentrations with sublethal concentrations of Malathion as well as of tricyclohexyltin methanesulphonate at the 0.01% (w/v) concentration with Malathion exerted strong synergistic effects (supplemental synergism) with toxicity index (T.I) values of 7.2, 19.8 and 10.1, respectively.
Studies on the in vitro inhibition of acetylcholinesterase prepared from the DBM larvae showed that while most of the triorganotin Compounds tested were without effect on the enzyme, compounds containing the thiocarbamylacetate or the dithiocarbamylacetate moieties demonstrated appreciable levels of inhibition, being comparable in efficacy to commercial grades of Malathion and Methomyl.
PMCID: PMC2364878  PMID: 18476213
13.  A Thioester Substrate Binds to the Enzyme Arthrobacter Thioesterase in Two Ionization States; Evidence from Raman Difference Spectroscopy 
4-Hydroxybenzoyl-CoA (4-HB-CoA) thioesterase from Arthrobacter is the final enzyme catalyzing the hydrolysis of 4-HB-CoA to produce coenzyme A and 4-hydroxybenzoic acid in the bacterial 4-chlorobenzoate dehalogenation pathway. Using a mutation E73A that blocks catalysis, stable complexes of the enzyme and its substrate can be analyzed by Raman difference spectroscopy. Here we have used Raman difference spectroscopy, in the non-resonance regime, to characterize 4-HB-CoA bound in the active site of the E73A thioesterase. In addition we have characterized complexes of the wild-type enzyme complexed with the unreactive substrate analog 4-hydroxyphenacyl-CoA (4-HP-CoA). Both sets of complexes show evidence for two forms of the ligand in the active site, one population has the 4-hydroxy group protonated, 4-OH, while the second has the group as the hydroxide, 4-O−. For bound 4-HP-CoA X-ray data show that glutamate 78 is close to the 4-OH in the complex and it is likely that this is the proton acceptor for the 4-OH proton. Although the pKa of the 4-OH group on the free substrate in aqueous solution is 8.6, the relative populations of ionized and neutral 4-HB-CoA bound to E73A remain invariant between pH 7.3 and pH 9.8. The invariance with pH suggests that the 4-OH and the -COO− of E78 constitute a tightly coupled pair where their separate pKas lose their individual qualities. Narrow band profiles are seen in the C=O double bond and C-S regions suggesting that the hydrolyzable thioester group is rigidly bound in the active site in a syn gauche conformation.
PMCID: PMC3280504  PMID: 22347769
Raman difference spectroscopy; thioesterase; ionization; conformation; enzyme-substrate complex
14.  Effects of Bazedoxifene Acetate with and without Conjugated Equine Estrogens on the Breast of Postmenopausal Monkeys 
Menopause (New York, N.Y.)  2012;19(11):10.1097/gme.0b013e318252e46d.
Concerns about increased breast cancer risk with estrogen and progestin therapy have led to an increased interest in progestin alternatives. The main objective of this study was to determine if bazedoxifene acetate (BZA), a new selective estrogen receptor modulator (SERM), would antagonize the proliferative and transcriptional effects of conjugated equine estrogens (CEE) in the breast.
As part of a 20 month preclinical trial, ninety-five ovariectomized cynomolgus macaques (Macaca fascicularis) were randomized to receive no treatment or treatment with BZA (20 mg/d), CEE (0.45 mg/d), or BZA and CEE in combination (women’s daily equivalent doses). Data presented here include breast effects following 6 months of treatment. Endpoints included histomorphometry, histopathologic evaluations, gene microarray assays, PCR quantification of specific ERα activity markers, and immunohistochemical detection of sex steroid receptors, and the proliferation marker Ki67.
BZA+CEE and BZA resulted in significantly less total epithelial density, lobular enlargement, and Ki67 immunolabeling in the terminal ducts compared to CEE alone (P < 0.05 for all). The addition of BZA to CEE antagonized the expression of ERα-regulated genes such as GREB1 and TFF1 (P < 0.01 for both), while BZA alone had minimal effects on ERα-mediated transcriptional activity. BZA and BZA+CEE did not significantly up-regulate genes related to cell cycle progression and proliferation. BZA with and without CEE also resulted in less lobular and terminal duct ERα immunolabeling compared to control and CEE (P < 0.0001 for all).
These findings demonstrate that BZA given at a clinically relevant dose is an estrogen antagonist in the breast, supporting the idea that CEE + BZA may provide a lower breast cancer risk profile compared to traditional estrogen + progestin therapies.
PMCID: PMC3762946  PMID: 23103754
Menopause; Hormone Therapy; Estrogen; Selective Estrogen Receptor Modulator; Estrogen Receptor; Breast
15.  Triphenyltin Ortho-Aminophenyl- and 2-Pyridyl-Thiolates: Synthesis and In Vitro Antitumour Activity 
Metal-Based Drugs  1996;3(2):75-78.
