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PubMed1979

Formation of aminosuccinyl peptides during acidolytic deprotection followed by their transformation to piperazine-2,5-dione derivatives in neutral media.

Prolonged acidic treatment of Boc-Leu-Asp(OBut)-Phe-NH2 with 4N HCl in acetic acid resulted in H-Leu-Asc-Phe-NH2 . HCl(Asc, aminosuccinyl), which transformed partially to cyclo[Leu-Asp(Phe-NH2)] during its purification by column chromatography on silica gel with a mixture of ethyl acetate/pyridine/acetic acid/water = 60:20:6:11, i.e. in neutral medium. Examination of the imide formation was extended to different reaction conditions (no imide derivative was detected in trifluoroacetic acid), to several protected derivatives of L-aspartyl-L-phenylalaninamide and to tripeptides containing an aspartyl residue in the middle position. It was clearly demonstrated that in strongly acidic media the imide derivatives are directly formed from the aspartyl peptides containing a free beta-carboxyl group. The influence of the C-terminal residue was greater than the N-terminal on both the rate of formation of the imide and its further transformation to piperazine-2,5-dione derivative. In aqueous ethanol the X-Asc-Y-NH2 (X, Pro, Leu; Y, Gly, Ala, Val, Phg, Phe) containing N-terminal proline are more readily transformed to piperazine-2,5-dione derivatives, but compared to simple proline dipeptides the rate of this transformation is relatively slow because of the crowdedness of the tricyclic transitional state.

Amino Acid Sequence↗
PubMed2002

Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.

Thalidomide (Thal) achieves responses even in the setting of refractory multiple myeloma (MM). Although increased angiogenesis in MM bone marrow and the antiangiogenic effect of Thal formed the empiric basis for its use in MM, we have shown that Thal and its immunomodulatory analogs (IMiDs) directly induce apoptosis or growth arrest of MM cells, alter adhesion of MM cells to bone marrow stromal cells, inhibit the production of cytokines (interleukin-6 and vascular endothelial growth factor) in bone marrow, and stimulate natural killer cell anti-MM immunity. In the present study, we demonstrate that the IMiDs trigger activation of caspase-8, enhance MM cell sensitivity to Fas-induced apoptosis, and down-regulate nuclear factor (NF)-kappa B activity as well as expression of cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein. IMiDs also block the stimulatory effect of insulinlike growth factor-1 on NF-kappa B activity and potentiate the activity of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), dexamethasone, and proteasome inhibitor (PS-341) therapy. These studies both delineate the mechanism of action of IMiDs against MM cells in vitro and form the basis for clinical trials of these agents, alone and coupled with conventional and other novel therapies, to improve outcome in MM.

Adjuvants, Immunologic↗
PubMed2005

Properties of thalidomide and its analogues: implications for anticancer therapy.

Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.

Angiogenesis Inhibitors↗
PubMed1990

Identification of the aspartimide structure in a previously-reported peptide.

The octapeptide Leu-Ser-Arg-Leu-Phe-Asp-Asn-Ala (hGH 6-13) has been reported to show insulin-potentiating properties, and its synthesis by conventional solid-phase synthesis was previously described. It is now shown that peptide synthesized with diisopropylethylamine or N-methylmorpholine as neutralizing base in each cycle does have the above structure. When triethylamine was used as neutralizing base however, the Asp residue was converted to its imide, the presence of which has been demonstrated by means of infrared, 1H-NMR and fast-atom bombardment mass spectra, and by reactivity studies, electrophoresis at several pH values, and enzymic hydrolysis. Only the imide form of the peptide possesses the previously reported biological properties. A study of imide formation from protected and unprotected peptides showed that cyclization occurred during a wide range of acid and base treatments, but 10% triethylamine in CH2Cl2 was most effective, producing over 40% of imide in 90 min. The results of the investigation are compared with others in the literature, including those for the peptide hormone secretin.

Amino Acid Sequence↗
PubMed2005

Immunomodulatory drugs in multiple myeloma.

