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PubMed2004

Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma.

Previous studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.

Antineoplastic Agents↗
PubMed2006

Use of fourier transform infrared spectroscopy to follow the heterocumulene aided thermal dehydration of phthalic and naphthalic acids.

Fourier transform infrared (FT-IR) spectroscopy has been successfully employed to follow the formation of phthalic anhydride and 1,8-naphthalic anhydride on heating their corresponding acids. The effects of three heterocumulenes, cyanamide, dicyandiamide, and sodium cyanate, on the temperature of formation of the anhydrides were also investigated using this method. It was found that the carbodiimides cyanamide and dicyandiamide dramatically lowered the temperature at which thermal dehydration of the acid led to anhydride formation. It was noted that cyanamide had a stronger catalytic effect than dicyandiamide, presumably due to the electron-withdrawing effect of the amidine group. Sodium cyanate was also found to promote the thermal dehydration of the acids to form the corresponding anhydrides. Under more severe conditions, phthalic acid anhydride formed is seen to react further, leading to the formation of phthalimide. The discrepancy between the products obtained with cyanamide and sodium cyanate leads to the conclusion that, unlike earlier claims, imide formation is not due to the reaction of the anhydride with the urea formed but with sodium cyanate itself. However, only the phthalic anhydride five-membered ring system is sufficiently reactive towards the CNO- nucleophile to form the imide; the six-membered 1,8-naphthalic anhydride system does not react in this way.

Journal Article↗
PubMedDate not supplied

Photochemical reduction of cytochrome c by a 1,4,5,8-naphthalenediimide radical anion.

Steady-state UV irradiation of aqueous solutions containing cytochrome c (cyt c) and N,N'-bis(2-phosphonoethyl)-1,4,5,8-naphthalenediimide (BPNDI), a water-soluble aromatic imide, resulted in the reduction of the heme iron from the Fe(III) to the Fe(II) oxidation state. The reaction kinetics were followed by the increase of the ferrocytochrome c absorbance band at 549 nm. The rate of the photochemical reaction was pH dependent, reaching its maximum values over the pH range 4-7. Addition of electrolyte (NaCl) at pH 5 resulted in a decrease in the reaction rate, as expected for reactions between oppositely charged species. Flash photolysis studies revealed that the actual reductant in the reaction was a photogenerated BPNDI radical anion, which transferred an electron to the cyt c heme iron. The participation of imide radicals in the process was confirmed by the ready reduction of cyt c by BPNDI radicals chemically generated with sodium dithionite.

Anions↗
PubMed2006

Immunomodulatory drugs as a therapy for multiple myeloma.

Thalidomide and the analogues lenalidomide (CC-5013, Revlimid) and CC-4047 (Actimid) belong to the family of immunomodulatory drugs (IMiDs). These agents have anti-angiogenic properties, modulate TNFalpha and IL-12 secretion, co-stimulate T cells, increase NK cell toxicity and have direct anti-tumour effects. These characteristics have made of them promising drugs for treatment of relapsed, refractory and newly diagnosed MM. It seems that lenalidomide and CC-4047 are more powerful in inhibiting TNFalpha and have, except for myelosuppression, less side effects than Thal. Combination of IMiDs with dexamethasone, bortezomib and with chemotherapeutic agents are tested in numerous trials, which will help in determining the optimal combination and administration schedule of different molecules to take advantage of non-overlapping toxicities and synergisms between those agents.

Animals↗
PubMed2000

Covalently bonded heparin to alter the pericardial calcification.

Calcification is the leading cause of failure of a wide spectrum of cardiovascular and non-cardiovascular medical devices. In this study our aim was to immobilize polyethylene glycol (PEG) and heparin on multiple crosslinked bovine pericardium with Glutaraldehyde (GA) and carbodiimide. Grafting of PEG and heparin through an intermediate tissue bound substrate containing aldehyde and imide functional groups showed reduction in calcification. In this experimental protocol, we used Golomb and Wagner's in vitro model for studying pericardial calcification and a diffusion cell with two compartments for evaluating the diffusion of calcium across the BP. The results showed that heparin immobilization on the surface reduces calcification independent of its concentration in the incubating medium. It is conceivable that inactivation of unpaired aldehydic moieties present in pericardium after exposure to GA act as potential site for PEG grafting and imide functionalities of EDC can covalently bind heparin, would be the key step in the prevention of calcification. It is well-established fact that heparin has a potent antithrombotic effect. But the exact role of heparin in the anticalcification process of bioprostheses still remain elusive.

