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At least 1,189 records · Page 66Linked to original sources
PubMed2003

Ruthenium(II) sulfoxide-maltolato and -nitroimidazole complexes: synthesis and MTT assay.

Ru(II) sulfoxide-maltolato complexes, Ru(ma)(2)(L)(2) (L = DMSO (1a) and TMSO (1b) or L(2) = BESE (1c)), were synthesized, as well as the analogous ethylmaltolato derivatives, Ru(etma)(2)(L)(2) (2a-c) (ma = 3-hydroxy-2-methylpyran-4-onate, etma = 2-ethyl-3-hydroxypyran-4-onate, TMSO = tetramethylene sulfoxide, BESE = 1,2-bis(ethylsulfinyl)ethane). A Ru(II) bidentate sulfoxide-metronidazole complex, RuCl(2)(BESE)(metro)(2) (3), was also synthesized (metro = metronidazole = 2-methyl-5-nitroimidazole-1-ethanol). The complexes were characterized generally by (1)H NMR, UV-vis, and IR spectroscopies, as well as MS, elemental analysis, solution conductivity, and cyclic voltammetry. The molecular structures of Ru(ma)(2)(S,R-BESE) (1c) and trans-RuCl(2)(R,R-BESE)(metro)(2) (3) were determined by X-ray crystallography. All sulfoxide ligands are S-bonded. The complexes were tested against human breast cancer cells (MDA-MB-435S) using an in vitro MTT assay, a colorimetric determination of cell viability: 2a,b exhibit the lowest IC(50) values of 190 +/- 10 and 220 +/- 10 microM, respectively. Cisplatin exhibits an IC(50) value of 30 +/- 5 microM.

Antineoplastic Agents↗
PubMed2005

Coordination chemistry and insulin-enhancing behavior of vanadium complexes with maltol C6H6O3 structural isomers.

Syntheses of vanadium complexes using the naturally occurring ligands isomaltol (Hima) and allomaltol (Hama), as well as a newly synthesized, potentially tetradentate diaminodipyrone [H(2)(en(ama)(2)], are reported. Complete characterization of the resulting compounds [trans-VO(ima)(2)(H(2)O), VO(ama)(2), V(ima)(3), V(ama)(3) and VO(en(ama)(2))], including X-ray crystallography analyses for trans-VO(ima)(2)(H(2)O) and V(ima)(3), are presented herein. Potentiometric titrations (25 degrees C, I = 0.16 M NaCl) were used to measure stability constants in the V(IV)-Hima system; these data were compared to previous data collected on the V(IV)-L (L = Hma, Hama) systems. The in vivo efficacy of these compounds to lower the blood glucose levels of STZ-diabetic rats was tested; all but VO(en(ama)(2)) produced significant decreases in plasma glucose levels. The results were compared to those of the benchmark compound BMOV [VO(ma)(2), bis(maltolato)oxovanadium(IV)], a known insulin-enhancing agent.

Animals↗
PubMed2004

Addressing lead toxicity: complexation of lead(II) with thiopyrone and hydroxypyridinethione O,S mixed chelators.

The lead(II) ion is regarded as a serious environmental contaminant. A considerable need exists to develop selective ligands for remediation of this metal ion. Herein, the coordination chemistry of lead(II) is investigated with three O,S donor ligands: thiomaltol, 3-hydroxy-1-methyl-2(1H)-pyridinethione (3,2-HOPTO), and 3-hydroxy-1,2-dimethyl-4(1H)-pyridinethione (3,4-HOPTO). The X-ray structures of [Pb(thiomaltolato)(2)] and [Pb(3,4-HOPTO)(2)] have been solved, revealing the expected 4-coordinate geometries. Electronic spectra have been obtained for the lead(II) complexes with all three ligands. Preliminary solution studies show that the thiomaltol ligand binds lead(II) preferentially over magnesium(II) and calcium(II); however, [Pb(thiomaltolato)(2)] is not stable in the presence of 1 equiv of EDTA. Tetradentate ligands derived from these O,S chelators are expected to generate higher affinity ligands for lead(II) sequestration.

