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Biomedical subjects

Thomas R Hoye

Publications and source records attributed to Thomas R Hoye.

At least 19 recordsLinked to original sources
PubMed2006

Topomimetics of amphipathic beta-sheet and helix-forming bactericidal peptides neutralize lipopolysaccharide endotoxins.

Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophages to produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bind to and neutralize LPS may provide a means to clinically prevent septic shock upon bacterial infection. Previously, we reported the design of antibacterial helix peptide SC4 and beta-sheet-forming betapep peptides that neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralize LPS rested in the common denominator of positively charged amphipathic structure. Here, we describe the design and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface topology, and compositional properties. From a small library of topomimetics, we identified several compounds that neutralize LPS in the 10-8 M range, making them as effective as bactericidal/permeability increasing protein and polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics are shown to be at least partially protective against challenges of LPS from different bacterial species. NMR studies provide mechanistic insight by suggesting the site of molecular interaction between topomimetics and the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions. This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.

Animals↗
PubMed2006

Silylative Dieckmann-like cyclizations of ester-imides (and diesters).

[Structure: see text] Trialkylsilyl triflates effect cyclization of ester-imides such as 2 to produce adducts such as 4a. Trapping of the in situ generated, nucleophilic ketene acetal (cf. 5a) is a key aspect of the transformation. A range of substrates amenable to this operationally simple reaction is reported. In many instances the levels of diastereoselectivity are very high. Mechanistic points are inferred from spectroscopic observations.

Cyclization↗
PubMed2006

Sequencing of three-component olefin metatheses: total synthesis of either (+)-gigantecin or (+)-14-deoxy-9-oxygigantecin.

[Structure: see text] An efficient, flexible, and highly convergent strategy for accessing skipped bis-THF containing Annonaceous acetogenins is demonstrated by the synthesis of each of (+)-gigantecin (1) and its constitutional isomer (+)-14-deoxy-9-oxygigantecin (11). The skeleton of each compound is produced, at will, from the same precursors via a three-component ring-closing/cross-metathesis sequence that differs only in the ordering of the RCM vs CM events. Another notable aspect is the use of in situ epoxide-closing and -opening of iodohydrins with dimethylsulfonium methylide to provide inverted allylic alcohols.

Alkenes↗
PubMed2006

Design of nonpeptidic topomimetics of antiangiogenic proteins with antitumor activities.

The inhibition of angiogenesis is a promising avenue for cancer treatment. Although some angiostatic compounds are in the process of development and testing, these often prove ineffective in vivo or have unwanted side effects. We have designed, synthesized, and evaluated a small library of nonpeptidic, calixarene-based protein surface topomimetics that display chemical substituents to approximate the molecular dimensions and amphipathic features (hydrophobic and positively charged residues) of the antiangiogenic peptide anginex, which, like many antiangiogenic proteins, consists primarily of an antiparallel beta-sheet structure as the functional unit. Two of the topomimetics (0118 and 1097) were potent angiogenesis inhibitors in vitro, as determined by endothelial cell proliferation, migration, and chick embryo chorioallantoic membrane assays. Moreover, both compounds were highly effective at inhibiting tumor angiogenesis and growth in two mouse models (MA148 human ovarian carcinoma and B16 murine melanoma). Our results demonstrate the feasibility of designing nonpeptidic protein surface topomimetics as novel pharmaceutical agents for clinical intervention against cancer through angiostatic or other mechanisms.

Angiogenesis Inhibitors↗
PubMed2006

Comparative Diels-Alder reactivities within a family of valence bond isomers: a biomimetic total synthesis of (+/-)-UCS1025A.

A synthesis of the structurally fascinating fungal metabolite UCS1025A (1) was accomplished. It features a likely biomimetic approach to the octalin subunit via an intramolecular Diels-Alder (IMDA) reaction of a putative triene precursor (2), preceded by an efficient construction of the bisheteratriquinane subunit within that compound. Specifically, an intramolecular silyl triflate-induced cyclization of an in situ-generated silyl ketene acetal onto an imide carbonyl group (e.g., 7 to 8) was developed. The IMDA relative reactivities of a family of valence bond isomers, each differing in the precise nature of the dienophilic subunit, were determined. Under biologically relevant conditions (D2O, pH 7.2 buffer, ca. 25 degrees C), triene 2, via its lactone ring-opened congener, underwent very fast (t1/2 = 10 min) conversion to the ring-opened forms of 1 (i.e., 5a) and the tetraepimeric, alternative endo-adduct, 3 [i.e., (tetraepi)-5a].

Acremonium↗
PubMed2005

Mixture of new sulfated steroids functions as a migratory pheromone in the sea lamprey.

