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PubMed1986

Elevated serum D dimer: a degradation product of cross-linked fibrin (XDP) after intravenous streptokinase during acute myocardial infarction.

D dimer, a degradation product of cross-linked fibrin, is generated by lysis of fibrin but not by lysis of fibrinogen and can be reliably detected by specific monoclonal antibody techniques. The generation of D dimer after intravenous streptokinase in acute myocardial infarction was studied with the use of a semiquantitative latex agglutination immunoassay. This assay utilizes the monoclonal antibody DD-3B6/22, raised by conventional hybridoma technology, against a highly purified preparation of human D dimer and is adjusted to give a positive agglutination at a D dimer serum concentration of greater than 200 ng/ml (upper limit of normal). Twenty-one patients with acute transmural myocardial infarction of less than 3 hours' duration were studied. Fifteen patients received 0.75 to 1.5 million U intravenous streptokinase and 6 patients were treated conventionally without thrombolytic therapy. An elevated serum level of D dimer was detected before treatment in only 1 of 15 patients receiving intravenous streptokinase and within 2 hours of treatment in the remaining 14 patients who received streptokinase. In contrast, an elevated serum D dimer level was not detected during the first 24 hours in any of the six conventionally treated patients, including two patients who manifested the clinical syndrome of spontaneous reperfusion. The data suggest that in patients with acute myocardial infarction, an elevated serum level of D dimer, a cross-linked fibrin degradation product occurs early after administration of a large dose of streptokinase, but is infrequent during the first 24 hours in conventionally treated patients with acute infarction. Measurement of D dimer may be potentially useful for monitoring thrombolysis in patients with acute myocardial infarction.

Aged↗
PubMed1988

Reaggregation behavior of different types of collagen in vitro: variations in the occurrence and structure of dimeric segment long-spacing collagen.

Segment long-spacing collagen (SLS) can be precipitated from solutions of collagen using ATP as the inducing agent. Dimeric SLS aggregates have been observed in addition to monomeric SLS. We have compared collagen types I, II, III, and V with respect to their ability to form dimeric SLS in vitro. These collagen types were isolated from bovine tissues and characterized by polyacrylamide slab gel electrophoresis of the respective alpha-chains. Only monomeric SLS can be detected in preparations of collagen types I and III. Dimeric SLS, on the other hand, accounts for the majority of the crystallites seen in preparations of collagen types II and V. Dimeric SLS from both collagen types II and V reveal overlap zones at the carboxy-terminal ends of the collagen molecules. However, dimeric SLS from collagen types II and V differ with respect to their overlap distances. Significant portions of the triple helical domains of collagen molecules are occupied by the overlap region of dimeric SLS from type II collagen. On the other hand, dimeric SLS from type V collagen is composed of molecules overlapping only at their short nonhelical telopeptides. It is concluded that the ability of collagen molecules to aggregate into dimeric SLS under defined experimental conditions is collagen type dependent.

Adenosine Triphosphate↗
PubMed1996

The Hin dimer interface is critical for Fis-mediated activation of the catalytic steps of site-specific DNA inversion.

