Abstract:
:Eight novel 2-(2,6-dioxopiperidin-3-yl)phthalimidine EM-12 dithiocarbamates 9 and 10, N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines 11-14 and 3-substituted 2,6-dioxopiperidines 16 and 18 were synthesized as tumor necrosis factor-α (TNF-α) synthesis inhibitors. Synthesis involved utilization of a novel condensation approach, a one-pot reaction involving addition, iminium rearrangement and elimination, to generate the phthalimidine ring required for the creation of compounds 9-14. Agents were, thereafter, quantitatively assessed for their ability to suppress the synthesis on TNF-α in a lipopolysaccharide (LPS)-challenged mouse macrophage-like cellular screen, utilizing cultured RAW 264.7 cells. Whereas compounds 9, 14 and 16 exhibited potent TNF-α lowering activity, reducing TNF-α by up to 48% at 30 μM, compounds 12, 17 and 18 presented moderate TNF-α inhibitory action. The TNF-α lowering properties of these analogs proved more potent than that of revlimid (3) and thalidomide (1). In particular, N-dithiophthalimidomethyl-3-(phthalimidin-2-yl)-2,6-dioxopiperidine 14 not only possessed the greatest potency of the analogs to reduce TNF-α synthesis, but achieved this with minor cellular toxicity at 30 μM. The pharmacological focus of the presented compounds is towards the development of well-tolerated agents to ameliorate the neuroinflammation, that is, commonly associated with neurodegenerative disorders, epitomized by Alzheimer's disease and Parkinson's disease.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Luo W,Yu QS,Salcedo I,Holloway HW,Lahiri DK,Brossi A,Tweedie D,Greig NHdoi
10.1016/j.bmc.2011.05.029subject
Has Abstractpub_date
2011-07-01 00:00:00pages
3965-72issue
13eissn
0968-0896issn
1464-3391pii
S0968-0896(11)00382-8journal_volume
19pub_type
杂志文章abstract::Hologram quantitative structure-activity relationships (HQSAR) were applied to a data set of 41 cruzain inhibitors. The best HQSAR model (Q(2)=0.77; R(2)=0.90) employing Surflex-Sim, as training and test sets generator, was obtained using atoms, bonds, and connections as fragment distinctions and 4-7 as fragment size....
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2007.10.048
更新日期:2008-01-15 00:00:00
abstract::Platinum compounds are the first-line therapy for many types of cancer. However, drug resistance has frequently been reported for and is a major limitation of platinum-based chemotherapy in the clinic. In the current study, we examined the anti-tumor activity of phomoxanthone A (PXA), a tetrahydroxanthone dimer isolat...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2019.115044
更新日期:2019-10-01 00:00:00
abstract::In vitro evaluation of the halogenated pyrrolo[3,2-d]pyrimidines identified antiproliferative activities in compounds 1 and 2 against four different cancer cell lines. Upon screening of a series of pyrrolo[3,2-d]pyrimidines, the 2,4-Cl compound 1 was found to exhibit antiproliferative activity at low micromolar concen...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2015.06.025
更新日期:2015-08-01 00:00:00
abstract::A series of 27 salicylanilide diethyl phosphates was prepared as a part of our on-going search for new antimicrobial active drugs. All compounds exhibited in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium strains, with minimum inhibitory concentration (MIC) values of ...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2013.12.016
更新日期:2014-01-15 00:00:00
abstract::A facile, one-pot enzymatic glycan remodeling of antibody rituximab to produce homogeneous high-mannose and hybrid type antibody glycoforms is described. This method was based on the unique substrate specificity of the endoglycosidase S (Endo-S) from Streptococcus pyogenes. While Endo-S efficiently hydrolyzes the bi-a...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2017.07.053
更新日期:2018-04-01 00:00:00
abstract::Peroxynitrite, a reactive nitrogen species generated from nitric oxide and superoxide anion radical, is an endogenous potential risk factor for human cancer. When 2'-deoxycytidine was incubated with peroxynitrite at neutral pH and 37 degrees C, the reaction was greatly enhanced by the addition of ammonium bromide. Bot...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2008.03.007
更新日期:2008-05-01 00:00:00
abstract::The synthesis of a novel potent cyclic peptide MC4-ligand by ring-closing metathesis (RCM) is described. Based on the Ac-Nle-Gly-Lys-D-Phe-Arg-Trp-Gly-NH2-MC4 ligand, Ac-Nle-Alg-Lys-D-Phe-Arg-Trp-Alg-NH2 was designed and synthesized followed by cyclization using RCM. Both compounds are high affinity and selective MC4-...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2005.04.027