Immunomodulatory drugs (IMiDs) are thalidomide analogues that retain the direct anticancer cytotoxic and immunological activity of their parent compound, but with a different toxicity profile. In vitro studies show that IMiDs have a more potent antitumour effect than thalidomide on multiple myeloma (MM) cell lines. This activity is mediated by multiple mechanisms: direct antiproliferative effect; inhibition of angiogenesis due to reduced IL-6 and vascular endothelial growth factor secretion; inhibition of cytokines production, especially TNF-alpha; and stimulation of T-cell activity. Two IMiDs, CC-5013 and CC-4047, have been tested in clinical trials in MM patients with progressive or refractory disease, and one trial is ongoing in newly diagnosed MM patients. Observed toxicities include thrombocytopoenia, neutropoenia and cardiovascular events, but no significant neurotoxicity has been reported. Partial responses (> or = 50% reduction in M-protein) ranged from 20 to 71% in different studies depending on the pretreatment status of the patients. The combination of IMiDs with dexamethasone may be beneficial.

Animals↗
PubMed2000

Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy.

Although thalidomide (Thal) was initially used to treat multiple myeloma (MM) because of its known antiangiogenic effects, the mechanism of its anti-MM activity is unclear. These studies demonstrate clinical activity of Thal against MM that is refractory to conventional therapy and delineate mechanisms of anti-tumor activity of Thal and its potent analogs (immunomodulatory drugs [IMiDs]). Importantly, these agents act directly, by inducing apoptosis or G1 growth arrest, in MM cell lines and in patient MM cells that are resistant to melphalan, doxorubicin, and dexamethasone (Dex). Moreover, Thal and the IMiDs enhance the anti-MM activity of Dex and, conversely, are inhibited by interleukin 6. As for Dex, apoptotic signaling triggered by Thal and the IMiDs is associated with activation of related adhesion focal tyrosine kinase. These studies establish the framework for the development and testing of Thal and the IMiDs in a new treatment paradigm to target both the tumor cell and the microenvironment, overcome classical drug resistance, and achieve improved outcome in this presently incurable disease.

Antineoplastic Agents↗
PubMed1985

Behavioural pharmacology of imidazole, a potential antidepressant agent.

Imidazole (IMID) inhibited (+/-) N-n-propylnorapomorphine (NPA) and BHT-920 induced penile erections (PE) and stretching and yawning (SY) in rats as well as apomorphine (APO) induced hypothermia in mice, enhanced shock-elicited aggressiveness in rats and antagonized sleep induced by clonidine in chicks. IMID moreover displayed activity in behavioural tests used in specific screening for antidepressants, potentiating yohimbine toxicity in mice and antagonizing immobility time in the despair test, with a potency in some cases equal to imipramine. IMID per se, depressed motor activity in both mice and rats. The possible mechanism of action and receptors involved are briefly discussed as well as IMID's profile as an antidepressant drug.

Aggression↗
PubMed2002

Synthesis of a novel, recyclable, solid-phase acylating reagent.

In this paper, we describe the synthesis of N-(6-cyano-1,3-dimethyl-2,4-dioxo-5-substituted-1,3-dihydropyridino[2,3-d] pyrimidin-7-yl)imides 1. We will show the synthesis of 1 using both conventional heating and microwave techniques. In addition, the imide was attached to polystyrene and this immobilized imide was equally as effective at acylating various primary and secondary amines as its solution-phase counterpart.

2-Propanol↗
PubMed1979

Cross-linking of ribosomal proteins by 4-(6-formyl-3-3-azidophenoxy)butyrimidate, a heterobifunctional, cleavable cross-linker.

For the identification of neighbor relationships between proteins in biological systems 4-(6-formyl-3-azidophenoxy)butyrimidate (FAPB-imidate), a heterobifunctional, cleavable cross-linker was synthesized. The reagent has an imido ester at one end, which is used for the attachment to amino groups of a specific protein whose environment has to be characterized. At the other end, the reagent has both an azido and an aldehyde group. The azido group can be used to cross-link the protein photochemically to a variety of chemical groups of neighboring proteins. The aldehyde group is able to cross-link the protein by reductive alkylatin to amino groups of neighboring proteins. In both cases, the cross-linker can be made radioactive with NaB3H4. the cross-linked complexes can be split at the band originating from the imidate group by treatment with ammonia. Hereby, the radioactive cross-linker remains covalently attached to the unknown neighboring protein, which can be therefore easily identified. In order to explore the usefulness of FAPB-imidate as a cross-linking agent, the compound was attached to ribosomal protein L7. With this modified L7, the existence of the well-known complex between L7 and ribosomal protein L10 could be demonstrated by the photochemical procedure. By the chemical procedure, the presence of dimers of L7 in solution could be shown.