Chelating Agents↗
PubMed2001

Total synthesis of fostriecin (CI-920).

The first total synthesis of the potent antitumor agent fostriecin (CI-920) is described, confirming the relative and absolute stereochemistry assignments. Fostriecin is a unique phosphate monoester which exhibits weak topoisomerase II inhibition (IC(50) = 40 microM) and more potent and selective protein phosphatase 2A and 4 (PP2A and PP4) inhibition (IC(50) = 40-3 nM and 1.5 nM), resulting in mitotic entry checkpoint inhibition. Phase I clinical trials with fostriecin, which were the first to explore the potential of this novel mechanism of action, were halted even before therapeutic concentrations were reached or dose-limiting toxicity established due to problems of drug stability observed during storage of naturally derived material. The synthesis of fostriecin detailed herein is the first stage of efforts that may serve to address these limitations to the clinical examination of this or related promising new antitumor agents.

Alkenes↗
PubMed2001

A practical synthesis of (+)-discodermolide and analogues: fragment union by complex aldol reactions.

A practical stereocontrolled synthesis of (+)-discodermolide (1) has been completed in 10.3% overall yield (23 steps longest linear sequence). The absolute stereochemistry of the C(1)-C(6) (7), C(9)-C(16) (8), and C(17)-C(24) (9) subunits was established via substrate-controlled, boron-mediated, aldol reactions of the chiral ethyl ketones 10, 11, and 12. Key fragment coupling reactions were a lithium-mediated, anti-selective, aldol reaction of aryl ester 8 (under Felkin-Anh induction from the aldehyde component 9), followed by in situ reduction to produce the 1,3-diol 40, and a (+)-diisopinocampheylboron chloride-mediated aldol reaction of methyl ketone 7 (overturning the inherent substrate induction from the aldehyde component 52) to give the (7S)-adduct 58. The flexibility of our overall strategy is illustrated by the synthesis of a number of diastereomers and structural analogues of discodermolide, which should serve as valuable probes for structure-activity studies.

Aldehydes↗
PubMed2002

Discovery of exceptionally efficient catalysts for solvent-free enantioselective hetero-Diels-Alder reaction.

Combinatorial coordination chemistry strategy combined with high-throughput screening techniques has been successfully applied to engineering practical enantioselective catalysts for asymmetric hetero-Diels-Alder reaction. The reaction of Danishefsky's diene with a variety of aldehydes can be carried out with 0.1-0.005 mol % of H4-BINOL/Ti/H4-BINOL or H4-BINOL/Ti/H8-BINOL catalysts at room temperature under solvent- and MS-free conditions to afford dihydropyrone derivatives with up to quantitative yield and 99.8% ee.

Aldehydes↗
PubMed2002

Utilization of molybdenum- and palladium-catayzed dynamic kinetic asymmetric transformations for the preparation of tertiary and quaternary stereogenic centers: a concise synthesis of tipranavir.

Tipranavir, an important antiviral agent in clinical development for the treatment of HIV, is synthesized in 15 linear steps from readily available starting materials in 25% overall yield by utilizing Pd- and Mo-catalyzed DYKAT reactions to control the quaternary and tertiary stereogenic centers, respectively.

Catalysis↗
PubMed2003

Total synthesis of an antitumor antibiotic, Fostriecin (CI-920).

The total synthesis of an antitumor antibiotic, fostriecin (CI-920), via a highly convergent route is described. A characteristic feature of the present total synthesis is that the synthesis was achieved via a coupling procedure of three segments A, B, and C. The unsaturated lactone moiety of fostriecin, corresponding to segment A, was constructed from a known Horner-Emmons reagent, and the stereochemistry of the C-5 position was introduced by asymmetric reduction with (R)-BINAl-H. Segment B having a series of stereogenic centers was synthesized from (R)-malic acid and the stereogenic centers at the C-8 and C-9 positions were prepared by a combination of Wittig reaction and Sharpless asymmetric dihydroxylation reaction. The conjugated Z,Z,E-triene moiety of fostriecin, corresponding to segment C, was eventually constructed by Wittig reaction and Stille coupling reaction. The phosphate moiety, which is known to be essentially important for the antitumor activity, was introduced via two routes: (i) direct phosphorylation of the monohydroxyl derivative in which other hydroxyl groups are protected with silyl groups; (ii) cyclic phosphorylation and selective cleavage of the cyclic phosphate derivative. Although the former route is basically the same as those reported by other groups, the latter route is novel and more effective than the former one. The present total synthesis would serve as a versatile synthetic route to not only fostriecin, but also its various analogues including stereoisomers.