BACKGROUND: Hin is a member of an extended family of site-specific recombinases--the DNA invertase/resolvase family--that catalyze inversion or deletion of DNA. DNA inversion by Hin occurs between two recombination sites and requires the regulatory protein Fis, which associates with a cis-acting recombinational enhancer sequence. Hin recombinase dimers bind to the two recombination sites and assemble onto the Fis-bound enhancer to generate an invertasome structure, at which time they become competent to catalyze DNA cleavage and strand exchange. In this report, we investigate the role of the Hin dimer interface in the activation of its catalytic functions. RESULTS: We show that the Hin dimer is formed at an interface that contains putative amphipathic alpha-helices in a manner that is very similar to gamma delta resolvase. Certain detergents weakened cooperative interactions between the subunits of the Hin dimer and dramatically increased the rate of the first chemical step of the reaction--double-strand cleavage events at the center of the recombination sites. Amino-acid substitutions within the dimer interface led to profound changes in the catalytic properties of the recombinase. Nearly all mutations strongly affected the ability of the dimer to cleave DNA and most abolished DNA strand exchange in vitro. Some amino-acid substitutions altered the concerted nature of the DNA cleavage events within both recombination sites, and two mutations resulted in cleavage activity that was independent of Fis activation in vitro. Disulfide-linked Hin dimers were catalytically inactive; however, subsequent to the addition of the Fis-bound enhancer sequence, catalytic activity was no longer affected by the presence of oxidizing agents. CONCLUSIONS: The combined results demonstrate that the Hin dimer interface is of critical importance for the activation of catalysis and imply that interactions with the Fis-bound enhancer may trigger a conformational adjustment within the region that is important for concerted DNA cleavage within both recombination sites, and possibly for the subsequent exchange of DNA strands.

Binding Sites↗
PubMed2002

Can a state-of-the-art D-dimer test be used to determine the need for CT imaging in patients suspected of having pulmonary embolism?

RATIONALE AND OBJECTIVES: The purpose of this study was to determine whether a simple rapid blood test can obviate computed tomography (CT) in a sizable percentage of patients suspected of having pulmonary embolism, based on the hypothesis that negative D-dimer results could eliminate any further search for pulmonary embolism. MATERIALS AND METHODS: At the authors' institution, 2,121 sequential patients underwent a whole-blood antibody agglutination test for cross-linked fibrin degradation products (D-dimer). Of these patients, 844 had positive test results and were not further considered. A retrospective review included reports of all multisection combined CT venographic and pulmonary angiographic studies obtained within 48 hours of the D-dimer assay for the 1,277 patients with negative D-dimer results; 229 (18%) of these 1,277 patients underwent combined CT venography and pulmonary angiography, usually within 24 hours. RESULTS: Retrospective review of the imaging examinations that were discrepant with the D-dimer results revealed only three false-negative D-dimer results. Of the 229 patients in whom combined CT venography and pulmonary angiography was performed for suspected pulmonary embolism, 226 (98.7%) had no evidence of acute pulmonary embolism or deep venous thrombosis. The negative predictive value of a negative D-dimer result was therefore 98.7% (confidence interval, 96.2%-99.7%). CONCLUSION: The D-dimer assay is a simple rapid blood test that is sensitive to the presence of acute thrombosis. Very few patients with negative results have acute deep venous thrombosis or pulmonary embolism, with combined CT venography and pulmonary angiography used as the reference standard.

Acute Disease↗
PubMed1993

Overexpression, purification, DNA binding, and dimerization of the Escherichia coli uvrD gene product (helicase II).

We have subcloned the Escherichia coli uvrD gene under control of the inducible phage lambda PL promoter and report a procedure for the large-scale purification of helicase II protein. Yields of approximately 60 mg of > 99% pure helicase II protein, free of detectable nuclease activity, are obtained starting from 250 g of induced E. coli cells containing the overexpression plasmid. Overproduction of helicase II protein at these levels is lethal in E. coli. The extinction coefficient of helicase II protein was determined to be epsilon 280 = 1.06 (+/- 0.05) x 10(5) M-1 (monomer) cm-1 [20 mM Tris-HCl (pH 8.3 at 25 degrees C), 0.2 M NaCl, and 20% (v/v) glycerol, 25 degrees C]. We also present a preliminary characterization of the dimerization and DNA binding properties of helicase II and a systematic examination of its solubility properties. The apparent site size of a helicase II monomer on ss-DNA is 10 +/- 2 nucleotides as determined by quenching of the intrinsic tryptophan fluorescence of the protein upon binding poly(dT). In the absence of DNA, helicase II protein can self-assemble to form at least a dimeric species at concentrations > 0.25 microM (monomer) and exists in a monomer-dimer equilibrium under a variety of solution conditions. However, upon binding short oligodeoxynucleotides, the dimeric form of helicase II is stabilized, and dimerization stimulates the ss-DNA-dependent ATPase activity, suggesting that the dimer is functionally important. On the basis of these observations and similarities between helicase II and the E. coli Rep helicase, which appears to function as a dimer [Chao, K., & Lohman, T. (1991) J. Mol. Biol. 221, 1165-1181], we suggest that the active form of helicase II may also be a dimer or larger oligomer.