Animals↗
PubMed2006

Immunomodulatory analogues of thalidomide in the treatment of multiple myeloma.

The design of innovative, more effective, less toxic therapy for multiple myeloma (MM) is emerging in parallel to a better understanding of the underlying pathophysiology of this common hematologic malignancy. Thalidomide has changed the treatment paradigm for patients with myeloma. Its efficacy, however, has been compromised to some degree by its side effects. Immunomodulatory drugs (IMiDs) are structural and functional analogues of thalidomide that were specifically designed to produce new agents with enhanced immunomodulating and anticancer properties but with less toxicity. In this article, we review the clinical trial development of second-generation IMiDs lenalidomide and CC-4047. Both agents demonstrate potent activity with manageable toxicities and provide another treatment opportunity for patients with MM.

Humans↗
PubMed2002

Immunological effects of thalidomide and its chemical and functional analogs.

Thalidomide has recently shown considerable promise in the treatment of a number of conditions, such as leprosy and cancer. Its effectiveness in the clinic has been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell costimulatory and antiangiogenic activity. Novel compounds with improved immunomodulatory activity and side effect profiles are also being evaluated. These include selective cytokine inhibitory drugs (SelCIDs), with greatly improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that are structural analogs of thalidomide, with improved properties. A third group recently identified within the SelCID group, with phosphodiesterase type 4-independent activity, is in the process of being characterized in laboratory studies. This review describes the emerging immunological properties of thalidomide, from a historical context to present-day clinical applications, most notably in multiple myeloma but also in other cancers, inflammatory disease, and HIV. We also describe the laboratory studies that have led to the characterization and development of SelCIDs and IMiDs into potentially clinically relevant drugs. Early trial data suggest that these novel immunomodulatory compounds may supercede thalidomide to become established therapies, particularly in certain cancers. Further evidence is required, however, to correlate the clinical efficacy of these compounds with their known immunomodulatory, antiangiogenic, and antitumor properties.

Adjuvants, Immunologic↗
PubMed2002

[Solid phase coordination synthesis and characterization of polymimide and Sm ion-under microwave radiation].

Solid phase coordination reaction of Sm3+ and the resultant of the imidization of polycondensor of polycondensation and imidization of benzoguanamine(BGA) and 2, 4-tolylenediisocyanate (TDI) and pyromellitic dianhydride (PMIDA) under microwave irradiation were synthesized and studied. The effect of microwave irradiation time (power), the composition of reactants and the reaction temperature on the yield and Sm content in complexes were studied. The complex was determined by Fourier transform infrared absorption (FTIR), Fourier transform Roman spectrum (FTRS), scanning electric minor (SEM), 13C solid state nuclear magnetic resonance spectrometry and X-ray powder diffraction. The fluorescence intensity was measured by fluorescent emission spectrum and compared with thermal coordination. The magnetic susceptibilities were measured by magnetic curve. The results showed that the complex had not characteristic fluorescence of Sm3+, which illustrated that the first excitation level of Sm3+ and polymer could not match at all. But the complex showed good magnetic property of the ion.

Magnetic Resonance Spectroscopy↗
PubMed1992

Chemical stability of insulin. 4. Mechanisms and kinetics of chemical transformations in pharmaceutical formulation.