Alkenes↗
PubMed2004

Rational pathway engineering of type I fatty acid synthase allows the biosynthesis of triacetic acid lactone from D-glucose in vivo.

Metabolic pathway engineering is a powerful tool to synthesize structurally diverse and complex chemicals via genetic manipulation of multistep catalytic systems involved in cell metabolism. Here, we report the rational design of a fatty acid biosynthetic pathway, Brevibacterium ammoniagenes fatty acid synthase B (FAS-B), that allows the microbial synthesis of triacetic acid lactone (TAL) from an inexpensive feedstock, d-glucose. TAL can be chemically converted to phloroglucinol, which is a core structure for the synthesis of various high value bioactive compounds and energetic compounds such as 1,3,5-triamino-2,4,6-trinitrobenzene (TATB). Synthesis of phloroglucinol from d-glucose using this combined biological and chemical synthesis may offer significant advantages over the current phloroglucinol manufacture, including environmental friendliness and reduction in the cost of phloroglucinol. More importantly, it represents a novel strategy for the benzene-free synthesis of aromatic chemicals.

Bacterial Proteins↗
PubMed2003

Total synthesis of leustroducsin B.

A convergent total synthesis of leustroducsin B (1), which is known to exhibit a variety of biological activities, was successfully carried out. Notable features of our synthesis include construction of the C8 stereocenter by lipase-mediated desymmetrization of meso-diol 4 (90.2% ee) and preparation of the C9-C11 anti-diol moiety by the addition of alkynylzinc reagent 20 to the aldehyde 19. Furthermore, a new diol protecting group, p-silyloxybenzylidene, was developed for the deprotection from densely functionalized substrates under weakly acidic conditions. The protecting group was easily removed in a two-step procedure ((HF)3.Et3N; AcOH-THF-H2O).

Colony-Stimulating Factors↗
PubMed2003

Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition.

Key derivatives and analogues of fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.

Alkenes↗
PubMed2005

Dinuclear asymmetric Zn aldol additions: formal asymmetric synthesis of fostriecin.

Direct asymmetric aldol reactions constitute a powerful methodology for the efficient synthesis of complex natural products. Herein we report the first application of our recently reported dinuclear Zn-catalyzed direct aldol addition of alkynyl ketones to aldehydes in a short and efficient formal asymmetric synthesis of fostriecin, a potent cyctotoxic natural product. This work highlights not only the power of the aldol methodology but also the utility of the akynyl silane aldol adducts, as it is subsequently utilized in a vinyl silane cross-coupling reaction which affords the target molecule in 14 steps for the longest linear sequence in 8.5% overall yield.

Aldehydes↗
PubMed2005

Crotylsilane reagents in the synthesis of complex polyketide natural products: total synthesis of (+)-discodermolide.

An efficient, highly convergent stereocontrolled synthesis of (+)-discodermolide has been achieved with 2.1% overall yield (27 steps longest linear sequence). The absolute stereochemistry of the C1-C6 (12), C7-C14 (13), and C15-C24 (11) subunits was introduced using asymmetric crotylation methodology. Key elements of the synthesis include the use of hydrozirconation-cross-coupling methodology for the construction of C13-C14 (Z)-olefin, acetate aldol reaction to construct the C6-C7 bond and install the C7 stereocenter with high levels of 1,5-anti stereoinduction, and the use of palladium-mediated sp(2)-sp(3) cross-coupling reaction to join the advanced fragments, which assembled the carbon framework of discodermolide.

Alkanes↗
PubMed2005

New insights into the interactions of serum proteins with bis(maltolato)oxovanadium(IV): transport and biotransformation of insulin-enhancing vanadium pharmaceuticals.