Adenosine Triphosphatases↗
PubMed1993

Mode of dimerization of HIV-1 genomic RNA.

Retroviral genomes consist of two identical RNA molecules joined noncovalently near their 5' ends, at domains called dimerization linked sequences (DLS). This physical linkage of the genomic RNAs is considered important for the control of several steps in the viral life cycle, such as recombination, translation, and encapsidation. The putative DLS of human immunodeficiency virus-1 (HIV-1), a 111-nucleotide, purine-rich stretch of RNA, has been found necessary and sufficient for a salt-induced dimerization of the genome in vitro. Our investigation into the mechanism of this dimerization reveals sharply varying influences of the different alkali cations on both the formation and the stabilization of the dimer, a pattern closely related to that of telomeric G-DNA complexes. To probe this phenomenon, we have carried out experiments using short antisense DNA oligomers to define the segments of the DLS that are required for dimerization and methylation protection to implicate sets of guanines in forming Hoogsteen hydrogen bonds within the dimer. Cumulatively, these data provide further evidence for the existence of guanine quartets within the dimerized HIV-1 DLS. We propose models in which guanine quartets not only allow the homodimerization of HIV-1 and other retroviral genomic RNAs but also permit the two RNA strands in a dimer to exist in an overall parallel orientation, as has been observed by electron microscopy.

Base Sequence↗
PubMed1992

Characterization of the tetramer-dimer-monomer equilibrium of the enzymatically active subunits of pigeon liver malic enzyme.

The tetrameric malic enzyme from pigeon liver was reversibly dissociated in the sequence of tetramer-dimer-monomer in an acidic environment (pH 4.5) or when the ionic strength or temperature of the solution was perturbed (0.2 M ammonium sulfate or < 10 degrees C). The dissociated monomer was enzymatically active according to the following criteria: (a) separation and direct activity staining of the monomer in the native gradient polyacrylamide gel, (b) activity staining of the monomer at its pI region in the isoelectric focusing gel, and (c) the enzyme showing lower but definite enzyme activity under conditions where only monomer existed in the solution. The catalytic constant (kcat) and specificity constant (kcat/KmMal) for the monomer were found to be 19 +/- 6 s-1 and 58 x 10(3) s-1.M-1, respectively, only one-seventh and one-seventeenth of those for the tetramer. Different types of interactions are involved in the monomer-monomer and dimer-dimer associations: (a) Two dissociation processes showed different pH dependences. The monomer-monomer interactions involve an amino acid with a side chain pKa value around 5.7, and an amino acid with a side chain pKa value of 7.2 is involved in the dimer-dimer association. (b) Ammonium sulfate up to 0.2 M only affects the monomer-monomer but not the dimer-dimer interactions. The Gibb's free energy, enthalpy, and entropy all have negative values for the above subunits' dissociations. The overall dissociation is an enthalpy-driven process. Association of the subunits to form dimers and tetramers involves salt-bridge, van der Waals, and hydrogen-bonding interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Dissociation and association of the HIV-1 protease dimer subunits: equilibria and rates.

