Mark A Lipton

Purdue University, West Lafayette, Indiana, United States

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Publications (37)123.75 Total impact

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    ABSTRACT: Resveratrol (3,5,4'-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation.
    Bioorganic & medicinal chemistry 07/2013; · 2.82 Impact Factor
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    ABSTRACT: A negatively charged biradical intermediate was successfully generated in the gas phase via cyclization of the deprotonated bicyclo[8.3.0]trideca-12-ene-2,7-diyn-1-one precursor. The inherent negative charge of this biradical allows its characterization via collision-activated dissociation and reactions with a variety of neutral substrates in an FT-ICR mass spectrometer. Although the biradical is unreactive toward reagents that usually react rapidly with positively charged biradicals, such as dimethyl disulfide, it reacts with the halogen-containing substrates carbon tetrachloride, carbon tetrabromide, and bromotrichloromethane via bromine or chlorine atom abstraction, which supports its biradical structure. The results presented in this study indicate that cyclizations commonly used in solution to form biradical intermediates from enediyne compounds may also occur in the gas phase.
    Journal of the American Society for Mass Spectrometry 03/2013; · 3.59 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 32(46).
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    ABSTRACT: All 4 diastereomeric possibilities for the 2,3-dihydroxy-2,6,8-trimethyldeca-(4Z,6E)-dienoic acid (Dhtda) residue, found in the cyclic depsipeptide natural products papuamides A-D and mirabamides A-D, were stereoselectively synthesized using a Z-selective Wittig reaction of both enantiomers of 2,4-dimethylhex-2-enyl-triphenylphosphonium bromide with all four diastereoisomers of ethyl-3-formyl-2-methyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate. To elucidate the configuration of Dhtda, the (1)H- and (13)C-NMR spectra of the synthetic isomers were compared to those of the natural residue. On the basis of that comparison, it is suggested that the likely configuration of the diastereomer present in Dhtda residue is either (2R,3S,8S) or (2S,3R,8S) in the papuamides and mirabimides.
    Tetrahedron Asymmetry 11/2008; 19(2):2546-2554. · 2.12 Impact Factor
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    ABSTRACT: Resveratrol (4,3',5'-trihydroxystilbene) is a naturally occurring antioxidant that inhibits cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and the transcription factor NF-kappaB. A 78-membered library of resveratrol analogues in which the substituents on the two aryl rings and alkene were varied was synthesized using a solid-phase Wittig olefination reaction. The library contains inhibitors against all three proteins that were more potent than resveratrol itself. Preliminary structure-activity relationships were also obtained from these data that permitted the derivation of pharmacophore models for each of the three targets.
    Bioorganic & medicinal chemistry 06/2008; 17(3):1044-54. · 2.82 Impact Factor
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    ABSTRACT: Resonant two-photon ionization (R2PI), resonant ion-dip infrared (RIDIR), and UV-UV hole-burning spectroscopies have been employed to obtain conformation-specific infrared and ultraviolet spectra under supersonic expansion conditions for O-(2-acetamidoethyl)-N-acetyltyramine (OANAT), a doubly substituted aromatic in which amide-containing alkyl and alkoxy side chains are located in para positions on a phenyl ring. For comparison, three single-chain analogs were also studied: (i) N-phenethyl-acetamide (NPEA), (ii) N-(p-methoxyphenethyl-acetamide) (NMPEA), and (iii) N-(2-phenoxyethyl)-acetamide (NPOEA). Six conformations of OANAT have been resolved, with S(0)-S(1) origins ranging from 34,536 to 35,711 cm(-1), denoted A-F, respectively. RIDIR spectra show that conformers A-C each possess an intense, broadened amide NH stretch fundamental shifted below 3400 cm(-1), indicative of the presence of an interchain H bond, while conformers D-F have both amide NH stretch fundamentals in the 3480-3495 cm(-1) region, consistent with independent-chain structures with two free NH groups. NPEA has a single conformer with S(0)-S(1) origin at 37,618 cm(-1). NMPEA has three conformers, two that dominate the R2P1 spectrum, with origin transitions between 35,580 and 35,632 cm(-1). Four conformations, one dominate and three minor, of NPOEA have been resolved with origins between 35,654 and 36,423 cm(-1). To aid the making of conformational assignments, the geometries of low-lying structures of all four molecules have been optimized and the associated harmonic vibrational frequencies calculated using density functional theory (DFT) and RIMP2 methods. The S(0)-S(1) adiabatic excitation energies have been calculated using the RICC2 method and vertical excitation energies using single-point time-dependent DFT. The sensitivity of the S(0)-S(1) energy separation in OANAT and NPOEA primarily arises from different orientations of the chain attached to the phenoxy group. Using the results of the single-chain analogs, tentative assignments have been made for the observed conformers of OANAT. The RIMP2 calculations predict that interchain H-bonded conformers of OANAT are 25-30 kJ/mol more stable than the extended-chain structures. However, the free energies of the interchain H-bonded and extended structures calculated at the preexpansion temperature (450 K) differ by less than 10 kJ/mol, and the number of extended structures far outweighs the number of H-bonded conformers. This entropy-driven effect explains the presence of the independent-chain conformers in the expansion, and cautions future studies that rely solely on relative energies of conformers in considering possible assignments.
