In the past Gary H. Posner has collaborated on articles with Ambler Thompson and Junwon Kim. One of their most recent publications is Mechanism-based design of simple, symmetrical, easily prepared, potent antimalarial endoperoxides. Which was published in journal Tetrahedron Letters.

More information about Gary H. Posner research including statistics on their citations can be found on their Copernicus Academic profile page.

Gary H. Posner's Articles: (22)

Mechanism-based design of simple, symmetrical, easily prepared, potent antimalarial endoperoxides

AbstractMechanism-based design, two-step synthesis, and in vitro antimalarial testing showed thermally stable, crystalline, bicyclic endoperoxides 2a and 2b to be potent antimalarials. Their reduction by FeBr2 proceeds via oxy-radicals and then carbon radicals that undergo β-scission to form an alkene and a high-valent FeO species.

Antimalarially potent, easily prepared, fluorinated endoperoxides

AbstractThree or four step chemical synthesis and in vitro antimalarial testing showed crystalline, thermally stable, bicyclic endoperoxides 3c and 4c to be potent antimalarials, having approximately 15% of the antimalarial activity of the clinically used, complex, sesquiterpene, lactone, natural product artemisinin (qinghaosu, 1). A novel mechanism involving reactive alkylating agents is proposed to account for the ability of endoperoxides 3c and 4c to kill malaria parasites.

[41] Chemiluminescent probes for singlet oxygen in biological reactions

Publisher SummaryThis chapter discusses the chemiluminescent (CL) probes for singlet oxygen in biological reactions. The CL probe t-MVP is specifically designed as an analog for the singlet oxygen-initiated CL of 7, 8-diol. Because of the t-MVP's structural similarity with 7, 8-diol and the broad structural specificities of cytochrome P- 450s, t-MVP is capable of being metabolized by the same enzymes, which catalyzed the production of a chemiluminescent intermediate from 7, 8-diol. This may not be the case in all biological reactions. One of the primary characteristics of enzymatic reactions is substrate specificity, and therefore, it may be necessary to tailor a CL probe specifically for application with a particular enzyme. There are two general scenarios for the production of free singlet oxygen in biological reactions. The first is where O2 is produced through either photosensitization or enzymatic reactions and released free into solution to react randomly with cellular constituents. As there is no substrate specificity, general CL probes should be sufficient to distinguish this case. The second is where O2 or singlet oxygen equivalents are produced and reacted with a bound substrate within the active site of the enzyme, necessitating the use of a CL probe with molecular structure that can be recognized and bound by the enzyme prior to reaction.

α-Fluorination of β-keto sulfoxides

AbstractWe have developed an efficient new procedure for α-fluorination of β-keto sulfoxide enolate anions which are generated in situ via nucleophilic addition reactions to cyclopentenone sulfoxide 7. Perchloryl fluoride is used as the fluorinating agent. Characterization of the product α-fluoro β-keto sulfoxides includes 19F NMR spectroscopy.

Ground state oxygen in synthesis of cyclic peroxides. Part 1: Benzo fused ketals

AbstractA thiol-olefin-cooxygenation (TOCO) radical chain reaction involving ground state molecular oxygen converts 2′-isopropenyl acetophenones directly into cyclic peroxy hemiketal products with three new bonds. Starting with 4-t-butylbenzenethiol, this TOCO process proceeds reproducibly on gram scale in 86% yield. Hemiketal→ketal and sulfide→sulfone transformations finally provide a series of sulfonyl cyclic peroxy ketals. The in vitro antimalarial activities of some of these structurally simple benzo-fused cyclic peroxides are reported.

New A-ring analogs of the hormone 1α,25-dihydroxyvitamin D3: (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D3

AbstractConceptually new, enantiomerically pure bicyclic tetrahydrofuro[1,2-a]-A-ring phosphine oxides (+)-4 and (−)-4 were successfully prepared from methyl 2-pyrone-3-carboxylate and (S)- or (R)-2-(tert-butyldimethylsilyloxy)methyl-2,3-dihydrofuran, respectively. In addition, (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D3 3a and 3b as new A-ring-modified analogs of the natural hormone 1α,25-dihydroxyvitamin D3 were readily synthesized by using Lythgoe-type coupling of the A-ring phosphine oxides (+)-4 and (−)-4 with C,D-ring ketone (+)-5.