Significant new insights into the interactions of the potent insulin-enhancing compound bis(maltolato)oxovanadium(IV) (BMOV) with the serum proteins, apo-transferrin and albumin, are presented. Identical reaction products are observed by electron paramagnetic resonance (EPR) with either BMOV or vanadyl sulfate (VOSO4) in solutions of human serum apo-transferrin. Further detailed study rules out the presence of a ternary ligand-vanadyl-transferrin complex proposed previously. By contrast, differences in reaction products are observed for the interactions of BMOV and VOSO4 with human serum albumin (HSA), wherein adduct formation between albumin and BMOV is detected. In BMOV-albumin solutions, vanadyl ions are bound in a unique manner not observed in comparable solutions of VOSO4 and albumin. Presentation of chelated vanadyl ions precludes binding at the numerous nonspecific sites and produces a unique EPR spectrum which is assigned to a BMOV-HSA adduct. The adduct species cannot be produced, however, from a solution of VOSO4 and HSA titrated with maltol. Addition of maltol to a VOSO4-HSA solution instead results in formation of a different end product which has been assigned as a ternary complex, VO(ma)(HSA). Furthermore, analysis of solution equilibria using a model system of BMOV with 1-methylimidazole (formation constant log K1 = 4.5(1), by difference electronic absorption spectroscopy) lends support to an adduct binding mode (VO(ma)2-HSA) proposed herein for BMOV and HSA. This detailed report of an in vitro reactivity difference between VOSO4 and BMOV may have bearing on the form of active vanadium metabolites delivered to target tissues. Albumin binding of vanadium chelates is seen to have a potentially dramatic effect on pharmacokinetics, transport, and efficacy of these antidiabetic chelates.

Apoproteins↗
PubMed2004

The total synthesis of (-)-SNF4435 C and (+)-SNF4435 D.

The size and positioning of substituents on a tetraene, along with the Woodward-Hoffmann rules, control the relative stereochemistry at the four adjacent chiral centers that are generated in the 8pi/6pi electrocyclization cascade. A biomimetic synthesis of (-)-SNF4435 C and (+)-SNF4435 D exploits these steric effects and allows confirmation of the predicted absolute stereochemistry of the natural products.

Immunosuppressive Agents↗
PubMed2004

Structure-reactivity relationships in oxidative carbon-carbon bond forming reactions: a mild and efficient approach to stereoselective syntheses of 2,6-disubstituted tetrahydropyrones.

Homobenzylic ethers with pendent enol acetate nucleophiles undergo highly efficient cleavage reactions followed by 6-endo cyclizations to form 2,6-disubstituted tetrahydropyrones with excellent stereocontrol at room temperature in the presence of the mild oxidant ceric ammonium nitrate. Cyclizations proceed through either stabilized or nonstabilized oxocarbenium ions. Structure-reactivity relationships are presented to provide a predictive guide for the design of radical cation cleavage processes. Unique sequences for preparing cyclization substrates based on stereoselective Lewis acid mediated acetal openings have been developed for the synthesis of complex substrates that are suitable for applications to the synthesis of biologically active natural products.

Cyclization↗
PubMed2004

Diastereoselective synthesis of 2,3,6-trisubstituted tetrahydropyran-4-ones via Prins cyclizations of enecarbamates: a formal synthesis of (+)-ratjadone A.

Enecarbamates are shown to be excellent terminating groups for Prins cyclizations. A noteworthy feature of this methodology is the easy, stereoselective construction of the cyclization precursors by alkylation of metalated (E)-enecarbamates with epoxides. The stereochemistry of the resultant trisubstituted (E)-enecarbamates is then transferred with high fidelity to afford the frequently observed and biologically significant all-cis-2,3,6-trisubstituted tetrahydropyran substructures of naturally occurring compounds. Other substituted tetrahydropyrans, including 2,3,5,6-tetrasubstituted, cis-2,3-disubstituted, and cis-2,6-disubstituted, are also accessible. This methodology facilitated an exceptionally concise formal total synthesis of the nuclear export inhibitor (+)-ratjadone A.

Carbamates↗