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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.
doi:10.1128/AEM.00301-12
PMCID: PMC3346408  PMID: 22447611
2.  Synthesis, Characterization, Semiempirical and Biological Activities of Organotin(IV) Carboxylates with 4-Piperidinecarboxylic Acid 
Organotin (IV) carboxylates with the general formulae R2Sn(Cl)L [R = Me (1), n-Bu (2), Ph (3)] and R3SnL [R = Me (4), Ph (5)] have been synthesized by the reaction of 4-piperidinecarboxylic acid (HL) with KOH and R2SnCl2 (R = Me, n-Bu, Ph)/R3SnCl (R = Me, Ph) in methanol under stirring conditions. The metal ligand binding site, structure, and stability of complexes have been verified by FT-IR, (1H, 13C) NMR, EI-MS technique, and semiempirical study. The FT-IR data indicate the bidentate chelating mode of the carboxylate ligand which is also confirmed by semiempirical study. In solution state, five and four coordinated geometry around tin was confirmed by NMR spectroscopy. The EI-MS data agreed well with the molecular structure of the complexes. Thermodynamic parameters and molecular descriptors were calculated by using semiempirical PM3 method. HOMO-LUMO calculations show that chlorodiorganotin complexes are more susceptible to nucleophilic attack as compared to triorganotin complexes. Computed negative heat of formation indicates that complexes 1–4 are thermodynamically stable. The organotin(IV) carboxylates displayed powerful antimicrobial activities against various strains of bacteria and fungi and their minimal inhibitory concentration were also evaluated. The complexes exhibited comparatively higher hemolytic activity as compared to free ligand.
doi:10.1155/2014/959203
PMCID: PMC4274932  PMID: 25548551
3.  Treatment with Bazedoxifene and Conjugated Estrogens Results in Regression of Endometriosis in a Murine Model1 
Biology of Reproduction  2014;90(6):121, 1-7.
ABSTRACT
Bazedoxifene (BZA), a selective estrogen receptor modulator (SERM), inhibits the action of estrogens on endometrial proliferation. Here, we evaluate the effect of a tissue-selective estrogen complex (TSEC) containing BZA and conjugated estrogens (CE) on ectopic endometrial lesions in a mouse model of endometriosis. Experimental endometriosis was created in 60 female CD-1 mice. The mice were randomly divided into 10 groups that received varying doses of either BZA (1, 2, 3, or 5 mg/kg/day), BZA (1, 2, 3, or 5 mg/kg/day) in combination with CE (3 mg/kg/day), CE treatment alone (3 mg/kg/day), or vehicle control for 8 wk. Treatment with BZA alone or the TSEC containing BZA/CE led to a decrease in endometriotic lesion size compared to controls. The mean surface area of the untreated lesions was 19.6 mm2. Treatment with BZA or BZA/CE resulted in reduced lesion size (to 8.8 and 7.8 mm2, respectively). No significant difference was found in lesion size between the BZA and BZA/CE treatment groups or between different doses of either treatment. Ovarian cyst formation was not evident in the treated groups. Treatment with the TSEC containing higher BZA dosages (3 and 5 mg/kg/day) led to significantly lower levels of estrogen receptor (Esr1) mRNA expression compared to the control treatment. No differences were observed in expression of progesterone receptor (Pgr). Immunohistochemical analysis also demonstrated a decrease in ESR protein. The combination of CE and BZA may prove to be a novel treatment option for endometriosis.
doi:10.1095/biolreprod.113.114165
PMCID: PMC4093999  PMID: 24740602
bazedoxifene (BZA); conjugated estrogen (CE); endometriosis; hormone receptors; tissue-specific estrogen complex (TSEC)
4.  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.
doi:10.1155/MBD.1998.189
PMCID: PMC2365126  PMID: 18475843
5.  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.
doi:10.2147/IJWH.S29346
PMCID: PMC3325004  PMID: 22505832
tissue selective estrogen complex; bazedoxifene; conjugated estrogens; menopause; osteoporosis; vasomotor symptoms
6.  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.
doi:10.1016/j.molmet.2013.12.009
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
7.  Incorporating bazedoxifene into the treatment paradigm for postmenopausal osteoporosis in Japan 
Osteoporosis International  2014;26(3):849-863.
The incidence of osteoporosis-related fractures in Asian countries is steadily increasing. Optimizing osteoporosis treatment is especially important in Japan, where the rate of aging is increasing rapidlyelderly population is increasing rapidly and life expectancy is among the longest in the world. There are several therapies currently available in Japan for the treatment of postmenopausal osteoporosis, each with a unique risk/benefit profile. A novel selective estrogen receptor modulator, bazedoxifene (BZA), was recently approved for the treatment of postmenopausal osteoporosis in Japan. Results from a 2-year, phase 2 trial in postmenopausal Japanese women showed that BZA significantly improved lumbar spine and total hip bone mineral density compared with placebo, while maintaining endometrial and breast safety, consistent with results from 2 global, phase 3 trials including a 2-year osteoporosis prevention study and a 3-year osteoporosis treatment study. In the pivotal 3-year treatment study, BZA significantly reduced the incidence of new vertebral fractures compared with placebo; in a post hoc analysis of a subgroup of women at higher risk of fractures, BZA significantly reduced the risk of nonvertebral fractures compared with placebo and raloxifene. A 2-year extension of the 3-year treatment study demonstrated the sustained efficacy of BZA over 5 years of treatment. BZA was generally safe and well tolerated in these studies. In a “super-aging” society such as Japan, long-term treatment for postmenopausal osteoporosis is a considerable need. BZA may be considered as a first choice for younger women anticipating long-term treatment, and also an appropriate option for older women who are unable or unwilling to take bisphosphonates.