Mild, asymmetric Diels-Alder cycloadditions of electronically matched 2-pyrones and vinyl ethers

AbstractSilica gel and a TADDOL-complexed titanium IV Lewis acid are shown to promote mild, practical, asymmetric [4+2]-cycloadditions of electron-poor 2-pyrone-3-carboxylates with electron-rich vinyl ethers to form isolable and useful bicyclic lactone adducts.

Sequential Michael-Michael-Michael-Ring Closure reactions for high-yield, one-pot, 4-component coupling

SummaryAn extraordinarily easy method is presented for connecting four components leading efficiently to functionalized cyclohexenes, cyclohexanols, cyclodecenones, and aromatic systems.

A convenient, one-step, high-yield replacement of an anomeric hydroxyl group by a fluorine atom using dast. Preparation of glycosyl fluorides.

AbstractThe anomeric hydroxyl group of various furanose and pyranose hemiacetals can be replaced by a fluorine atom stereoselectively, conveniently, mildly, and on gram-scale using DAST in THF at room temperature.

Enantiocontrolled synthesis of quaternary carbon centers. 3,3-Disubstituted cyclopentanones. (+)-α-cuparenone.

AbstractAsymmetric synthetic methodology is introduced for preparation of 3,3-disubstituted cyclopentanones, including (+)-α-cuparenone, of high enantiomeric purity.

Lewis acid catalysed rearrangements of unsaturated bicyclic [2.2.n] endoperoxides in the presence of vinyl silanes; access to novel Fenozan BO-7 analogues

AbstractReactions of a series of unsaturated bicyclic [2.2.n] endoperoxides with allyltrimethylsilane in the presence TMSOTf or SnCl4 provides the cis-configured endoperoxides 9a–12. It is proposed that this novel reaction proceeds via attack of the allylsilane on the carbocation derived from heterolytic cleavage of the endoperoxide bridge. The reaction proceeds with a high degree of diastereoselectivity and we propose that the bulky –CH2SiMe3 substituent adopts an equatorial position in a product-like transition state. In contrast to Fenozan B0-7, these compounds displayed poor antimalarial activity versus chloroquine-resistant parasites in vitro.

Highly regiocontrolled and stereocontrolled syntheses of polysubstituted aminocyclohexanes: mild inverse-electron-demand Diels–Alder cycloadditions of electrophilic 2-pyridones

Highlights•Developed procedure for IEDDA cycloadditions under mild conditions and avoiding undesired N- to O-sulfonyl group migration.•These [4+2] cycloadditions very strongly favor regioselective and stereoselective formation of endo bicyclic lactams.•These IEDDA cycloadditions produce highly functionalized pentasubstituted and hexasubstituted cyclohexanes.

Less calcemic Vitamin D analogs enhance creatine kinase specific activity and modulate responsiveness to gonadal steroids in the vasculature

AbstractVitamin D receptors are widely expressed in the cardiovascular system, in which Vitamin D and its metabolites exert a variety of biological activities such as regulation of cellular proliferation and differentiation, cell calcium transients and cell energy metabolism in vitro. The latter is mediated through the control of the brain type creatine kinase specific activity (CK), which serves to provide a readily available reservoir for ATP generation under increased work-load. In the present study we undertook to assess the role of Vitamin D on energy metabolism in the rat heart and aorta in vivo by using CK, which is a key energy metabolizing enzyme and compare Vitamin D depleted and repleted animals.Vascular tissues from female or male Vitamin D-depleted rats showed 61–80% lower CK activity in the aorta (Ao) and left ventricle of the heart (Lv) than control, Vitamin D-replete rats. Moreover, neither estradiol-17β (E2) nor dihydrotestosterone (DHT), which increases CK specific activity in Ao and Lv of intact female or male rats, respectively, were able to stimulate CK in Vitamin D-depleted rats.Treatment of intact female rats for 2 weeks or 2 months with the less-calcemic Vitamin D analogs JKF 1624F2-2 (JKF) or QW 1624F2-2 (QW) (Fig. 1), did not significantly affect CK specific activity. However, after pretreatment with these analogs, there was an up regulation of the E2-induced CK response in Ao and Lv. In intact female rats, all Vitamin D analogs also potentiated the in vivo CK response to the SERMs raloxifene (Ral) and tamoxifen (TAM) in Ao and Lv. However the inhibitory effect of Ral or TAM on E2-induced CK activity was lost after pretreatment with Vitamin D analogs. The non-calcemic analog CB 1093 (CB) induced a significant increase in estradiol receptor α (ERα) protein in both myocardial and aortic tissue from intact and from ovariectomized female rats. Collectively, these results indicate that Vitamin D analogs modulate cell energy homeostasis in vascular tissues through induction of CK and up regulation of the response and sensitivity of CK in vascular tissues to E2 and to SERMs, possibly through via an increase in ERα protein in female derived organs. These results corroborate our previous in vitro studies in human vascular cells and further suggest that the Vitamin D system plays an important physiological role in maintaining normal cell energy reservoir in the vasculature.