Azides↗
PubMed1993

Analogues of platelet activating factor. 8. Antagonists of PAF containing an aromatic ring linked to a pyridinium ring.

A series of platelet activating factor (PAF) antagonists containing a quaternary pyridinium ring connected through an amide, imide, or carbamate linkage to a substituted aromatic ring was prepared. Of these compounds, those containing a branched imide linkage of the form (CON-(COCH3)CH2, 37-51, and 59) generally showed excellent PAF antagonist properties in vitro. Structure-activity relationships within this series of compounds were studied extensively with respect to substituents and the position of substitution in both the aromatic and pyridinium rings. Several of these compounds (40 and 44) showed in vitro PAF antagonism at less than 0.1 microM and are as potent as CV-6209, the most potent PAF antagonist reported in the literature. Less active PAF antagonists were those bearing simple amide linkages (20-23, 27-29, and 31-35), linear imide linkages (62-63), or carbamate linkages (66 and 68), between the two aromatic rings. A number of our PAF antagonists were tested in vivo in mice and rabbits for their ability to protect these animals against a lethal injection of PAF. Those antagonists that are particularly potent (IC50 < 0.1 microM) provide excellent protection against an LD97 dose of PAF in rabbits. The relationships between structure and activity in vitro and in vivo are presented and compared to literature standards.

Amides↗
PubMed2002

Weakly coupled molecular photonic wires: synthesis and excited-state energy-transfer dynamics.

Molecular photonic wires, which absorb light and undergo excited-state energy transfer, are of interest as biomimetic models for photosynthetic light-harvesting systems and as molecular devices with potential applications in materials chemistry. We describe the stepwise synthesis of four molecular photonic wires. Each wire consists of an input unit, transmission element, and output unit. The input unit consists of a boron-dipyrrin dye or a perylene-monoimide dye (linked either at the N-imide or the C9 position); the transmission element consists of one or three zinc porphyrins affording short or long wires, respectively; and the output unit consists of a free base (Fb) porphyrin. The components in the arrays are joined in a linear architecture via diarylethyne linkers (an ethynylphenyl linker is attached to the C9-linked perylene). The wires have been examined by static absorption, static fluorescence, and time-resolved absorption spectroscopy. Each wire (with the exception of the C9-linked perylene wire) exhibits a visible absorption spectrum that is the sum of the spectra of the component parts, indicating the relatively weak electronic coupling between the components. Excitation of each wire at the wavelength where the input unit absorbs preferentially (typically 480-520 nm) results in emission almost exclusively from the Fb porphyrin. The static emission and time-resolved data indicate that the overall rate constants and quantum efficiencies for end-to-end (i.e., input to output) energy transfer are as follows: perylene-(N-imide)-linked short wire, (33 ps)(-1) and >99%; perylene-(C9)-linked short wire, (26 ps)(-1) and >99%; boron-dipyrrin-based long wire, (190 ps)(-1) and 81%; perylene-(N-imide)-linked long wire, (175 ps)(-1) and 86%. Collectively, the studies provide valuable insight into the singlet-singlet excited-state energy-transfer properties in weakly coupled molecular photonic wires.

Coloring Agents↗
PubMed2005

Ultrafast dynamics of pyrrolidinium cation ionic liquids.

We have investigated the ultrafast molecular dynamics of five pyrrolidinium cation room temperature ionic liquids using femtosecond optical heterodyne-detected Raman-induced Kerr effect spectroscopy. The ionic liquids studied are N-butyl-N-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide P14+/NTf2-), N-methoxyethyl-N-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide P1EOE+/NTf2-), N-ethoxyethyl-N-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide P1EOE+/NTf2-), N-ethoxyethyl-N-methylpyrrolidinium bromide P1EOE+, and N-ethoxyethyl-N-methylpyrrolidinium dicyanoamide P1EOE+/DCA-). For comparing dynamics among the five ionic liquids, we categorize the ionic liquids into two groups. One group of liquids comprises the three pyrrolidinium cations P14+, P1EOM+, and P1EOE+ paired with the NTf2- anion. The other group of liquids consists of the P1EOE+ cation paired with each of the three anions NTf2-, Br-, and DCA-. The overdamped relaxation for time scales longer than 2 ps has been fit by a triexponential function for each of the five pyrrolidinium ionic liquids. The fast ( approximately 2 ps) and intermediate (approximately 20 ps) relaxation time constants vary little among these five ionic liquids. However, the slow relaxation time constant correlates with the viscosity. Thus, the Kerr spectra in the range from 0 to 750 cm(-1) are quite similar for the group of three pyrrolidinium ionic liquids paired with the NTf2- anion. The intermolecular vibrational line shapes between 0 and 150 cm(-1) are fit to a multimode Brownian oscillator model; adequate fits required at least three modes to be included in the line shape.