    The Journal of Chemical Physics 01/2008; 127(23):234315. · 3.12 Impact Factor
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    ABSTRACT: The desmethoxy analogue of the cytotoxic, cyclic depsipeptide callipeltin B was synthesized to evaluate the role of its beta-MeOTyr residue. The IC(50) of desmethoxycallipeltin B, in which the beta-MeOTyr residue was replaced by d-Tyr, against HeLa cells was found to be 128+/-10 microM in an MTT assay, compared to 98+/-5 microM for the natural product itself. The roughly comparable cytotoxicities suggest that the cytotoxicity of callipeltin B does not arise through the formation of a quinone methide intermediate.
    Bioorganic & Medicinal Chemistry Letters 10/2007; 17(18):5136-8. · 2.34 Impact Factor
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    David C Cranfill, Mark A Lipton
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    ABSTRACT: The nonproteinogenic amino acid (2R,3R)-beta-methoxytyrosine, a constituent of several cyclic depsipeptide natural products, was synthesized in protected form (8) from a readily available cinnamate ester in four steps and 62% overall yield with a greater than 28:1 er and 19:1 dr. This method provides a highly efficient, enantio- and diastereoselective synthesis of an important amino acid.
    Organic Letters 09/2007; 9(18):3511-3. · 6.14 Impact Factor
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    ABSTRACT: 1,1-Dimethylallyl (DMA) esters of various N-protected amino acids have been synthesized using prenyldimethylsulfonium tetrafluroborate, a reagent that can be readily made and stored, in conjunction with catalytic CuBr. These reactions were complete within several hours and afforded DMA esters in high yields. As has been previously shown in our group, DMA esters represent a palladium-labile proctecting group for carboxylic acids that resists nucleophilic attack as a tert-butyl ester would.
    The Journal of Organic Chemistry 01/2007; 71(25):9517-8. · 4.56 Impact Factor
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    ABSTRACT: The cytotoxic, cyclic heptadepsipeptide, natural product callipeltin B was synthesized on a solid-phase support in 15% overall yield. Comparison of the 1H NMR spectra of three synthetic isomers with those of callipeltin B confirmed the configurational reassignment of its threonine residues as d-allothreonine and the assignment of the configuration of its beta-methoxytyrosine residue as (2R,3R).
    Journal of the American Chemical Society 01/2007; 128(48):15392-3. · 10.68 Impact Factor
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    ABSTRACT: A series of acetoxy-substituted enyne-allenes, fused to cyclopentene and cyclohexene ring systems, were synthesized and treated with methyllithium to generate the corresponding enolates. It was found that whereas the cyclohexannulated examples underwent either C2-C7 (Myers-Saito) cycloaromatization or C2-C6 (Schmittel) cyclization depending on their terminal subsituents, the cyclopentannulated examples either failed to cyclize altogether or underwent C2-C7 cyclization. Both of these results lie in contrast to the behavior of their benzannulated analogues, which underwent exclusive C2-C6 cyclization independent of substituents. These findings are rationalized on the basis of both ring strain effects and the steric encumbrance of the terminal alkynyl and allenyl subsituents.