Difluoromethyl analogs of the natural hormone 1α,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation

AbstractThree new Vitamin D analogs 3–5 incorporating a –CHF2 group as an –OH surrogate have been prepared. Two of these new analogs (3 and 5) are strongly antiproliferative toward murine keratinocytes and are approximately 50 times less calciuric in vivo than the natural hormone calcitriol. The transcriptional activity of the 25-CHF2 analog 3 is higher than that of the 1-CHF2 analog 4.

The survival times of malaria-infected mice are prolonged more by several new two-carbon-linked artemisinin-derived dimer carbamates than by the trioxane antimalarial drug artemether

AbstractSixteen new artemisinin-derived 2-carbon-linked trioxane dimers were prepared to study chemical structure/antimalarial activity relationships (SAR). Administering a very low single oral dose of only 5 mg/kg of dimer secondary alcohol 6a or 6b plus 15 mg/kg of mefloquine hydrochloride prolonged the lives of Plasmodium berghei-infected mice to an average of 25 days after infection. This ACT chemotherapy result is of high medicinal significance because the antimalarial efficacy of the popular trioxane drug artemether (2) plus mefloquine under the same conditions was significantly lower (only 20 day average survival). NH-aryl carbamate derivatives 7e, 7i, and 7j of 2-carbon-linked dimer alcohol 6b also significantly outperformed artemether (2) in prolonging the survival times (25–27 days) of malaria-infected mice.

2,2-Disubstituted analogues of the natural hormone 1α,25-dihydroxyvitamin D3: chemistry and biology

AbstractSix new 2,2-disubstituted analogues of the natural hormone calcitriol have been prepared. Chemical novelty includes (1) the first example of an inverse-electron-demand Diels–Alder cycloaddition using a pyrone diene and a difluorinated vinyl ether dienophile, leading to difluorinated analogues 7 and (2) a conceptually streamlined approach to dimethylated 19-nor analogues 8. Analogues 7a and 8a are similar to calcitriol in terms of in vitro antiproliferative activity, but they are different from calcitriol in terms of transcriptional activity: difluorinated analogue 7a is 2–3 times more active transcriptionally than calcitriol, whereas dimethylated analogue 8a is 7.5 times less active transcriptionally. Whereas the in vivo calcemic activity of difluorinated analogue 7a is similar to that of calcitriol, dimethylated analogue 8a is considerably less calcemic than calcitriol. Dimethylated analogue 8a strongly suppresses parathyroid hormone (PTH) secretion.

Novel A-ring analogs of the hormone 1α,25-dihydroxyvitamin D3: synthesis and preliminary biological evaluation

AbstractPrepared from a commercial prostaglandin building block, novel vitamin D3 analogs with a contracted five-membered A-ring were designed and synthesized to mimic the A-ring diol structure of the natural hormone 1α,25-dihydroxyvitamin D3. Prepared from commercial 1,4-cyclohexanedione, a structurally simplified analog was designed and synthesized in which a suitably oriented primary allylic hydroxyl group at the C-2 position might be a surrogate for the biologically important 1α-OH in the natural hormone.

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