Insulin decomposes by a multitude of chemical reactions [1-3]. It deamidates at two different residues by entirely different mechanisms. In acid, deamidation at AsnA21 is intramolecularly catalyzed by the protonated C-terminal, whereas above pH 6 an intermediate imide formation at residue AsnB3 leads to isoAsp and Asp derivatives. The imide formation requires a large rotation around the alpha-carbon/peptide carbonyl carbon bond at B3, corresponding to a 10 A movement of the B-chain N-terminal. The main determinant for the rate of B3 deamidation, as well as for the ratio between the two products formed, is the local conformational structure, which is highly influenced by various excipients and the physical state of the insulin. An amazing thermolysin-like, autoproteolytic cleavage of the A-chain takes place in rhombohedral insulin crystals, mediated by a concerted catalytic action by several, inter-hexameric functional groups and Zn2+. Intermolecular, covalent cross-linking of insulin molecules occurs via several mechanisms. The most prominent type of mechanism is aminolysis by the N-terminals, leading to isopeptide linkages with the A-chain side-chain amides of residues GlnA15, AsnA18 and AsnA21. The same type of reaction also leads to covalent cross-linking of the N-terminal in protamine with insulin. Disulfide exchange reactions, initiated by lysis of the A7-B7 disulfide bridge, lead mainly to formation of covalent oligo- and polymers. Activation energy (Ea) for the neutral deamidation and the aminolysis reactions was found to be 80 and 119 KJ/mol, respectively.

Amino Acid Sequence↗
PubMed2004

Synthesis and properties of N-methyl and N-phenyl derivatives of 1,4-dioxo-1,2,3,4-tetrahydropyrido[3,4-d]pyridazines.

2-Methoxy- and 2-ethoxy-6-methyl-3,4-pyridinedicarboximides (XI, XII) reacted with N-methylhydrazine giving 2- and 3-methyl derivatives of the appropriate 1,4-dioxo-1,2,3,4-tetrahydropyrido[3,4-d]pyridazines (XV, XIII and XVI, XIV). In both cases 3-methyl isomer (XIII, XIV) was formed in higher yield than 2-methyl derivative (XV, XVI). Reaction of the imide XII with N-phenylhydrazine gave the salts of the suitable N-phenyldihydropyrido[3,4d]pyridazines with NH2-NHC6H5 (XXI and XXII) which transformed into N-phenylaminoimide (XXIII) during the boiling in 80% CH3COOH. Imide XXIII isomerized to the appropriate 2-phenyl and 3-phenylpyrido[3,4-d]pyridazines (XXIV - main reaction product and XXV) under the influence of heating in ethanolic solution of C2H5ONa. Some of N-phenylpiperazinylhydroxyalkyl(alkyl) derivatives of compound XXIV (XXVII, XXVIII) were pharmacologically active.

Analgesics, Non-Narcotic↗
PubMed1998

[Study on the infrared spectra of 9-methoxy benzoxanthene-3,4-dicarboximide fluorescent dyes].

The characteristic infrared spectra of eight novel 9-methoxy benzoxanthene-3, 4-dicarboximide fluorescent dyes was studied and the substiuent influences on the spectrum nature was also pointed out. The nature of N-substituent group in the imide ring affects the position of v(c=o) by mesomeric and inductive effects. Imides give the rise to two vc=o absorptions, namely v(a)(c=o) and v(as)(c=o) (1600-1700cm(-1)). The separations between v(a)(c=)o and v(as)(c=o) were about 36-43cm(-1).

English Abstract↗
PubMedDate not supplied

The hydrolysis activation of the doxorubicin cardioprotective agent ICRF-187 [+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane).

ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] has shown promise [Speyer et al., N. Engl. J. Med. 319, 745 (1988)] as a cardioprotective agent against what may be an iron-based doxorubicin (Adriamycin)-induced cardiotoxicity. ICRF-187 likely exerts its action through its rings-opened hydrolysis product, a compound that has an EDTA-type structure and, likewise, strongly binds metal ions. The hydrolysis of ICRF-187 was followed spectrophotometrically in the ultraviolet and was shown to be pseudo-first-order over a wide pH range. The hydrolysis mechanism was shown to have a hydroxide-catalyzed path and a pH-independent path similar to the hydrolysis of other imides. The anionic form of ICRF-187 (with a pKa of 9.6 at 37 degrees C) was resistant to hydroxide attack. The kinetically, spectroscopically and potentiometrically determined pKa values were all in excellent agreement and thus provided a test of the mechanism. Each imide group underwent hydrolysis and ionization independently of the other. The rate of ICRF-187 hydrolysis was also followed by observation of the removal of Cu2+ from a Cu2(+)-doxorubicin complex by the ICRF-187 hydrolysis product.