Cations↗
PubMed2005

Synthesis and reactions of some new substituted pyridine and pyrimidine derivatives as analgesic, anticonvulsant and antiparkinsonian agents.

A series of substituted pyridine and pyrimidine derivatives were synthesized as analgesic, anti convulsant, and antiparkinsonian agents by using compounds 1, 2, and 9 as starting materials. Pyr idino-imide derivative 3 was prepared by condensation of 1 with tetrachlorophthalic anhydride and compounds 4 and 5 were also obtained by reaction of compound 1 with 1,2,4,5-benzene-tetra carboxylic dianhydride and 1,4,5,8-naphthalenetetracarboxylic dianhydride, respectively. Similarly, compound 2 was reacted with previous anhydrides to afford the corresponding imide 6 and bis-imide derivatives 7 and 8, respectively. Bis-arylmethylene derivatives 9 were treated with hydrogen peroxide to afford the corresponding bis-oxiranocycloalkanone derivatives 10, which condensed with thiourea to give the corresponding thioxopyrimidine derivatives 11. Treatment of compound 11 with chloroacetic acid in the presence of anhydrous sodium acetate afforded the corresponding thiazolopyrim idine derivative 12 which condensed with aromatic aldehydes in acetic acid/acetic anhydride to give arylmethylene derivative 13. Also, compounds 13 could be prepared by reaction of compounds 11 with chloroacetic acid, aromatic aldehydes, and sodium acetate in a mixture of acetic acid and acetic anhydride. The pharmacological screening showed that many of these obtained compounds have good analgesic, anticonvulsant, and antiparkinsonian activities comparable to Valdecoxib, Carbamazepine, and Benzatropine as reference drugs.

Analgesics, Non-Narcotic↗
PubMed2006

Electrodeposition of nano- and microcrystalline aluminium in three different air and water stable ionic liquids.

The present work shows, for the first time, a comparative experimental study on the electrodeposition of aluminium in three different water and air stable ionic liquids, namely 1-butyl-1-methylpyrrolidinium-bis(trifluoromethylsulfonyl)imide ([BMP]Tf2N), 1-ethyl-3-methylimidazolium-bis(trifluoromethylsulfonyl)imide ([EMIm] Tf2N), and trihexyl-tetradecyl-phosphoniumbis(trifluoromethylsulfonyl)imide (P(14,6,6,6) Tf2N). The ionic liquids [BMP]Tf2N and [EMIm]Tf2N show biphasic behaviour in the AlCl3 concentration range from 1.6 to 2.5 mol L(-1) and 2.5 to 5 mol L(-1), respectively. The biphasic mixtures become monophasic at temperatures >/=80 degrees C. It was found that nanocrystalline aluminium can be electrodeposited in the ionic liquid [BMP]Tf2N saturated with AlCl3. The deposits obtained are generally uniform, dense, shining, and adherent with very fine crystallites in the nanometer size regime. However, coarse cubic-shaped aluminium particles in the micrometer range are obtained in the ionic liquid [EMIm]Tf2N. In this liquid the particle size significantly increases as the temperature rises. A very thin, mirrorlike aluminium film containing very fine crystallites of about 20 nm is obtained in the ionic liquid [trihexyl-tetradecyl-phosphonium]Tf(2)N at room temperature. At 150 degrees C, the average grain size is found to be 35 nm.

Journal Article↗
PubMed1990

Occurrence and role of cis peptide bonds in protein structures.