doi:10.1007/s00198-014-2940-x
PMCID: PMC4331605  PMID: 25448837
Bazedoxifene; Fracture; Japan; Osteoporosis; Selective estrogen receptor modulator (SERM)
8.  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.
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PMCID: PMC342209  PMID: 693321
9.  Characterization of the adenosine receptors of the rat superior cervical ganglion. 
British Journal of Pharmacology  1993;110(2):854-860.
1. Adenosine analogues caused hyperpolarization and inhibition of the depolarizing response to muscarine of the rat isolated superior cervical ganglion (SCG) measured by a 'grease gap' recording technique. The receptors mediating these responses have been characterized by use of a range of selective adenosine analogues and adenosine receptor antagonists. 2. In decreasing order of potency N6-cyclopentyladenosine (CPA), 2-chloroadenosine (2CA), adenosine, 2-phenylaminoadenosine (PAA), caused concentration-dependent hyperpolarizations whilst N6-(9-fluorenylmethyl)adenosine (PD 117,413) was inactive at up to 100 microM. 3. The order of potency of adenosine analogues in depressing depolarization caused by a submaximal concentration of muscarine (100 nM) was: CPA > R-PIA = 2CA > NECA > S-PIA > BZA > adenosine > PAA, where R- and S-PIA = R(-)- and S(+)-N6-(2-phenylisopropyl)adenosine, NECA = 5'N-ethylcarboxamidoadenosine and BZA = N6-benzyladenosine. PD 117,413 was inactive at concentrations up to 100 microM. The maximum inhibitions of the muscarine-induced depolarization by CPA, 2CA, NECA and BZA were similar. R-PIA, S-PIA and PAA produced similar maximal inhibitions which were significantly smaller than those produced by CPA. 4. Hyperpolarizations caused by adenosine were antagonized by the P1-purinoceptor selective antagonist 1,3-dimethyl-8-phenylxanthine (8PT) and by the selective A1-adenosine receptor antagonist, 1,3-dipropyl-8-(4-((2-aminoethyl)amino)carbonylmethyloxyphenyl++ +)xanthine (XAC). Hyperpolarizations caused by CPA, adenosine and PAA were antagonized by the A1-selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) but not by the A2-selective antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX).(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC2175924  PMID: 8242261
10.  The Effects of Bazedoxifene, Conjugated Equine Estrogens, and a Tissue Selective Estrogen Complex (TSEC) Containing Both Bazedoxifene and Conjugated Equine Estrogens on Cerebral Artery Atherosclerosis of Postmenopausal Monkeys 
Menopause (New York, N.Y.)  2014;21(1):10.1097/GME.0b013e31829370e5.
Objective
To evaluate the effects of a new selective estrogen receptor modulator (bazedoxifene acetate, BZA) and a tissue specific estrogen complex (TSEC = BZA combined with conjugated equine estrogens (CEE), on atherosclerosis extent and severity of cerebral arteries.
Methods
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. After an experimental period of 20 months (approximately equivalent to 5 years of patient experience), the extent and severity of atherosclerosis in the common carotid artery, carotid bifurcation, internal carotid artery and the basilar artery was determined. Lesion severity was determined using the American Heart Association grading system (AHA, grades 0-5).
Results
BZA had no consistent adverse effects on the extent or severity of atherosclerosis in the cerebral arteries and did not attenuate the beneficial effects of CEE on common carotid artery atherosclerosis severity. Although CEE had only modest beneficial effects on atherosclerosis extent of the carotid bifurcation, the severity of lesions and numbers of affected cases in the common carotid artery were reduced with CEE treatment. As reported previously, plasma lipid profiles did not differ among the treatment groups.
Conclusions
In this long-term (equivalent to 5 human patient years) nonhuman primate trial, BZA had no consistent adverse effect on cerebral artery atherosclerosis and did not attenuate the modest beneficial effect of CEE on common carotid arteries. Furthermore, CEE inhibited the development of complicated plaques in the common carotid artery
doi:10.1097/GME.0b013e31829370e5
PMCID: PMC3760976  PMID: 23676638
Cerebral atherosclerosis; menopause; estrogens; SERMS; bazedoxifene
11.  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.
doi:10.3390/ph5090899
PMCID: PMC3816651  PMID: 24280697
hormone therapy; tissue selective estrogen complex (TSEC); bazedoxifene; conjugated estrogens; menopause
12.  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.