Chemical Phenomena↗
PubMed2000

Hierarchical self-organization of perylene bisimide--melamine assemblies to fluorescent mesoscopic superstructures.

A series of three perylene tetracarboxylic acid bisimide dyes 3a-c bearing phenoxy substituents at the four bay positions of the perylene core were synthesized and their complexation behavior to complementary ditopic dialkyl melamines 8a-c was investigated. Binding constants and Gibbs binding energies for the hydrogen bonds between the imide and the complementary melamine moiety have been determined in several solvents by NMR and UV/Vis titration experiments with monotopic model compounds 5 and 9. The effects of the solvent polarity and specific solvent-solute interactions on the degree of polymerization of (3 x 8)n are discussed, and a general formula to estimate the chain length of [AA-BB]n nylon-type supramolecular polymers is derived. In addition to the formation of a hydrogen-bonded supramolecular chain. pi-pi interactions were observed for perylene bisimide-melamine assemblies 3b x 8b and 3b x 8c in aliphatic solvents. The orthogonal nature of hydrogen bonding and pi-pi interactions leads to three-dimensional growth yielding large-sized aggregates already in dilute solution. On suitable substrates, densely intertwined networks of nano- to mesoscopic strands are formed which have been investigated by electron microscopy, confocal fluorescence microscopy and optical polarization microscopy. The high fluorescence and excellent photostability of these superstructures is promising for future studies on energy migration and artificial light harvesting at the nano- and mesoscopic length scale.

Chlorophyll↗
PubMed2002

Photoinduced electron transfer in bisporphyrin-diimide complexes.

The bisporphyrin host ZnH was synthesized, and its complexation with two aromatic diimide guest molecules, bis(pyridyl)naphthalenediimide NIN and bis(pyridyl)phenyldiimide PIN, was investigated by (1)H NMR and UV/Vis spectroscopy. The diimide guests were complexed simultaneously with both metalloporphyrins of the host, with association constants on the order of 10(8)M(-1). The processes occurring in the complex after excitation of the porphyrinic host were studied by steady-state and time-resolved emission and transient absorption spectroscopy. Complexation alters the photophysical properties of the host ZnH; the luminescence bands shift to the red by 30 nm in the complexed forms, while the emission quantum yield and the lifetime decrease. Comparison of a complex between ZnH and a model guest unable to undergo photoinduced processes allowed us to establish that, in the diimide complexes, quenching of the porphyrinic luminescence occurs with a rate of 1.1 x 10(10)s(-1). The process is identified as an electron transfer from the excited singlet of the porphyrinic host to the imide guest, which yields charge-separated states with a lifetime of 710 ps for ZnH(+)-NIN(-) and 260 ps for ZnH(+)-PIN(-).

Binding Sites↗
PubMed2005

Paradoxical solvent effects on the absorption and emission spectra of amino-substituted perylene monoimides.

In N-(2,5-di-tert-butylphenyl)-9-pyrrolidinoperylene-3,4-dicarboximide (5PI) the absorption and emission spectra display large solvatochromic shifts, but, remarkably, the Stokes shift is practically independent of solvent polarity. This unique behavior is caused by the extraordinarily large ground-state dipole moment of 5PI, which further increases upon increasing the solvent polarity, whereas the excited-state dipole moment is less solvent dependent. In the corresponding piperidine compound, 6PI, this effect is much less important owing to the weaker coupling between the amino group and the aromatic imide moiety, and in the corresponding naphthalimide, 5NI, it is absent. The latter shows the conventional solvatochromic behavior of a push-pull substituted conjugated system, that is, minor shifts in absorption and a larger change in the emission energy with solvent polarity.

Amines↗
PubMed1989

Hypolipidemic activity of cyclic imido alkyl ethers, thioethers, sulfoxides, and sulfones.