The sea lamprey is an ancient, parasitic fish that invaded the Great Lakes a century ago, where it triggered the collapse of many fisheries. Like many fishes, this species relies on chemical cues to mediate key aspects of its life, including migration and reproduction. Here we report the discovery of a multicomponent steroidal pheromone that is released by stream-dwelling larval lamprey and guides adults to spawning streams. We isolated three compounds with pheromonal activity (in submilligram quantities from 8,000 l of larval holding water) and deduced their structures. The most important compound contains an unprecedented 1-(3-aminopropyl)pyrrolidin-2-one subunit and is related to squalamine, an antibiotic produced by sharks. We verified its structure by chemical synthesis; it attracts adult lamprey at very low (subpicomolar) concentrations. The second component is another new sulfated steroid and the third is petromyzonol sulfate, a known lamprey-specific bile acid derivative. This mixture is the first migratory pheromone identified in a vertebrate and is being investigated for use in lamprey control.

Animal Migration↗
PubMed2005

Divergent kinetic control of classical versus ozonolytic lactonization: mechanism-based diastereoselection.

A strategy has been developed in which mechanistically distinct lactonization reactions are used to prepare diastereomeric delta-lactones relevant to the C1-C9 fragment of (+)-peloruside A. Depending upon which of two reaction types is used, the central (C5) hydroxyl group can be directed to differentiate the C1 versus C9 termini of pseudosymmetric substrates to provide diastereomeric lactones. Thus, the 5-hydroxy-1,9-diester substrate 1 (an azelaic ester) cyclizes under classical (acid- or base-catalyzed) lactonization conditions to give a predominance of one diastereomer, whereas the 5-hydroxy-1,10-diene congener 2 provides the opposite sense of diastereoselectivity when subjected to ozonolytic lactonization (O3, MeOH, NaOH, at -78 degrees C). Thus, this under-utilized oxidative transformation is mechanistically orthogonal to the classical reaction.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2005

Reaction titration: a convenient method for titering reactive hydride agents (Red-Al, LiAlH4, DIBALH, L-Selectride, NaH, and KH) by No-D NMR spectroscopy.

The concentration of reactive metal hydride (Met-H) reducing agents can be determined (in < or = 20 min) using No-D NMR spectroscopy. The method involves (i) reacting Met-H with an excess of p-methoxybenzaldehyde, (ii) quenching with excess acetic acid, (iii) recording the No-D NMR spectrum of this homogeneous mixture, and (iv) deducing the concentration of Met-H from the % conversion (as measured by integration). By a conceptually related method, the titer of the basic alkali metal hydrides KH and NaH can also be determined.

Hydrogen↗
PubMed2005

Alkyne haloallylation [with Pd(II)] as a core strategy for macrocycle synthesis: a total synthesis of (-)-haterumalide NA/(-)-oocydin A.

The rarely used haloallylation reaction, first described by Kaneda and Teranishi in 1974, employs a Pd(II) catalyst to join an alkyne with an allylic halide to produce a 1-halo-1,4-diene subunit. It is shown here that functionalized and tertiary allylic chlorides perform well as substrates in this reaction under the action of PdCl2(PhCN)2 in THF solution. When the alkyne is added slowly to the reaction mixture, the two reactants can be used in a nearly equimolar ratio. This fact means (i) that reasonably complex pairs of alkyne and allylic halide substrates are tolerated and, therefore, (ii) that an intramolecular version of the reaction is suitable as a core strategy for complex molecule construction. The latter is demonstrated in the macrocyclization of 2b to 17b, which is the central step in the total synthesis of (-)-haterumalide NA/(-)-oocydin A (1) that is reported. The final key to the completion of the synthesis was the choice of the acid-labile PMB ester of 1 as the penultimate intermediate.

Alkynes↗
PubMed2005

No-D NMR study of the pathway for n-BuLi "oxidation" of 1,5-cyclooctadiene to dilithium cyclooctatetraene dianion [Li2COT2-].

[Reaction: see text] The transformation of 1,5-cyclooctadiene (1) into cyclooctatetraene (3) by way of dianion 2 is an interesting reaction of considerable preparative value. The mechanism was initially suggested to involve lithium hydride loss from 4a/4b, followed by two deprotonations to produce 2. This No-D 1H NMR study indicates the long-term stability of 4a/4b (in the absence of additional n-BuLi) and suggests a different mechanistic sequence, in which 4a/4b is deprotonated a second time prior to LiH ejection.

Alkadienes↗
PubMed2004

Relay ring-closing metathesis (RRCM): a strategy for directing metal movement throughout olefin metathesis sequences.

