- Synthesis and biological evaluation of curcumin derivatives with water-soluble groups as potential antitumor agents: An in vitro investigation using tumor cell lines
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Three series of curcumin derivatives including phosphorylated, etherified, and esterified products of curcumin were synthesized, and their anti-tumor activities were assessed against human breast cancer MCF-7, hepatocellular carcinoma Hep-G2, and human cervical carcinoma HeLa cells. Compared with curcumin, compounds 3, 8, and 9 exhibited stronger antitumor cell line growth activities against HeLa cells. Compound 12 also showed higher antitumor cell line growth activities on MCF-7 cells than curcumin. Among them, 4-((1E,6E)-7-(4-Hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dienyl)-2-methoxyphenyl dihydrogen phosphate(3) showed the strongest activity with an half maximal inhibitory concentration (IC50) of 6.78 μM against HeLa cells compared with curcumin with an IC50 of 17.67 μM. Stabilities of representatives of the three series were tested in rabbit plasma in vitro, and compounds 3 and 4 slowly released curcumin inplasma. The effect of compound 3 on HeLa cell apoptosis was determined by examining morphological changes by DAPI (4′,6-diamidino-2-phenylindole) staining as well as Annexin V-FITC/Propidium Iodide (PI) double staining and flow cytometry. The results showed that 3 induced cellular apoptosis in a dose-dependent manner. Together our findings show that 3 merits further investigation as a new potential antitumor drug candidate.
- Ding, Luyang,Ma, Shuli,Lou, Hongxiang,Sun, Longru,Ji, Mei
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p. 21501 - 21514
(2016/01/25)
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- Isolation, structure elucidation and total synthesis of lajollamide a from the marine fungus Asteromyces cruciatus
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The marine-derived filamentous fungus Asteromyces cruciatus 763, obtained off the coast of La Jolla, San Diego, USA, yielded the new pentapeptide lajollamide A (1), along with the known compounds regiolone (2), hyalodendrin (3), gliovictin (4), 1N-norgliovicitin (5), and bis-N-norgliovictin (6). The planar structure of lajollamide A (1) was determined by Nuclear Magnetic Resonance (NMR) spectroscopy in combination with mass spectrometry. The absolute configuration of lajollamide A (1) was unambiguously solved by total synthesis which provided three additional diastereomers of 1 and also revealed that an unexpected acid-mediated partial racemization (2:1) of the L-leucine and L-N-Me-leucine residues occurred during the chemical degradation process. The biological activities of the isolated metabolites, in particular their antimicrobial properties, were investigated in a series of assay systems.
- Gulder, Tobias A. M.,Hong, Hanna,Correa, Jhonny,Egereva, Ekaterina,Wiese, Jutta,Imhoff, Johannes F.,Gross, Harald
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p. 2912 - 2935
(2013/02/23)
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- Design and synthesis of Hsp90 inhibitors: Exploring the SAR of Sansalvamide A derivatives
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Utilizing the structure-activity relationship we have developed during the synthesis of the first two generations and mechanism of action studies that point to the interaction of these molecules with the key oncogenic protein Hsp90, we report here the design of 32 new Sansalvamide A derivatives and their synthesis. Our new structures, designed from previously reported potent compounds, were tested for cytotoxicity on the HCT116 colon cancer cell line, and their binding to the biological target was analyzed using computational studies involving blind docking of derivatives using Autodock. Further, we show new evidence that our molecules bind directly to Hsp90 and modulate Hsp90's binding with client proteins. Finally, we demonstrate that we have integrated good ADME properties into a new derivative.
- Sellers, Robert P.,Alexander, Leslie D.,Johnson, Victoria A.,Lin, Chun-Chieh,Savage, Jeremiah,Corral, Ricardo,Moss, Jason,Slugocki, Tim S.,Singh, Erinprit K.,Davis, Melinda R.,Ravula, Suchitra,Spicer, Jamie E.,Oelrich, Jenna L.,Thornquist, Andrea,Pan, Chung-Mao,McAlpine, Shelli R.
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experimental part
p. 6822 - 6856
(2010/10/18)
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- From peptides to their alternating ester-urea analogues: Synthesis and influence of hydrogen bonding motif and stereochemistry on aggregation
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(Chemical Equation Presented) Peptide-mimicking scaffolds with an incorporated ester-urea motif, replacing two adjacent amide residues, were synthesized and their aggregation behavior was studied in dependence of hydrogen bonding sites as well as backbone stereochemistry. Two oligomer series containing either 50% or 100% ester-urea units and either all-(L) or (D)-alt-(L) backbone configuration were prepared via ester and amide couplings, using a divergent/convergent exponential growth strategy. Their aggregation behavior in organic solution was investigated by means of concentration-dependent NMR spectroscopy and compared to the parent peptide series. Interestingly, the naturally occurring peptide scaffold exhibits the largest tendency to associate in combination with the strongest difference in aggregation behavior between all-(L) and (D)-alt-(L) backbone stereochemistry. With increasing incorporation of the ester-urea motif the aggregation strength decreases and become much less dependent on the backbone configuration. The obtained structure-aggregation relationships reveal the importance of the commensurability and multivalency of hydrogen bonding sites as well as conformational restriction for peptide association and should hence aid the design of peptide mimics, such as β -sheet breakers or gelators. 2009 American Chemical Society.