N-Substituted alkyl ethers, thioethers, sulfoxides, and sulfones of cyclic imides (e.g., phthalimide, saccharin, 1,8-naphthalimide, succinimide, and 2,3-dihydrophthalazine-1,4-dione) were shown to have potent hypolipidemic activity at doses of 10 and 20 mg/kg/d in rodents. These N-substitutions afforded no improvement over other known N-substitutions (e.g., butyl, 3-butanone, or the propionic acid derivatives of phthalimide, saccharin, and 2,3-dihydrophthalazine-1,4-dione) compared with the respective parent compounds. However, 2-(methoxyethyl)-1H-benz[de]isoquinoline-1,3-(2H)dione (3a), 2-[2-methylsulfinyl]ethyl-1H-benz[de]isoquinoline-1,3-(2H)dione (3c), 1-(2-methylsulfinyl)-2,5-pyrrolidenedione (4c), and 1-(2-methoxyethyl-2,5-pyrrolidenedione (4a) significantly improved activity compared with parent compounds, as well as previously reported N-substituted analogues, reducing serum cholesterol levels and serum triglyceride levels by 40%. The thioether of succinimide afforded a 54% reduction of serum cholesterol and a 41% reduction of serum triglyceride levels in mice after 16 d. The alkyl thioethers of 1,8-naphthalimide and succinimide significantly lowered cholesterol levels in serum VLDL and LDL, while the alkyl thioethers of succinimide elevated HDL cholesterol content. Tissue lipids were reduced in the liver and aorta by these selected derivatives. The activities of regulatory enzymes in de novo synthesis of hepatic cholesterol and triglyceride were inhibited by the selected 1,8-naphthalimide derivatives. In situ cholesterol and cholic acid reabsorption from intestines were suppressed by the presence of the agents.

Animals↗
PubMed1988

Pharmacokinetics of Amonafide in dogs.

Amonafide, one of a series of imide derivatives of 1,8-naphthalic acid synthesized by Brana et al. has shown significant antitumor activity against a variety of experimental tumors, including L1210 leukemia and P388 leukemia. Along with the clinical trial at our institute, we have studied the disposition of Amonafide in dogs by HPLC and fluorometry. Six dogs received Amonafide i.v. at 5 mg/kg (100 mg/m2) over 15 min; three were sacrificed at 6 h, and three at 24 h. The initial plasma t1/2 of Amonafide was 2.4 +/- 0.4 min, the intermediate t1/2, 26.8 +/- 3.7 min, and the terminal t1/2, 21.7 +/- 4.0 h. The peak plasma concentration achieved was 6.3 +/- 1.7 micrograms/ml. The average apparent volume of distribution was 12.84 +/- 0.54 1/kg, and the total clearance was 0.56 +/- 0.16 1/kg/h. In 24 h, 9.5% +/- 0.2% of the administered dose was excreted in the urine as the parent drug, and 7.4% +/- 1.4% in the bile in 6 h. Amonafide penetrated the CSF readily and achieved the highest concentration 20-25 min after administration, which was 30% of the concurrent plasma level. Amonafide underwent extensive metabolism to at least three major metabolites and two or more minor metabolites. The alpha and beta plasma t1/2 of the major metabolite, an N-oxide derivative, were 24.8 min and 28.6 h, respectively. The 24-h cumulative urinary excretion was 1.4% of the injected dose, and the cumulative biliary excretion was 16.7% in 6 h. At autopsy 6 h after dosing, the liver contained the highest percentage (0.23% of administered dose) of unchanged Amonafide, followed by the stomach (0.11%), lung (0.04%), kidney (0.04%), and pancreas (0.03%). The rest of the major organs retained less than 0.02% of the Amonafide dose. One day after dosing, no detectable amount of Amonafide was found in any of these tissues, indicating that Amonafide appears to be extensively metabolized and not significantly retained in the dog.

Adenine↗
PubMed1995

Phase II study of amonafide in patients with recurrent glioma.

Amonafide, a novel imide derivative with broad preclinical antitumor activity, achieves significant cerebrospinal fluid levels in animal models. In order to test its antitumor activity in patients with recurrent diffuse infiltrative glioma of the astrocytic and oligodendroglial type, we performed a phase II clinical trial. Of the 22 eligible and evaluable patients treated, 2 (9%) experienced tumor regression lasting more than one year. No other patients experienced tumor regression; one remained stable more than six months. Toxicities consisted primarily of myelosuppression, vomiting, and venous irritation at the infusion site. We conclude that amonafide has minimal activity in recurrent glioma patients. Further investigations are not warranted in this study population.

Adenine↗