The kinetics and equilibrium properties were investigated for the interconversion between the active dimer of human immunodeficiency virus 1 (HIV-1) protease and its inactive monomeric subunits. The equilibrium dissociation constant (Kd) of the dimeric protease as well as the monomer association rate were obtained by monitoring the fluorescence change of an active-site-directed fluorescent probe (L-737244) upon its binding to the protease. The Kd of the HIV-1 protease is strongly pH dependent. At pH 5.5 where the enzyme is most active catalytically, the extrapolated values of Kd are 0.75 and 3.4 nM at 30 and 37 degrees C, respectively. The rate constant for HIV-1 monomer association, approximately 4 x 10(5) M-1 s-1, is within the range commonly observed for protein-protein interactions. Dimer dissociation was further scrutinized in the presence of an inactive, point mutant form of the enzyme. As a result of subunit exchange between the native and mutant enzymes and the formation of an inactive heterodimer, there was a time-dependent decrease in the activity of the native protease. Enzyme activity could be reinstated with the addition of an active-site-directed inhibitor (L-365862) which selectively binds active dimers. The rate of dimer dissociation was found to also decrease with pH. At pH 5.5 and 30 degrees C, the half-life for subunit dissociation is about 0.5 h. The slow dissociation, coupled with the high stability for dimer association, attests to the importance of allowing sufficient time for dimer-monomer equilibration in kinetic assays in order to avoid reaching erroneous conclusions in studies of dimer dissociation.

Amino Acid Sequence↗
PubMed1994

Subunit dissociation affects DNA binding in a dimeric lac repressor produced by C-terminal deletion.

The reduction in apparent operator binding affinity found for dimeric lac repressor proteins produced by disruption of the C-terminal coiled-coil interaction has been proposed to derive from thermodynamic linkage between dimer-monomer and protein-DNA equilibria [Brenowitz et al. (1991) J. Biol. Chem. 266, 1281]. To explore this linkage, we have employed two dimeric proteins, a deletion mutant (-11 aa) missing 11 amino acids at the C-terminus that has diminished apparent operator binding affinity [Chen & Matthews (1992) J. Biol. Chem. 267, 13843] and a mutant (R3) that binds to operator with wild-type affinity in which the C-terminal leucine heptad repeats of lac repressor were replaced by the GCN4 dimerization sequence [Alberti et al. (1993) EMBO J. 12, 3227; Chen et al. (1994) J. Biol. Chem. (in press)]. To avoid the complexities of working at the low concentrations of protein required by the high affinity between the monomer subunits, urea denaturation studies were undertaken to determine the free energy change(s) for dissociation and/or unfolding. Under denaturing conditions, dimer dissociation and monomer unfolding were found to be concerted processes, and the free energy change for the overall process of dimer to unfolded monomer was derived from these experiments for the two dimeric proteins. A monomeric mutant (Y282D) of the lactose repressor was examined to determine the free energy change of protomer unfolding. From the combination of these data, the Kd for -11 aa dimer dissociation was determined to be 7.7 x 10(-8) M, and the corresponding value for R3 protein was 3.2 x 10(-11) M.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA↗
PubMed1991

Interaction of the alpha beta dimers of the insulin-like growth factor I receptor is required for receptor autophosphorylation.

We have recently found that association of the two alpha beta dimers of the insulin-like growth factor I (IGF I) receptor is required for formation of a high-affinity binding site for IGF I [Tollefsen, S. E., & Thompson, K. (1988) J. Biol. Chem. 263, 16267-16273]. To determine the structural requirements for IGF I activated kinase activity, we have examined the effect of dissociation of the two alpha beta dimers of the IGF I receptor on beta subunit autophosphorylation. The alpha beta dimers formed after treatment with 2 mM dithiothreitol (DTT) at pH 8.75 for 5 min were separated from IGF I receptor remaining as tetramers after DTT treatment by fast protein liquid chromatography on a Superose 6 gel filtration column. Purification of the alpha beta dimers was confirmed by Western blot analysis using 125I-labeled alpha IR-3, a monoclonal antibody to the IGF I receptor. Autophosphorylation of the IGF I receptor (alpha beta)2 tetramer, treated without DTT or remaining after DTT treatment, is stimulated 1.6-2.9-fold by IGF I. In contrast, autophosphorylation of the alpha beta dimers incubated in the presence or absence of IGF I (100 ng/mL) does not occur. Both IGF I receptor dimers and tetramers exhibit similar kinase activities using the synthetic substrate Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly, indicating that the failure to detect autophosphorylation of the IGF I receptor dimers does not result from inactivation of the kinase by DTT treatment. We conclude that autophosphorylation of the IGF I receptor depends upon the interaction of the two alpha beta dimers.