- Hartwig, Sebastian,Schwarz, Jutta,Hecht, Stefan
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supporting information; experimental part
p. 772 - 782
(2010/07/05)
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- Comprehensive study of sansalvamide A derivatives and their structure-activity relationships against drug-resistant colon cancer cell lines
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We report an extensive structure-activity relationship (SAR) of 62 compounds active against two drug-resistant colon cancer cell lines. Our comprehensive evaluation of two generations of compounds utilizes SAR, NMR, and molecular modeling to evaluate the
- Otrubova, Katerina,Lushington, Gerald,Vander Velde, David,McGuire, Kathleen L.,McAlpine, Shelli R.
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p. 530 - 544
(2008/09/18)
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- Synthesis and cytotoxicity of a new class of potent decapeptide macrocycles
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(Chemical Equation Presented) Described are the syntheses of five decapeptides that are C-2-symmetrical derivatives of the natural product pentapeptide sansalvamide A. Derivatives were made using a succinct convergent synthesis. These analogues share no s
- Davis, Melinda R.,Styers, Thomas J.,Rodriguez, Rodrigo A.,Pan, Po-Shen,Vasko, Robert C.,McAlpine, Shelli R.
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p. 177 - 180
(2008/09/19)
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- A templating approach for monodisperse self-assembled organic nanostructures
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The precise structural control is known for self-assembly into closed spherical structures (e.g., micelles), but similar control of open structures is much more challenging. Inspired by natural tobacco mosaic virus, we present the use of a rigid-rod template to control the size of a one-dimensional self-assembly. We believe that this strategy is novel for organic self-assembly and should provide a general approach to controlling size and dimension. Copyright
- Bull, Steve R.,Palmer, Liam C.,Fry, Nathaniel J.,Greenfield, Megan A.,Messmore, Benjamin W.,Meade, Thomas J.,Stupp, Samuel I.
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p. 2742 - 2743
(2008/09/20)
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- Synthesis, crystal structure, and coordination properties of a helical peptide having β-(3-pyridyl)-l-alanine and l-glutamic acid residues
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A novel helical peptide containing β-(3-pyirdyl)-l-alanine (Pal) and l-glutamic acid (Glu) residues has been designed and successfully prepared as a model ligand of metalloenzyme active sites. The helical peptide, Boc-Leu-Aib-Glu-Leu-Leu-Pal-Aib-Leu-OEt (1) (Boc = tert-butoxycarbonyl, Aib = 2-aminoisobutylic acid) yields fine crystals as an acetnitrile solvate. The metal ion binding affinities of 1 were tested for CoCl2 using UV/vis, CD, Raman, and 1H NMR spectroscopies. The non-linear fitting calculations have revealed the 1:1 complex for CoCl2 with the binding constant 3.6 (±0.7) × 102 M-1.
- Oku, Hiroyuki,Kimura, Yosuke,Ohama, Mitsuo,Ueyama, Norikazu,Yamada, Keiichi,Katakai, Ryoichi
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- Synthesis of second-generation Sansalvamide A derivatives: Novel templates as potential antitumor agents
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We report the synthesis of 34 second-generation Sansalvamide A derivatives. San A derivatives have unique anticancer properties and target multiple cancers, including colon, pancreatic, breast, prostate, and melanoma. As novel templates, the derivatives d
- Rodriguez, Rodrigo A.,Pan, Po-Shen,Pan, Chung-Mao,Ravula, Suchitra,Lapera, Stephanie,Singh, Erinprit K.,Styers, Thomas J.,Brown, Joseph D.,Cajica, Julia,Parry, Emily,Otrubova, Katerina,McAlpine, Shelli R.
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p. 1980 - 2002
(2007/10/03)
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- MACROCYCLIC PEPTIDES AND METHODS FOR MAKING AND USING THEM
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The invention provides novel macrocyclic peptides and methods for their preparation. The invention also provides pharmaceutical compositions and methods to treat, prevent or ameliorate a cell proliferative disease or conditions, e.g., a cancer, in a subje
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Page/Page column 42
(2008/06/13)
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- High-yielding macrocyclization conditions used in the synthesis of novel Sansalvamide A derivatives
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Described are the syntheses of nine Sansalvamide A derivatives using new, high-yielding, in situ deprotection-cyclization conditions that are general for this series of macrocycles, 55% average for both steps. This is 10-fold greater than previously repor
- Styers, Thomas J.,Rodriguez, Rodrigo,Pan, Po-Shen,McAlpine, Shelli R.