The title concept involves the use of structurally modified RCM substrates that contain extender arms, terminating in a remote reactive alkene. Initiation of an RCM sequence at that reactive alkene is followed by rapid intramolecular relay of the metal center to an initially less reactive alkene in the parent substrate. This permits one to control the relative timing (or direction) of a metathesis sequence. For example, one can reverse the inherent tendency of an unsymmetrical alpha,omega-diene substrate to close, say, left-to-right, to that of right-to-left. Four distinct types of application of the RRCM concept are demonstrated. Among other things, they show the preparation of tetrasubstituted electron-deficient alkenes using G1 [(Cy3P)2(Cl2)Ru=CHPh], complementary control of directionality (endedness), auxiliary benefits (enzyme specificity) from the incorporation of additional steric bulk, the activation of otherwise ineffective substrates for RCM closure, the use of unorthodox alkenes as initiation sites for ring closure, and control of product olefin geometry.

Alkenes↗
PubMed2004

No-D NMR (no-deuterium proton NMR) spectroscopy: a simple yet powerful method for analyzing reaction and reagent solutions.

[reaction: see text] The title technique is a convenient and powerful method for directly monitoring or assaying any reaction mixture or reagent solution. Examples of some common processes (Fischer esterification, lithiation, butyllithium/THF compatibility, olefin metathesis, and a quantification assay), each interrogated in its native solvent, are presented. The spectral data are easy to acquire, and the information content makes a compelling case for routine use of No-D NMR spectroscopy.

Deuterium↗
PubMed2003

Design of a partial peptide mimetic of anginex with antiangiogenic and anticancer activity.

Based on structure-activity relationships of the angiostatic beta-sheet-forming peptide anginex, we have designed a mimetic, 6DBF7, which inhibits angiogenesis and tumor growth in mice. 6DBF7 is composed of a beta-sheet-inducing dibenzofuran (DBF)-turn mimetic and two short key amino acid sequences from anginex. This novel antiangiogenic molecule is more effective in vivo than parent anginex. In a mouse xenograft model for ovarian carcinoma, 6DBF7 is observed to reduce tumor growth by up to 80%. It is suggested that the activity is based on antiangiogenesis, because in vitro tube formation is inhibited, and because treatment of tumor-bearing mice led to a significant reduction in microvessel density within the tumor. This partial peptide mimetic is the first endothelial cell-specific molecule designed as a substitute for an angiostatic inhibitory peptide.

Alanine↗
PubMed2003

Macrolactonization via Ti(IV)-mediated epoxy-acid coupling: a total synthesis of (-)-dactylolide [and zampanolide].

A total synthesis of dactylolide (1) is described. The key feature involves the Ti(IV)-mediated coupling of structurally complex "Sharpless epoxides" and carboxylic acids in either an intramolecular (macrolactonization) or an intermolecular mode. Other notable aspects include a proton-catalyzed, cis-selective construction of the 4-methylenetetrahydropyran ring; a selective oxidation of an allylic alcohol in the presence of a 1,2-diol by an oxoammonium ion; an efficient ring-closing metathesis reaction of an in situ (bis-TMS) protected alpha,omega-diene-vic-diol; and an aluminum-mediated aza-aldol reaction of a primary amide to 1 to construct the acyclic carbinolamide in zampanolide.

Animals↗
PubMed2002

Toward computing relative configurations: 16-epi-latrunculin B, a new stereoisomer of the actin polymerization inhibitor latrunculin B.

The title compound, 16-epi-latrunculin B (3), has been isolated from the sponge Negombata magnifica collected from the Red Sea near Hurghada, Egypt. This new natural product was determined to be an epimer of latrunculin B (1), which was found in the same sponge collection. The structure of 3 was initially deduced from proton and carbon NMR chemical shift trends and proton-proton nuclear Overhauser effect experiments. The cytotoxicity (murine tumor and normal cell lines) and antiviral (HSV-1) properties of 3 and 1 were determined. A computational study applicable to this class of stereochemical problems was then investigated. Specifically, the complete set of vicinal and allylic coupling constants was calculated for each of the four diastereomers whose configurations differed at C(8) and C(16). These computed J's were then compared with the experimental J values (28 in number) determined for 1 and 3. This analysis resulted in the same assignment of relative configuration for compound 3 reached using the more classical methods. The validity of the method is established by the fact that the 28 computed coupling constants for (known) 1 and (newly determined) 3 varied from the experimental J values with an average of just 0.57 and 0.53 Hz, respectively. This strategy represents a general, powerful, and readily adoptable tool for determining the relative configuration of complex molecules.

Actins↗
PubMed2002

A method for easily determining coupling constant values: an addendum to "A practical guide to first-order multiplet analysis in 1H NMR spectroscopy".

A systematic procedure to decipher first-order 1H NMR multiplets is described. This method is a very practical tool for extracting coupling constant values. It requires only that one (a) learn to identify each of the 2n (n = number of spin 1/2 nuclei to which the proton is coupled) "units of intensity" of a multiplet and (b) then apply a clearly delineated sequence of iterative steps that allows the J's to be assigned in order (from smallest to largest). The approach is even easier to use than one described previously (J. Org. Chem. 1994, 59, 4096-4103).

Algorithms↗