The synthesis, spectroscopic characterization and in vitro antitumour activity of two triorganotin compounds, triphenyltin ortho-aminophenylthiolate (1) and triphenyltin 2-pyridylthiolate, compound (2) are reported. The structure of 1 is confirmed by X-ray diffraction, with the tin atom in a distorted tetrahedral geometry because of monodentate coordination, as a thiolate (Sn-S 2.431(2) Å), of the ortho-aminophenylthiolate ligand. The in vitro antitumour activities of 1 and 2, against a number of cell lines, are comparable to those exhibited by methotrexate and doxorubicin, and higher than those of carboplatin and cisplatin.
PMCID: PMC2365004  PMID: 18472799
16.  A Prenylation Inhibitor Prevents Production of Infectious Hepatitis Delta Virus Particles 
Journal of Virology  2002;76(20):10465-10472.
Hepatitis delta virus (HDV) causes both acute and chronic liver disease throughout the world. Effective medical therapy is lacking. Previous work has shown that the assembly of HDV virus-like particles (VLPs) could be abolished by BZA-5B, a compound with farnesyltransferase inhibitory activity. Here we show that FTI-277, another farnesyltransferase inhibitor, prevented the production of complete, infectious HDV virions of two different genotypes. Thus, in spite of the added complexity and assembly determinants of infectious HDV virions compared to VLPs, the former are also sensitive to pharmacological prenylation inhibition. Moreover, production of HDV genotype III virions, which is associated with particularly severe clinical disease, was as sensitive to prenylation inhibition as was that of HDV genotype I virions. Farnesyltransferase inhibitors thus represent an attractive potential class of novel antiviral agents for use against HDV, including the genotypes associated with most severe disease.
PMCID: PMC136538  PMID: 12239323
17.  High In-Vitro Antitumour Activity of Triphenyltin Coumarin 3-Carboxylate and its Coordination Complexes With Monodentate Oxygen Donor Ligands Against the Epstein Barr Virus (EBV)-DNA Positive Raji and the P-388 Murine Leukaemia Cell Lines, and Evidence for the Suppression by Organotin of the Early Antigen Complex in the EBV Lytic Cycle 
Metal-Based Drugs  2000;7(5):245-251.
Triphenyltin coumarin-3-carboxylate and its coordination complexes with ethanol, triphenylphosphine oxide, triphenylarsine oxide, diphenylcyclopropenone and quinoline N-oxide exhibited high in vitro cytotoxicity (LC50 values in the range 0.25-3.4 μg/mL) when tested against EBV-DNA positive Raji cells and P-388 leukaemia cells, compared to the standard drug 5-Fluorouracil, which showed LC50 values of 11 and >50 μg/mL, respectively, against these cells. Additional tests performed on the Raji cells incubated with the quinoline N-oxide complex in the presence of the tumour promoters, TPA and sodium butyrate, revealed that the diffused and restricted protein components of the early antigen complex were suppressed relative to the control containing only the promoters, indicating impaired function of the genes involved as transactivators in the early lytic cycle of the EBV. The failure of the restriction enzymes Eco R1 and Hind III to cleave the extracted DNA from such treated cells in contrast to the control, coupled with the amplification of the BMLF-1 gene by the PCR technique which was realised only with the DNA of the control and not of the treated sample, point to a punitive interaction of the organotin with the nuclear DNA of the Raji cells.
PMCID: PMC2365233  PMID: 18475952
18.  3-Amino­benzoic acid–4,4′-bipyridine (2/3) 
The asymmetric unit of the title compound, 3C10H8N2·2C7H7NO2, consists of three mol­ecules of 4,4′-bipyridine (bpy) and two mol­ecules of 3-amino­benzoic acid (bza). Two mol­ecules of bza and two mol­ecules of bpy are connected via O—H⋯N, N—H⋯N and N—H⋯O hydrogen bonds, forming forming infinite double-stranded zigzag chains along the c axis. The third mol­ecule of bpy is linked to the chain by weak C—H⋯O inter­actions. Adjacent chains are linked via π–π inter­actions [centroid–centroid distances = 3.759 (3)–3.928 (3) Å] involving the pyridine rings of bpy mol­ecules, resulting in a sheet-like structure parallel to (100). These sheets are stacked via C—H⋯π inter­actions, resulting finally in the formation of a three-dimensional supra­molecular structure.
PMCID: PMC3415010  PMID: 22904997
19.  Effects of Bazedoxifene Alone and with Conjugated Equine Estrogens on Coronary and Peripheral Artery Atherosclerosis of Postmenopausal Monkeys 
Menopause (New York, N.Y.)  2013;20(3):274-281.