更新日期:2005-07-01 00:00:00
abstract::A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepar...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2013.04.013
更新日期:2013-06-01 00:00:00
abstract::A series of methyllycaconitine (1a, MLA) analogs was synthesized where the (S)-2-methylsuccinimidobenzoyl group in MLA was replaced with a (R)-2-methyl, 2,2-dimethyl-, 2,3-dimethyl, 2-phenyl-, and 2-cyclohexylsuccinimidobenzoyl (1b-f) group. The analogs 1b-f were evaluated for their inhibition of [(125)I]iodo-MLA bind...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2006.10.061
更新日期:2007-01-15 00:00:00
abstract::The medicinal chemist toolbox is plenty of (bio)isosteres when looking for a carboxylic acid replacement. However, systematic assessment of acid surrogates is often time consuming and expensive, while prediction of both physicochemical properties (logP and logD) as well as acidity would be desirable at early discovery...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2020.115731
更新日期:2020-08-28 00:00:00
abstract::Substituted diphenyl sulfones (10a-n) were synthesised, and the structures were confirmed by NMR, LC-MS and X-ray crystallography. Their antagonistic activities towards 5-HT₆ receptor were assessed in a cell-based functional assay. Diphenyl sulfone 10a, in spite of being the smallest and simplest known sulfonyl-contai...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2013.05.040
更新日期:2013-08-01 00:00:00
abstract::Grapefruit juice has been shown to increase the oral bioavailability of several clinically important drugs by inhibiting first pass metabolism. Several compounds in grapefruit juice have shown different biological activities. Unique among them are furocoumarins with potent inhibitory activity against cytochrome P450 e...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2007.03.047
更新日期:2007-06-01 00:00:00
abstract::Natural (-)-huperzine B (HupB), isolated from Chinese medicinal herb, displayed moderate inhibitory activity of acetylcholinesterase (AChE). Based on the active dual-site of AChE, a series of novel derivatives of bis- and bifunctional HupB were designed and synthesized. The AChE inhibition potency of most derivatives ...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2006.11.009
更新日期:2007-02-01 00:00:00
abstract::Magnetic resonance imaging (MRI) contrast agents are effective tools in both medical diagnosis and life science research. Various smart contrast agents have been developed for the visualization of biological phenomena. These contrast agents have molecular switches that increase or reduce MRI signal intensity in respon...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2011.12.005
更新日期:2012-01-15 00:00:00
abstract::A series of novel cinnamic acyl sulfonamide derivatives (9a-16e) have been designed and synthesized and their biological activities were also evaluated as potential tubulin polymerization inhibitors. Among all the compounds, 10c showed the most potent growth inhibitory activity against B16-F10 cancer cell line in vitr...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2011.06.088
更新日期:2011-08-15 00:00:00
abstract::The preparation of a novel series of N-aryl CBI derivatives in which an aryl substituent could be used to predictably modulate the reactivity of the resulting CC-1065/duocarmycin alkylation subunit analogue is detailed and its extension to a unique series of N-alkenyl derivatives is reported. The N-aryl derivatives we...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2004.08.032
更新日期:2004-11-15 00:00:00
abstract::In this study a new set of thiazolo[5,4-d]pyrimidine derivatives was synthesized. These derivatives bear different substituents at positions 2 and 5 of the thiazolopyrimidine core while maintaining a free amino group at position-7. The new compounds were tested for their affinity and potency at human (h) A1, A2A, A2B ...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2018.05.048
更新日期:2018-07-23 00:00:00
abstract::The purpose of this study is to probe the suitability of DFT based chemical reactivity parameter, electrophilicity index as a possible biological activity descriptor in the development of QSAR. Testosterone derivatives with activity described in terms of various biological activity parameters and the estrogen derivati...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2004.08.013
更新日期:2004-11-01 00:00:00