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p. 515 - 517
(2007/10/03)
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- Synthesis of Sansalvamide A derivatives and their cytotoxicity in the MSS colon cancer cell line HT-29
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We report the synthesis of thirty-six Sansalvamide A derivatives, and their biological activity against colon cancer HT-29 cell line, a microsatellite stable (MSS) colon cancer cell-line. The thirty-six compounds can be divided into three subsets, where t
- Styers, Thomas J.,Kekec, Ahmet,Rodriguez, Rodrigo,Brown, Joseph D.,Cajica, Julia,Pan, Po-Shen,Parry, Emily,Carroll, Chris L.,Medina, Irene,Corral, Ricardo,Lapera, Stephanie,Otrubova, Katerina,Pan, Chung-Mao,McGuire, Kathleen L.,McAlpine, Shelli R.
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p. 5625 - 5631
(2007/10/03)
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- Synthesis and cytotoxicity of novel Sansalvamide A derivatives
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(Chemical Equation Presented) Described are the syntheses of 14 derivatives of the natural product Sansalvamide A, where two are more active against HCT 116 colon cancer cell lines than the natural product. These derivatives were synthesized using a combi
- Carroll, Chris L.,Johnston, Jennifer V. C.,Kekec, Ahmet,Brown, Joseph D.,Parry, Emily,Cajica, Julia,Medina, Irene,Cook, Kristina M.,Corral, Ricardo,Pan, Po-Shen,McAlpine, Shelli R.
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p. 3481 - 3484
(2007/10/03)
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- Antibody recognition of chiral surfaces. Enantiomorphous crystals of leucine-leucine-tyrosine
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Monoclonal antibodies were selected after immunization with crystals of the tripeptide L-leucine-L-leucine-L-tyrosine. They interact with the tripeptide crystals, but do not interact with the tripeptide molecule, with other crystalline surfaces, or with adsorbed protein. The interactions of two antibodies with crystals of L-Leu-L-Leu-L-Tyr and of its enantiomer D-Leu-D-Leu-D-Tyr were characterized in depth. Antibody 48E is stereoselective and enantioselective: it recognizes only the {011} faces of the L-Leu-L-Leu-L-Tyr crystals, and not the enantiomorphous {011} faces of D-Leu-D-Leu-D-Tyr crystals, or any other faces of either crystal. In contrast, antibody 602E is poorly stereoselective and is not enantioselective: it recognizes the crystals of both enantiomers, interacting with a number of different faces of each. The different recognition patterns are explained on the basis of the nature of the interactions and the structure of the interacting surfaces. Understanding this antibody specificity advances our general understanding of surface recognition and transfer of chiral information across biological interfaces.
- Geva, Merav,Frolow, Felix,Eisenstein, Miriam,Addadi, Lia
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p. 696 - 704
(2007/10/03)
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- Liquid phase peptide synthesis of KL-4 pulmonary surfactant
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The invention relates to improved liquid phase processes for the preparation of the 21 residue protein component, (Lys-Leu4)4-Lys, of the pulmonary surfactant KL-4. These process are amenable to large scale synthesis and one process employs a method of saponifying an ester which reduces the inherent racemization of the alpha -carbon.
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- 4-Acetamidophenyl esters and 4-acetamidoanilides of L-arginine,p-guanidino-L-phenylalanine, L-lysine, N2-[D-fructos-3-O-yl and D-glucos-3-O-yl]acetyl-L-lysine as potential acrosin inhibitors
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Syntheses of4-acetamidophenyl esters and 4-acetamidoanilides of L-lysine,p-guanidino-L-phenylalanine,L-leucyl-L-lysine, L-leucyl-L-leucyl-L-lysine, N 2-[(1-2-O-isopropylidene-α-D-glucofuranos-3-O-yl)acetyl]-L- rysine, N 2-[(1,2-O-iso
- Chrusciel, R. Alan,Bauer, Ludwig,Kaminski, JoAnne M.,Zaneveld, Lourens J. D.
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p. 8831 - 8854
(2007/10/02)
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- 15N NMR Spectroscopy. 19 - Spectroscopic Characterization of Cyclodipeptides (2,5-Dioxopiperazines)
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Various cyclodipeptides containing glycine, alanine, leucine, valine, phenylalanine, phenylglycine and sarcosine units were synthesized by cyclization of dipeptide pentachlorophenyl esters.The 13C and natural abundance 15N NMR spectra of these heterocycles were measured in trifluoroacetic acid and compared with the spectra of the corresponding amino acids and polypeptides.The 13C NMR carbonyl signals of all cyclodipeptides show a 1.5-4.0 ppm upfield shift relative to the corresponding polypeptides.The 15N NMR signals show no such consistent relationship.The substituent effects and the neighbouring residue effects observed in the 15NMR spectra of the cyclodipeptides are different from those of polypeptides, while the one bond N-H coupling constant of cis and trans amide groups was almost identical.The nitrogen and the carbonyl signal of the Gly units in cyclo-Gly-Phe show an extraordinary downfield shift, reflecting the interaction of the phenyl group with the 2,5-dioxopiperazine ring.
- Kricheldorf, Hans R.
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