The objective was to evaluate the effects of bazedoxifene acetate (BZA), a new selective estrogen receptor modulator, on coronary and peripheral artery atherosclerosis and to determine if it would antagonize the atheroprotective effects of conjugated equine estrogens (CEE) in a monkey model.
Ninety-eight surgically postmenopausal monkeys (Macaca fascicularis) were fed a moderately atherogenic diet and then randomized to receive no treatment, or women’s equivalent doses of BZA (20 mg/day), CEE (0.45 mg/day) or BZA+CEE. The experiment period was for 20 months (approximately equivalent to 5 years of patient experience) during which interim measures were made of cardiovascular risk factors. At the end of the experimental period, the extent and severity of coronary and iliac artery atherosclerosis was quantified.
Body weight, adiposity, fasting glucose concentrations and plasma lipid profiles were not different among treatment conditions. BZA had no adverse effects on coronary artery nor common iliac artery atherosclerosis extent or severity when compared to no-treatment. CEE, administered soon after inducing menopause, had a robust atheroprotective effect on both iliac and coronary artery extent and severity. The addition of BZA to the CEE treatment antagonized the atheroprotective effect of the CEE.
In this nonhuman primate trial, treatment with BZA alone, CEE alone and BZA and CEE in combination did not have significant effects on plasma lipid profiles. CEE markedly inhibited the progression and complication of both coronary and iliac artery atherosclerosis. BZA had no adverse effects on atherosclerosis but attenuated the atheroprotective effects of CEE.
PMCID: PMC3578175  PMID: 23435024
Coronary atherosclerosis; menopause; estrogens; SERMS; bazedoxifene
20.  Biological and Spectral Studies of Newly Synthesized Triazole Schiff Bases and Their Si(IV), Sn(IV) Complexes 
The Schiff bases HL1-3 have been prepared by the reaction of 5-bromothiophene-2-carboxaldehyde with 4-amino-5-mercapto-3-methyl/propyl/isopropyl-s-triazole, respectively. Organosilicon(IV) and organotin(IV) complexes of formulae (CH3)2MCl(L1-3), (CH3)2M(L1-3)2 were synthesized from the reaction of (CH3)2MCl2 and the Schiff bases in 1 : 1 and 1 : 2 molar ratio, where M = Si and Sn. The synthesized Schiff bases and their metal complexes have been characterized with the aid of various physicochemical techniques like elemental analyses, molar conductance, UV, IR, 1H, 13C, 29Si, and 119Sn NMR spectroscopy. Based on these studies, the trigonal bipyramidal and octahedral geometries have been proposed for these complexes. The ligands and their metal complexes have been screened in vitro against some bacteria and fungi.
PMCID: PMC3150780  PMID: 21826133
21.  Preparation, Characterization, and Antimicrobial Activities of Bimetallic Complexes of Sarcosine with Zn(II) and Sn(IV) 
Heterobimetallic complexes of Zn(II) and Sn(IV) with sarcosine have been synthesized at room temperature under stirring conditions by the reaction of sarcosine and zinc acetate in 2 : 1 molar ratio followed by the stepwise addition of CS2 and organotin(IV) halides, where R = Me, n-Bu, and Ph. The complexes were characterized by elemental analysis, FT-IR and NMR (1H, 13C) spectroscopy. IR data showed that the ligand acts in a bidentate manner. NMR data revealed the four coordinate geometry in solution state. In vitro antimicrobial activities data showed that complexes (3) and (4) were effective against bacterial and fungal strains with few exceptions.
PMCID: PMC3819876  PMID: 24235910
22.  Management of osteoporosis and menopausal symptoms: focus on bazedoxifene/conjugated estrogen combination 
Loss of estrogen production in women during menopause results in a state of estrogen deficiency which has been associated with multiple problems, including vasomotor symptoms, symptoms of vulvovaginal atrophy, bone loss, and difficulties with sleep, mood, memory, and sexual activity. The only treatment option currently available to address multiple postmenopausal symptoms in women with an intact uterus is estrogen/progestin-containing hormone therapy (HT). Concerns surrounding side effects and published data regarding the association of HT with the increased risk for breast cancer have induced a decrease in the number of women seeking, initiating, and continuing this type of therapy. A combination containing bazedoxifene and conjugated estrogens (BZA/CE) maintains the established benefits of estrogen therapy for treatment of postmenopausal vasomotor symptoms, vulvovaginal atrophy, and osteoporosis, while certain estrogenic effects, such as stimulation of the uterus and breast, are antagonized without the side effects associated with HT. BZA/CE has been evaluated in a series of multicenter, randomized, double-blind, placebo-controlled, and active-controlled Phase III trials known as the Selective estrogens, Menopause, And Response to Therapy (SMART) trials. BZA/CE demonstrated clinically meaningful improvements in vasomotor symptoms, vulvovaginal atrophy, and a protective effect on the skeleton. These clinical benefits were associated with an acceptable safety profile and an improved tolerability compared with HT. BZA/CE showed a favorable safety profile on the breast, endometrium, and ovaries. The incidence of venous thromboembolism was low and the risk does not appear to be any greater than for CE alone or BZA alone or greater than HT. The incidence of coronary heart disease and cerebrovascular accidents were similar to placebo. The overall incidence of cancer (including breast cancer) was low and similar to placebo. The SMART trials demonstrate that BZA/CE is an alternative option for treating non-hysterectomized, symptomatic, postmenopausal women.
