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381.
Total syntheses of thiocoraline and BE-22179 and assessment of their DNA binding and biological properties. 总被引:3,自引:0,他引:3
D L Boger S Ichikawa W C Tse M P Hedrick Q Jin 《Journal of the American Chemical Society》2001,123(4):561-568
Full details of the total syntheses of thiocoraline (1) and BE-22179 (2), C(2) symmetric bicyclic octadepsipeptides possessing two pendant 3-hydroxyquinoline chromophores, are described in which their relative and absolute stereochemistry were established. Key elements of the approach include the late-stage introduction of the chromophore, symmetrical tetrapeptide coupling, macrocyclization of the 26-membered octadepsipeptide conducted at the single secondary amide site following disulfide formation, and a convergent assemblage of the tetradepsipeptide with introduction of the labile thiol ester linkage in the final coupling reaction under near racemization free conditions. By virtue of the late-stage introduction of the chromophore and despite the challenges this imposes on the synthesis, this approach provides ready access to a range of key chromophore analogues. Thiocoraline and BE-22179 were shown to bind to DNA by high-affinity bisintercalation analogous to echinomycin, but with little or no perceptible sequence selectivity. Both 1 and 2 were found to exhibit exceptional cytotoxic activity (IC(50) = 200 and 400 pM, respectively, L1210 cell line) comparable to echinomycin and one analogue, which bears the luzopeptin chromophore, was also found to be a potent cytotoxic agent. 相似文献
382.
Zvi Drezner 《Annals of Operations Research》2009,167(1):327-336
In this paper we consider Weber-like location problems. The objective function is a sum of terms, each a function of the Euclidean
distance from a demand point. We prove that a Weiszfeld-like iterative procedure for the solution of such problems converges
to a local minimum (or a saddle point) when three conditions are met. Many location problems can be solved by the generalized
Weiszfeld algorithm. There are many problem instances for which convergence is observed empirically. The proof in this paper
shows that many of these algorithms indeed converge. 相似文献
383.
The synthesis and evaluation of a series of C3-substituted 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of the CC-1065 and duocarmycin alkylation subunits are detailed, including methyl and the full series of halogens. Introduction of the key substituent was accomplished through directed metalation of the seco-CBI core followed by reaction of the resultant aryllithium with an appropriate electrophile. C3-Bromo and iodo substituents were only effectively installed on the hindered aryllithium intermediate using a novel halogen source, 1-bromo- and 1-iodophenylacetylene, that should prove generally useful beyond the studies we describe. X-ray crystal structures of the series show substantial distortion in the vinylogous amide due to unfavorable steric interactions between the C3-substituent and the N(2)-carbamate. In the halogen series, the N2-C2a bond length and the torsional angle chi(1) smoothly increase with the increasing size of the C3 substituent indicative of decreasing vinylogous amide conjugation through the series (H > F > Cl > Br > I). Unlike N-Boc-CBI, this series of substituted CBI analogues proved remarkably reactive toward solvolysis even at pH 7, where the reaction is uncatalyzed and the reactivity order (I > Br > Cl > F > H) follows a trend consistent with the extent of vinylogous amide conjugation and stabilization. The implications of these observations on the source of catalysis for the DNA alkylation reaction of the natural products are discussed. 相似文献
384.
Andrew B. Rodd David E. Dunstan Simon B. Ross-Murphy David V. Boger 《Rheologica Acta》2001,40(1):23-29
A large body of literature is focused on the accurate determination of a gel point for systems undergoing a sol-gel phase
transition. Investigation into the limiting strain and stress for linear viscoelastic behaviour at various stages of a phase
transition such as gelation is a subject that is rarely commented on. The small amplitude oscillatory rheological behaviour
of a biopolymer cross-linker system through a thermally activated sol-gel transition is presented. Mechanical spectra were
interpreted through application of the gelation criteria of Chambon and Winter (Winter and Chambon 1986; Chambon and Winter
1987), where the (so-called gel strength) parameter S, and relaxation exponent, n are obtained. A detailed study of the limit of linear viscoelasticity yields important trends in critical stress (σ°c) and critical strain (γ°c) limits highlighting the possible experimental difficulties associated with mechanical measurements obtained in close proximity
to the gel point.
Received: 17 March 2000 Accepted: 2 October 2000 相似文献
385.
In this paper we investigate the problem of locating a new facility servicing a set of demand points. A given set of collection depots is also given. When service is required by a demand point, the server travels from the facility to the demand point, then from the demand point to one of the collection depots (which provides the shortest route back to the facility), and back to the facility. The problem is analyzed and properties of the solution point are formulated and proved. Computational results on randomly generated problems are reported. 相似文献
386.