Adenosine Triphosphate↗
PubMed1987

Dimerization of the operator binding domain of phage lambda repressor.

Dimerization of lambda repressor is required for its binding to operator DNA. As part of a continuing study of the structural basis of the coupling between dimer formation and operator binding, we have undertaken 1H NMR and gel filtration studies of the dimerization of the N-terminal domain of lambda repressor. Five protein fragments have been studied: three are wild-type fragments of different length (1-102, 1-92, and 1-90), and two are fragments bearing single amino acid substitutions in residues involved in the dimer interface (1-102, Tyr-88----Cys; 1-92, Ile-84----Ser). The tertiary structure of each species is essentially the same, as monitored by the 1H NMR resonances of internal aromatic groups. However, significant differences are observed in their dimerization properties. 1H NMR resonances of aromatic residues that are involved in the dimer contact allow the monomer-dimer equilibrium to be monitored in solution. The structure of the wild-type dimer contact appears to be similar to that deduced from X-ray crystallography and involves the hydrophobic packing of symmetry-related helices (helix 5) from each monomer. Removal of two contact residues, Val-91 and Ser-92, by limited proteolysis disrupts this interaction and also prevents crystallization. The Ile-84----Ser substitution also disrupts this interaction, which accounts for the severely reduced operator affinity of this mutant protein.

Amino Acids↗
PubMed1996

Presence of a slow dimerization equilibrium on the thermal unfolding of the 205-316 thermolysin fragment at neutral pH.

Differential scanning calorimetry and size-exclusion chromatography have been used to characterize the dimerization and unfolding of the 205-316 C-terminal fragment of thermolysin at pH 7.5. We show that the folded fragment dimerizes at low temperature with a moderate affinity and undergoes thermal unfolding according to a N(2) <==> 2N <==> 2U model. This behavior has already been observed at acid pH, where a similar dissociation equilibrium has been found [Azuaga, A., Conejero-Lara, F., Rivas G., De Filippis, V., Fontana A., & Mateo, P. L. (1995) Biochim. Biophys. Acta 1252, 95-102]. Nevertheless, at pH 7.5 the dimerization equilibrium slows down below about 30 degrees C, with virtually no interconversion between the monomeric and the dimeric states of the fragment. We have studied the kinetics of interconversion between monomer and dimer by size-exclusion chromatography experiments and have shown that a very high energy barrier (83.8 kJ/mol at 26.5 degrees C) exists between either state. A mathematical analysis of the DSC thermograms on the basis of the proposed model has allowed us to obtain the thermodynamic characterization of the dimerization and the unfolding processes of the fragment and confirms the kinetic parameters obtained in the chromatographic experiments. The thermodynamic functions for the unfolding of the fragment are compatible with some degree of disorder in the structures of both the monomer and the dimer. According to circular dichroism measurements, the dimerization of the fragment seems to be linked to some conformational change in the subunits, most probably due to a rearrangement of the existing secondary-structure elements. This fragment displays several features already observed in folding intermediates, such as the partial disorder of the polypeptidic chain, association processes, and kinetic barriers between different regions in the conformational space.

Bacillus↗
PubMed1996

A model of PSI dimerization: destabilization of the C278-G303 stem-loop by the nucleocapsid protein (NCp10) of MoMuLV.