    The Journal of Organic Chemistry 11/2006; 71(22):8372-7. · 4.56 Impact Factor
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    ABSTRACT: Two possible isomers of the natural product callipeltin E (1, 5) were synthesized by using an Fmoc-based solid-phase strategy in 7 steps, in 20% and 26% overall yields, respectively. The (1)H NMR spectrum of synthetic 5 correlated closely with that of the natural product, whereas that of 1 did not, providing confirmation of the configurational reassignment of the N-terminal residue of callipeltin E as D-allothreonine. This result strongly implies that the corresponding residue in the closely related cyclic depsipeptides callipeltins A and B should also be considered a D-allothreonine residue.
    The Journal of Organic Chemistry 09/2006; 71(17):6351-6. · 4.56 Impact Factor
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    ABSTRACT: [structure: see text] The lipopeptide callipeltin D (1) was synthesized using an Fmoc-based solid-phase strategy in seven steps and 35% overall yield. The 1H NMR of synthetic 1 correlated closely with that of the natural product, confirming the configurational assignment of the novel amino acid constituent (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid.
    Organic Letters 01/2006; 7(26):5881-3. · 6.14 Impact Factor
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    ABSTRACT: The absolute stereochemistry of the three unresolved structural components in neamphamide A (1) was determined to be (R)-beta-methoxy-L-tyrosine, (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid, and (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid. Stereochemical assignments were made by chemical degradation of 1, derivatization of the resulting products, and then spectroscopic and chromatographic comparison of the derivatives with synthetically prepared standards. Using the same analytical protocol developed for 1, the beta-methoxytyrosine residue in papuamide B (2) was found to be (R)-beta-methoxy-D-tyrosine. This represents a rare example of divergent stereochemistry in an unusual amino acid residue that is present in two closely related classes of peptides.
    The Journal of Organic Chemistry 09/2005; 70(17):6842-7. · 4.56 Impact Factor
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    Selçuk Calimsiz, Mark A Lipton
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    ABSTRACT: N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine (6) was synthesized from tert-butyl N-Boc-(2S,3S,4R)-dimethylpyroglutamate (13). This synthesis involved selective deprotection of a Boc group from a lactam nitrogen in the presence of a tert-butyl ester, Fmoc protection of the lactam, and a lanthanide-catalyzed transamidation reaction of the Fmoc-protected lactam, using ammonia and dimethylaluminum chloride. The scope of Lewis acid-catalyzed transamidation of acylated lactams was explored through the variation of lanthanide, lactam, acyl group, amine, and aluminum reagent. The reactivity of various metal triflates was found to vary in the following qualitative order: Yb approximately Sc > Er approximately Eu approximately Sm > Ce approximately Ag(I) > Cu(II) approximately Zn. Intriguingly, catalysis was only observed when ammonia was the nitrogen nucleophile; addition of other amidoaluminum complexes to acyl lactams was found to be insensitive to the addition of lanthanides.
    The Journal of Organic Chemistry 09/2005; 70(16):6218-21. · 4.56 Impact Factor
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    ABSTRACT: The C2-C6 (Schmittel)/ene cyclization of enyne-allenes is studied by a combination of kinetic isotope effects, theoretical calculations, and dynamics trajectories. For the cyclization of allenol acetate 9, the isotope effect (k(CH3)/k(CD3) is approximately 1.43. The isotope effect is interpreted in terms of a highly asynchronous transition state near the concerted/stepwise boundary. This is supported by density functional theory calculations that locate a highly asynchronous transition structure for the concerted ene reaction. However, calculations of both the experimental system and a model reaction were unable to locate a transition structure for formation of the diradical intermediate of a stepwise mechanism. The stepwise mechanism and the asynchronous concerted mechanism start out geometrically similar, and the two pathways appear to have merged as far as the initial transition structure. For the model reaction, quasiclassical direct dynamics trajectories emanating from the initial transition structure afforded the diradical intermediate in 29 out of 101 trajectories. A large portion of the remaining trajectories completes hydrogen transfer before carbon-carbon bond formation, despite the advanced carbon-carbon bond formation in the asynchronous transition structure. Overall, the single minimum-energy path from starting material to product is inadequate to describe the reaction, and a consideration of dynamic effects is necessary to understand the mechanism. The implications of these observations toward questions of concert in other reactions are discussed.