It has been widely assumed that the occurrence of cis peptide bonds in proteins is quite rare due to unfavorable contacts between adjacent amino acid residues in this isomeric form. To investigate this assumption, the Brookhaven Protein Data Bank was examined for the occurrences of cis peptide bonds. Out of 31,005 amide bonds, only 17, or 0.05%, are cis, while 99 of the 1534 imide bonds (X-Pro), or 6.5%, are cis. These figures are considerably less than the distribution predicted on the basis of the potential energy difference between the cis and trans isomeric forms and experimental data on small peptides. It is not known whether the lower than expected occurrence of cis peptide bonds arises from constraints imposed by the protein environment, or from assumptions made in the solution of the X-ray crystal structures. However, when the occurrence of cis bonds in the data base is examined relative to the resolution of the structures, the number of cis bonds increases with increasing resolution. The distributions seen for these peptide omega bonds in the data base are not the same shape as the distributions predicted from simple potential energy barriers. They are sharper in the main, but they are also broader at the base with significant numbers of nonplanar peptide bonds. Cis peptide bonds are found primarily in bends and turns and, in the case of cis imide bonds (X-PRO), this correlation is so high that it suggests a specific role for cis imide groups in such structures.

Animals↗
PubMed2004

Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner.

Immunomodulatory drugs (IMiDs) are potent inhibitors of TNF-alpha and IL-1beta and elevators of IL-10 production in LPS-stimulated human PBMC. They are currently in clinical trials for various diseases, including multiple myeloma, myelodysplastic syndrome, and melanoma. In the present study, we have investigated the effects of thalidomide, CC-5013 and CC-4047 on the expression of COX-2 by stimulated PBMC. Our results show that thalidomide and IMiDs inhibited the expression of COX-2 but not the COX-1 protein in LPS-TNF-alpha and IL-1beta stimulated PBMC and shortened the half-life of COX-2 mRNA in a dose-dependent manner. They also inhibited the synthesis of prostaglandin E2 from LPS-stimulated PBMC. While anti-TNF-alpha or IL-1beta neutralizing antibodies had no effect on COX-2 expression, anti-IL-10 neutralizing antibody elevated the expression of COX-2 mRNA, and protein from treated PBMC. These data suggest that the anti-inflammatory and anti-tumor effects of IMiDs may be due in part to elevation of IL-10 production and its subsequent inhibition of COX-2 expression.

Blotting, Northern↗
PubMed2004

Reaction of N-phenyl maleimide with aminosilane monolayers.

Reaction of N-phenyl maleimide (NPM) with silica surfaces modified with a self-assembled monolayer of (aminopropyl)triethoxysilane (APTES) was investigated using infrared spectroscopy (FTIR), elemental analysis, and titration assays. This reaction is of interest as a test case for using amine-maleimide coupling for immobilization of biomolecules. Addition of NPM to surface APTES residues was consistently sub-stoichiometric, with typical yields of about 75% on monolayers with a coverage of 1.15 APTES residues/nm2. Titration analysis found negligible presence of imide alkene C=C bonds in modified supports, indicating that addition of NPM to APTES proceeded via amine attack at the imide olefinic bond. FTIR measurements also revealed presence of amide bands which intensified over periods of 10 h. These observations were attributed to a slower secondary process in which APTES amines attack imide carbonyls to produce amide linkages. Stability of NPM-modified surfaces was examined under room temperature storage in pH 7 buffer up to 72 h and for 2 h exposure to buffer at temperatures up to 90 degrees C. It was found that stability was determined by robustness of APTES-silica attachment, with about 30% loss under the harshest conditions investigated.

Amines↗
PubMed2006

Thalidomide and lenalidomide in the treatment of multiple myeloma.

Although multiple myeloma (MM) is incurable with currently available treatments, the introduction of thalidomide and the development of safer and more active thalidomide analogues represent a major advance in the therapy of this disease. Thalidomide, initially introduced for treatment of MM because of its anti-angiogenic properties, has shown remarkable activity alone and in combination with other drugs in patients across all stages of the disease. Given the potential for teratogenicity with thalidomide and the non-haematologic toxicities of the drug, several analogues referred to as "immunomodulatory drugs" (IMiDs) were developed with the intent of enhancing the immunomodulatory effect while minimizing the teratogenic risk. Lenalidomide (CC-5013) and Actimid (CC-4047) are the first such analogues to undergo clinical testing. Lenalidomide has shown impressive activity in relapsed refractory myeloma as well as newly diagnosed disease. The precise mechanism of anti-MM activity of thalidomide and the IMiDs is not clear, but studies suggest that several other mechanisms besides anti-angiogenic effects may play a role. In this paper we review the development, pharmacology, mechanism of action, pre-clinical and clinical efficacy, and the current status of thalidomide and the IMiDs in the treatment of MM.

Angiogenesis Inhibitors↗