We have shown that at low ionic strength (i.e., 100 mM NaCl) a short autocomplementary sequence spanning nucleotides C283 to G298 of MoMuLV RNA genome is involved in the process of PSI dimerization in vitro [Girard, P.-M., Bonnet-Mathonière, B., Muriaux, D., & Paoletti, J. (1995) Biochemistry 34, 9785-9794]. In order to identify other contributions of the PSI structure to RNA dimerization, we studied the kinetics of dimerization as a function of salt concentration of short RNA transcripts comprising or not the autocomplementary sequence C283-G298. We propose that, apart from the crucial role of this sequence in RNA dimerization, the 364-565 domain of PSI can interfere, in vitro, with the initiation of dimer formation. Intermolecular loop-loop recognitions involving the 364-565 domain could stabilize, in a salt concentration-dependent manner, a transient RNA dimer built around the loop-loop U288-A293 interaction. This dimer evolves toward a more stable structure which mainly corresponds to the annealing of two C283-G298 sequences. We also show that chemically synthesized NCp10 does not modify these steps but rather helps the system to pass over the energy barriers associated with the transition to stable RNA structures comprising the stem-loop C278-G303. Data obtained in the presence of NCp10 suggest a binding site size of 9 +/- 1 nucleotides per protein at 37 degrees C and a 10-20-fold increase in the rate constant (i.e., k1 = 24 000 +/- 7000 M-1 s-1) of dimer formation.

Base Sequence↗
PubMed1997

Monomer-dimer equilibrium of uncomplemented M15 beta-galactosidase from Escherichia coli.

A series of gel filtration, native polyacrylamide gel electrophoresis (PAGE) and sucrose density experiments showed that uncomplemented M15 beta-galactosidase is in a monomer-dimer equilibrium and that only under some specific conditions does the equilibrium strongly favor dimerization. The ratio of dimer to monomer increased as a function of the protein concentration, and a very good fit to a theoretical plot of the effect of protein concentration on an associating system of this type was found. The Kdiss (equilibrium constant for dimer dissociation) was 2.5 x 10(-7) M. The addition of 20 mM Mg2+ lowered the Kdiss to 1.5 x 10(-7) M, and the addition of 150 mM NaCl lowered the value to 0.4 x 10(-7) M. Thiol reagents (2-mercaptoethanol and dithiothreitol) caused the equilibrium to shift totally to the dimeric form. The monomer-dimer equilibrium was also found to be dependent upon the pH. The dissociation increased as the pH was raised to 8.5, but there was a reversal of the equilibrium in favor of dimer formation at pH 9.0. This suggests that one (or more) residues with a pKa value of about 8.0 is involved. Tyr and Lys were eliminated as possible residues involved and it is, therefore, likely that one or more Cys are involved. Further evidence that uncomplemented M15 beta-galactosidase is in a monomer-dimer equilibrium was that the gel-filtration peaks were not totally resolved and that native PAGE bands were diffuse under all conditions except at high thiol concentration.

Centrifugation, Density Gradient↗
PubMed2003

Induction of a remarkable conformational change in a human telomeric sequence by the binding of naphthyridine dimer: inhibition of the elongation of a telomeric repeat by telomerase.

The binding of a dimeric form of the 2-amino-1,8-naphthyridine derivative (naphthyridine dimer) to a human telomeric sequence, TTAGGG, was investigated by UV melting, CD spectra, and CSI-MS measurements. Both the 9-mer d(TTAGGGTTA) and the 15-mer d(TTAGGGTTAGGGTTA) showed apparent melting temperatures (T(m)) of 45.6 and 63.6 degrees C, respectively, in the presence of naphthyridine dimer (30 microM) in sodium cacodylate buffer (50 mM, pH 7.0) containing 100 mM NaCl. The CD spectra at 235 and 255 nm of the 9-mer increased in intensity accompanied with strong induced CDs at 285 and 340 nm upon complex formation with naphthyridine dimer. UV titration of the binding of naphthyridine dimer to the 9-mer at 320 nm showed a hypochromism of the spectra. A Scatchard plot of the data showed the presence of multiple binding sites with different association constants. Cold spray ionization mass spectrometry of the complex between naphthyridine dimer and the 9-mer clearly showed that one to three molecules of the ligand bound to the dimer duplex of the 9-mer. Telomeric repeat elongation assay showed that the binding of naphthyridine dimer to the telomeric sequence inhibits the elongation of the sequence by telomerase.