PMCID: PMC3743641  PMID: 23966802
tissue selective estrogen complex; bazedoxifene; conjugated estrogens; menopause; osteoporosis; vasomotor symptoms
23.  Mixtures of l-Amino Acids as Reaction Medium for Formation of Iron Nanoparticles: The Order of Addition into a Ferrous Salt Solution Matters 
Owing to Mössbauer spectroscopy, an advanced characterization technique for iron-containing materials, the present study reveals previously unknown possibilities using l-amino acids for the generation of magnetic particles. Based on our results, a simple choice of the order of l-amino acids addition into a reaction mixture containing ferrous ions leads to either superparamagnetic ferric oxide/oxyhydroxide particles, or magnetically strong Fe0-Fe2O3/FeOOH core-shell particles after chemical reduction. Conversely, when ferric salts are employed with the addition of selected l-amino acids, only Fe0-Fe2O3/FeOOH core-shell particles are observed, regardless of the addition order. We explain this phenomenon by a specific transient/intermediate complex formation between Fe2+ and l-glutamic acid. This type of complexation prevents ferrous ions from spontaneous oxidation in solutions with full air access. Moreover, due to surface-enhanced Raman scattering spectroscopy we show that the functional groups of l-amino acids are not destroyed during the borohydride-induced reduction. These functionalities can be further exploited for (i) attachment of l-amino acids to the as-prepared magnetic particles, and (ii) for targeted bio- and/or environmental applications where the surface chemistry needs to be tailored and directed toward biocompatible species.
PMCID: PMC3821566  PMID: 24071943
γ-Fe2O3; FeOOH; zero-valent iron; NZVI; Mössbauer spectroscopy; SERS; arginine; arginate; glutamic acid; glutamate; nanomagnetism
24.  Crystal Structure and Antitumor Activity of the Novel Zwitterionic Complex of tri-n-Butyltin(IV) with 2-Thiobarbituric Acid 
A novel tri-n-butyl(IV) derivative of 2-thiobarbituric acid (HTBA) of formula [(n-Bu)3Sn(TBA) H2O] (1) has been synthesized and characterized by elemental analysis and 119Sn-NMR and FT-IR spectroscopic techniques. The crystal structure of complex 1 has been determined by single crystal X-ray diffraction analysis at 120(2) K. The geometry around Sn(IV) is trigonal bipyramidal. Three n-butyl groups and one oxygen atom from a deprotonated 2-thiobarbituric ligand are bonded to the metal center. The geometry is completed with one oxygen from a water molecule. Compound 1 exhibits potent, in vitro, cytotoxicity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (PAH, benzo[a]pyrene) carcinogenesis. In addition, the inhibition caused by 1, in the rate of lipoxygenase (LOX) catalyzed oxidation reaction of linoleic acid to hyperoxolinoleic acid, has been also kinetically and theoretically studied. The results are compared to that of cisplatin.
PMCID: PMC2288696  PMID: 18401456
25.  Organotin(IV) Derivatives of L-Cysteine and their in vitro Anti-Tumor Properties 
The synthesis and characterization of the organotin compounds [(n-C4H9)2Sn(cys)] (1), [(C6H5)2Sn(cys)] (2), [(C6H5)3Sn(Hcys).(H2o)] (3), {[(CH3)2Sn(Kcys)2].2(H20)} (4), {[(n-C4H9)2Sn(Kcys)2].2(H20)} (5) and {[(C6H5)2Sn(Kcys)2].2(H20)} (6) (where H2cys = L-cysteine) are reported. The compounds have been characterized by elemental analysis and 1H-NMR, Uv-Vis, FT-IR and MOssbauer spectroscopic techniques. Attempted recrystallization of (2) in DMSO/methanol 2:1 solution yielded after several days unexpectedly the dimeric compound bis(tri-phenyltin)sulphide {[(C6H5)3Sn]2S} (7) which has been characterized by x-ray analysis. The structure of the parent complex (2) as well as the mechanism of the decomposition of cysteine are being further investigated. The in vitro anticancer activity of complexes (I)- (6), against human leukemia (HL60), human liver (Bel7402), human stomach (BGC823) and human cervix epithelial human carcinoma (Hela), nasopharyngeal carcinoma (KB) and lung cancer (PG) tumor cells, were evaluated.
PMCID: PMC2267074  PMID: 18365068

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