doi:10.1177/1933719112463251
PMCID: PMC3826278  PMID: 23171676
TSECS; SERMS; HOXA10; leukemia inhibitory factor (LIF); progesterone receptor; EMX2; ishikawa
13.  Breast-related effects of selective estrogen receptor modulators and tissue-selective estrogen complexes 
A number of available treatments provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis. However, as breast safety is a major concern, new options are needed, particularly agents with an improved mammary safety profile. Results from several large randomized and observational studies have shown an association between hormone therapy, particularly combined estrogen-progestin therapy, and a small increased risk of breast cancer and breast pain or tenderness. In addition, progestin-containing hormone therapy has been shown to increase mammographic breast density, which is an important risk factor for breast cancer. Selective estrogen receptor modulators (SERMs) provide bone protection, are generally well tolerated, and have demonstrated reductions in breast cancer risk, but do not relieve menopausal symptoms (that is, vasomotor symptoms). Tissue-selective estrogen complexes (TSECs) pair a SERM with one or more estrogens and aim to blend the positive effects of the components to provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis without stimulating the breast or endometrium. One TSEC combination pairing conjugated estrogens (CEs) with the SERM bazedoxifene (BZA) has completed clinical development and is now available as an alternative option for menopausal therapy. Preclinical evidence suggests that CE/BZA induces inhibitory effects on breast tissue, and phase 3 clinical studies suggest breast neutrality, with no increases seen in breast tenderness, breast density, or cancer. In non-hysterectomized postmenopausal women, CE/BZA was associated with increased bone mineral density and relief of menopausal symptoms, along with endometrial safety. Taken together, these results support the potential of CE/BZA for the relief of menopausal symptoms and prevention of postmenopausal osteoporosis combined with breast and endometrial safety.
doi:10.1186/bcr3677
PMCID: PMC4076629  PMID: 25928299
14.  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.
doi:10.1155/S1565363303000189
PMCID: PMC2267064  PMID: 18365056
15.  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).
doi:10.1155/2012/698491
PMCID: PMC3352140  PMID: 22611347
16.  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.
doi:10.5402/2012/873035
PMCID: PMC3767334  PMID: 24052853
17.  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.
doi:10.1155/MBD.1995.297
PMCID: PMC2364992  PMID: 18472781
18.  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.
doi:10.1002/jrs.3002
PMCID: PMC3280504  PMID: 22347769
Raman difference spectroscopy; thioesterase; ionization; conformation; enzyme-substrate complex
19.  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.
doi:10.1155/MBD.1994.1
PMCID: PMC2364878  PMID: 18476213
20.  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.
Objective
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/gme.0b013e318252e46d
PMCID: PMC3762946  PMID: 23103754
Menopause; Hormone Therapy; Estrogen; Selective Estrogen Receptor Modulator; Estrogen Receptor; Breast
21.  The endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model 
Menopause (New York, N.Y.)  2013;20(7):777-784.
Objective
Concerns of breast cancer risk in postmenopausal women taking combined estrogen+progestin therapy have generated interest in the use of selective estrogen receptor modulators (SERMs) as potential progestin alternatives. Endometrial proliferation and cancer risk are major concerns, however, for estrogens and certain types of SERMs when given alone. The primary aim of this study was to evaluate the endometrial profile of bazedoxifene acetate (BZA), a third-generation SERM, alone and in combination with conjugated equine estrogens (CEE) in a postmenopausal primate model.
Methods
Ninety-eight ovariectomized cynomolgus monkeys (Macaca fascicularis) were randomized to receive no hormone treatment (control), BZA 20 mg, CEE 0.45 mg, or the combination of BZA 20 mg + CEE 0.45 mg once daily for 20 months in a parallel-arm study design. The primary outcome measure was endometrial epithelial proliferation.
Results
BZA+CEE and BZA treatment resulted in significantly less endometrial epithelial area and Ki67 expression compared to CEE (P < 0.001 for all). The prevalence of endometrial hyperplasia and other estrogen-induced morphologic changes in the BZA+CEE and BZA groups were not significantly different from control. The addition of BZA to CEE completely inhibited the expression of ERα-regulated genes (TFF1 and PGR), while BZA alone had no effect. BZA+CEE and BZA treatment also resulted in lower ERα protein expression in the endometrium compared to control and CEE (P < 0.05 for all).
Conclusions
BZA given at a clinically relevant dose inhibits estrogen effects on the endometrium and lacks uterotropic effects when given alone.
doi:10.1097/GME.0b013e31827ce57a
PMCID: PMC3893023  PMID: 23793168
Estrogens; menopause; hormone therapy; selective estrogen receptor modulator; bazedoxifene acetate; endometrial cancer
22.  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.
doi:10.1155/MBD.1996.75
PMCID: PMC2365004  PMID: 18472799
23.  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.
doi:10.1128/JVI.76.20.10465-10472.2002
PMCID: PMC136538  PMID: 12239323
24.  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.
doi:10.1155/MBD.2000.245
PMCID: PMC2365233  PMID: 18475952
25.  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.
doi:10.1107/S1600536812033181
PMCID: PMC3415010  PMID: 22904997

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