Vancomycin analogues bearing an A-ring trimethylammonium salt modification were synthesized and their antimicrobial activity against vancomycin-resistant Enterococci (VRE) was evaluated. The modification increased antimicrobial potency and provided the capability to induce bacteria cell membrane permeabilization, but both properties were weaker than that found with our earlier reported similar C-terminus modification. The results provide further insights on the additive effect and generalizability of the structural and site-specific nature of a peripheral quaternary trimethylammonium salt modification of vancomycin. 相似文献
387.
An effective synthesis of [Psi[CH(2)NH]Tpg(4)]vancomycin aglycon (5) is detailed in which the residue 4 amide carbonyl of vancomycin aglycon has been replaced with a methylene. This removal of a single atom was conducted to enhance binding to D-Ala-D-Lac, countering resistance endowed to bacteria that remodel their D-Ala-D-Ala peptidoglycan cell wall precursor by a similar single atom change (ester O for amide NH). Key elements of the approach include a synthesis of the modified vancomycin ABCD ring system featuring a reductive amination coupling of residues 4 and 5 for installation of the deep-seated amide modification, the first of two diaryl ether closures for formation of the modified CD ring system (76%, 2.5-3:1 kinetic atropodiastereoselectivity), a Suzuki coupling for installation of the hindered AB biaryl bond (90%) on which the atropisomer stereochemistry could be thermally adjusted, and a macrolactamization closure of the AB ring system (70%). Subsequent DE ring system introduction enlisted a room-temperature aromatic nucleophilic substitution reaction for formation of the remaining diaryl ether (86%, 6-7:1 kinetic atropodiastereoselectivity), completing the carbon skeleton of 5. Consistent with expectations and relative to the vancomycin aglycon, 5 exhibited a 40-fold increase in affinity for D-Ala-D-Lac (K(a) = 5.2 x 10(3) M(-1)) and a 35-fold reduction in affinity for D-Ala-D-Ala (K(a) = 4.8 x 10(3) M(-1)), providing a glycopeptide analogue with balanced, dual binding characteristics. Beautifully, 5 exhibited antimicrobial activity (MIC = 31 microg/mL) against a VanA-resistant organism that remodels its D-Ala-D-Ala cell wall precursor to d-Ala-d-Lac upon glycopeptide antibiotic challenge, displaying a potency that reflects these binding characteristics. 相似文献
388.
Schnermann MJ Romero FA Hwang I Nakamaru-Ogiso E Yagi T Boger DL 《Journal of the American Chemical Society》2006,128(36):11799-11807
Full details of the total synthesis of piericidin A1 and B1 and its extension to the preparation of a series of key analogues are described including ent-piericidin A1 (ent-1), 4'-deshydroxypiericidin A1 (58), 5'-desmethylpiericidin A1 (73), 4'-deshydroxy-5'-desmethylpiericidin A1 (75), and the corresponding analogues 51, 59, 76, and 77 bearing a simplified farnesyl side chain. The evaluation of these key analogues, along with those derived from their further functionalizations, permitted a scan of the key structural features providing new insights into the role of the substituents found in both the pyridyl core as well as the side chain. A strategic late stage heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain permitted ready access to the analogues in which each half of the molecule could be systematically and divergently modified. The pyridyl cores were assembled enlisting inverse electron demand Diels-Alder reactions of N-sulfonyl-1-azabutadienes, while key elements of side chain syntheses include an anti selective asymmetric aldol to install the C9 and C10 relative and absolute stereochemistry (for natural and ent-1) and a modified Julia olefination for formation of the C5-C6 trans double bond with convergent assemblage of the side chains. 相似文献
389.
Screening combinatorial libraries for inhibition of Paxillin binding to the cytoplasmic tail of the integrin alpha4 provided the first inhibitors of this protein-protein interaction implicated in enhanced rates of cell migration and chronic inflammation. The preparation of substructure analogs of the lead identified features required for activity, those available for modification, and those that may be removed. The most potent lead structure was shown to inhibit alpha(4)beta(1)-mediated human Jurkat T cell migration in a dose-dependent manner, validating the intracellular Paxillin/alpha4 interaction as a useful and unique target for therapeutic intervention. Moreover, the lead structure emerged from a library that was prepared in two formats: (1) a traditional small mixture format composed of 100 mixtures of 10 compounds and (2) a positional scanning library. Their parallel testing provided the rare opportunity to critically compare two approaches. 相似文献
390.
Zvi Drezner 《The Journal of the Operational Research Society》1989,40(12):1137-1144
In this paper we deal with the location of one facility on the surface of the sphere (globe) that minimizes the weighted sum of distances to a given set of demand points on the surface of the sphere. We assume that demand points are randomly generated on the sphere, and so are the weights. We prove that when the number of demand points increases to infinity, then the ratio between the maximum possible value of the objective function and the minimum possible value of the objective function converges to one. We also show that the expected number of demand points that are a local minimum is approximately one when there are a large number of demand points. Some computational experiments are presented. 相似文献