abstract::The molecular structure of 2alpha-hydroxyneoanisatin, a positional isomer of the potent neurotoxin anisatin, was determined by X-ray crystallographic analysis. This compound and four further seco-prezizaane type sesquiterpene lactones previously isolated from Illicium floridanum, which represent different structural t...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0968-0896(99)00240-0
更新日期:1999-12-01 00:00:00
abstract::A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data an...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2019.07.042
更新日期:2019-10-01 00:00:00
abstract::Malaria and HIV are among the most important global health problems of our time and together are responsible for approximately 3 million deaths annually. These two diseases overlap in many regions of the world including sub-Saharan Africa, Southeast Asia and South America, leading to a higher risk of co-infection. In ...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2012.06.038
更新日期:2012-09-01 00:00:00
abstract::Multidrug-resistant bacterial infections continue to be a rising global health concern. Herein is described the development of a class of novel 2-aminobenzimidazoles with antibiotic activity. These active 2-aminobenzimidazoles retain their antibiotic activity against several strains of multidrug-resistant Staphylococc...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2009.12.003
更新日期:2010-01-15 00:00:00
abstract::The following study describes the synthesis of new benzanilide derivatives and their pharmacological investigation on smooth muscle preparations of guinea pigs. All compounds were synthesized in good yields and showed a spasmolytic activity without significant effect on vascular smooth muscles and heart muscle prepara...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2008.04.057
更新日期:2008-06-01 00:00:00
abstract::A series of zatebradine analogues, differing in the basic moiety and in the methylene spacer, have been synthesized; their negative chronotropic activity has been determined in guinea pig atria. The most active compounds have been studied for their blocking properties on the hyperpolarization-activated current If (whi...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2004.11.017
更新日期:2005-02-15 00:00:00
abstract::The cells of Bacillus stearothermophilus contain an NADH-dependent diacetyl (acetoin) reductase. The enzyme was easily purified to homogeneity, partially characterised, and found to be composed of two subunits with the same molecular weight. In the presence of NADH, it catalyses the stereospecific reduction of diacety...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/0968-0896(96)00086-7
更新日期:1996-08-01 00:00:00
abstract::A series of N-(3-acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thiourea derivatives were investigated as vanilloid receptor ligands in an effort to discover a novel class of analgesics. The proposed pharmacophore model of resiniferatoxin. which includes the C20 homovanillic moiety, the C3-carbonyl and the ort...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0968-0896(00)00216-9
更新日期:2001-01-01 00:00:00
abstract::Structurally modified phthalimide derivatives were prepared through condensation of phthalic and tetrafluorophthalic anhydride with selected sulfonamides with variable yields. All compounds were screened for their antimycobacterium activity against Mycobacterium tuberculosis H37Ra (ATCC 25177) using a micro broth dilu...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2012.04.060
更新日期:2012-07-01 00:00:00
abstract::Heteroaromatic carboxylic esters of (nor)tropine were synthesized. Tropine esters displaced [(3)H]strychnine binding to glycine receptors of rat spinal cord with low Hill slopes. Two-site displacement resulted in nanomolar IC(50,1) and micromolar IC(50,2) values, and IC(50,2)/IC(50,1) ratios up to 615 depending on the...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2009.08.029
更新日期:2009-10-01 00:00:00
abstract::In this work, we further investigated a previously introduced class of cholinesterase inhibitors. The removal of the carbamic function from the lead compound xanthostigmine led to a reversible cholinesterase inhibitors 3. Some new 3-[omega-(benzylmethylamino)alkoxy]xanthen-9-one analogs were designed, synthesized, and...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2006.09.026
更新日期:2007-01-01 00:00:00
abstract::Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on...
journal_title:Bioorganic & medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.bmc.2016.03.037
更新日期:2016-05-01 00:00:00