    Journal of the American Chemical Society 07/2005; 127(25):9216-23. · 10.68 Impact Factor
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    Minoo Sedighi, Mark A Lipton
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    ABSTRACT: [reaction: see text] Carboxylic acids were converted in high yield to their 1,1-dimethylallyl (DMA) esters in two steps. Palladium-catalyzed deprotection of DMA esters was shown to be compatible with tert-butyl, benzyl, and Fmoc protecting groups, and Fmoc deprotection could be carried out selectively in the presence of DMA esters. DMA esters were also shown to be resistant to nucleophilic attack, suggesting that they will serve as alternatives to tert-butyl esters when acidic deprotection conditions need to be avoided.
    Organic Letters 05/2005; 7(8):1473-5. · 6.14 Impact Factor
  • B S Barth, A C Myers, M A Lipton
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    ABSTRACT: A novel 'ureidopeptide' substrate analog inhibitor of the HIV-1 protease, created by substitution of a urea for the scissile amide bond of a hexapeptide substrate, was synthesized and tested for inhibition of HIV-1 protease. This inhibitor was designed as a stereochemical mutant of an earlier ureidopeptide inhibitor in which the P1' phenylalanine residue was changed from an l-isomer to a d-isomer. This was done in an attempt to increase binding to the enzyme by compensating for a lengthening of the peptide backbone. The inhibitor was synthesized from two protected tripeptide precursors using an oxidative Hoffmann rearrangement of a C-terminal peptide amide. The new inhibitor was found to inhibit HIV-1 protease with an observed IC(50) of 47 mum.
    European Journal of Allergy and Clinical Immunology 04/2005; 65(3):352-4. · 1.30 Impact Factor
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    ABSTRACT: A new procedure that employs a one-pot, oxidative Hofmann rearrangement to incorporate a urea linkage into peptide backbones is detailed herein. This methodology was used to replace the scissile peptide bonds of [Leu5]enkephalin and a hexapeptide HIV-1 protease substrate. The [Leu5]enkephalin analogue was found to inhibit cleavage of hippurylhistidylleucine (HHL) by porcine kidney angiotensin-converting enzyme (PK-ACE) with a 0.88 mM IC50 value, comparable to the Michaelis constant of [Leu5]enkephalin with the same enzyme. The HIV-1 protease substrate analogue was shown to inhibit HIV-1 protease with an IC50=34 microM.
    Bioorganic & Medicinal Chemistry Letters 11/2004; 14(20):5219-22. · 2.34 Impact Factor
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    ABSTRACT: Unusual amino acids such as beta-methoxytyrosine (beta-MeOTyr), allo-threonine (allo-Thr) and allo-isoleucine (allo-Ile) were derivatized with N-alpha-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (FDAA), 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC), (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester (S-NIFE), or o-phthalaldehyde/isobutyryl-L-cysteine (OPA-IBLC), and then separated via reversed-phase high-performance chromatography followed by UV and electrospray ionization mass spectrometry detection. FDAA generally showed the highest enantioselectivity but the lowest sensitivity among the chiral derivatizing agents (CDAs) investigated. The detection limit of FDAA-derivatized amino acids was in the low picomolar range. Although the enantioselectivity of FDAA derivatives was generally quite high, its selectivity among beta-MeOTyr isomers was poor. The best separation of beta-MeOTyr stereoisomers was achieved with S-NIFE. Due to the complex relationships between the investigated CDAs, stereochemical analyses using a combination of two or more of the CDAs gave the most reliable results for a given separation problem. In general, the methods described are selective and reliable, and are being applied to the analysis of unusual amino acids as they occur in marine peptides.
    Journal of Chromatography A 06/2004; 1035(2):211-9. · 4.61 Impact Factor