Base Pair Mismatch↗
PubMed2005

Syntheses, structures, spectroscopic properties, and pi-dimeric interactions of [n.n]quinquethiophenophanes.

A cyclophane-type of dimeric quinquethiophenes (4a-e) with the bridge chains consecutively varying from two to six methylenes has been synthesized and studied as ideal pi-dimer models. The double-decker structures of these compounds are verified by upfield shifts for the proton NMR signals of the inside thiophenes, as compared to those of monomeric dimethylquinquethiophene (3). The electronic absorption and emission spectra of 4a-e are perturbed by through-space pi-electronic interactions involving exciton-exciton coupling between the two overlapped quinquethiophenes, which become marked with shortening of the bridged alkylene chains. One-electron oxidation of 4a-e with FeCl(3) in dichloromethane results in the appearance of specific polaronic bands in the near-infrared region of the electronic absorption spectra, due to the generation of a radical cation species (polaron) on one of the quinquethiophenes, which electronically interacts with the remaining neutral species. Two-electron oxidation of 4a-e introduces spectral changes, revealing that the resulting two quinquethiophene radical cations readily form an intramolecular pi-dimer, thanks to their close stacking, in contrast to the difficult formation of an intermolecular pi-dimer from 3. The pi-dimeric spectra of 4b-e are comprised of two strong absorption bands, similar to that of 3, the low-energy band of which is considerably red-shifted by an effective pi-dimeric interaction depending on the lengths of the bridged alkylene chains. Quite different is the spectrum of 4a with three absorption bands inherent in pi-dimer, presumably because the two short bridging chains of 4a force the pi-dimer to take a constrained, strongly interactive structure.

Journal Article↗
PubMed1980

DNA intercalating compounds as potential antitumor agents. 2. Preparation and properties of 7H-pyridocarbazole dimers.

In order to obtain antitumor agents, various 7H-pyridocarbazole dimers were prepared by quaternization of the pyridinic nitrogens of the different isomeric 7H-pyridocarbazole rings with halogenoamino alicyclic or aliphatic chains. The dimers interact with DNA more markedly than with the corresponding monomers, and the bisintercalation depends upon the nature, the flexibility, and the ionization state of the linking chains. They most often bisintercalate at pH 5 where the chain is protonated and monointercalate at pH 7.4. The apparent binding constants (kap) range from 10(8) to 10(9) M-1 at pH 5 and from 5 X 10(5) to 2 X 10(7) M-1 at pH 7.4. The bisintercalating dimers covered four DNA base pairs, whereas most of the monointercalating dimers covered two bases pairs. The antitumor activity against L1210 murine leukemia is strongly dependent on the position of attachment, the nature of the linking chain, and its rigidity. Three highly active dimers were obtained in the series of 7H-pyrido[4,3-c]carbazole dimers with rigid bis(ethylpiperidinyl) chains. On the other hand, two ellipticine dimers were prepared which were found completely inactive on L1210. These results show that in the series of 7H-pyridocarbazoles the process of dimerization leads to very active antitumor compounds.

Animals↗
PubMed2003

Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy.

In only two steps and in 70% overall yield, naturally occurring trioxane artemisinin (1) was converted on a gram scale into C-10-carba trioxane dimer 3. This new, very stable dimer was then transformed easily in one additional step into four different dimers 4-7. Alcohol and diol dimers 4 and 5 and ketone dimer 7 are 10 times more antimalarially potent in vitro than artemisinin (1), and alcohol and diol dimers 4 and 5 are strongly growth inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives 8aand 9 were easily prepared in one additional step from dimers 4 and 5. Carboxylic acid dimers 8a and 9 are thermally stable even at 60 degrees C for 24 h, are more orally efficacious as antimalarials in rodents than either artelinic acid or sodium artesunate, and are strongly inhibitory but not cytotoxic toward several human cancer cell lines.

Administration, Oral↗