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PubMed1987

Relationships between DNA-binding kinetics and biological activity for the 9-aminoacridine-4-carboxamide class of antitumor agents.

The kinetics of dissociation of calf thymus DNA complexes of the new intercalating antitumor drug N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (5) and selected derivatives have been investigated by using the surfactant-sequestration method. The derivatives studied include those where the position (14 and 15) and nature of attachment (20 and 21) of the cationic side chain is modified, those where the distance (16-19) and composition (22-24) of the cationic group are varied, and those in which the chromophore is further substituted (25-31). While all of the compounds dissociate by a mechanism that involves at least three intermediate bound forms, derivatives bearing a 4-CONH(CH2)2NR1R2 side chain (where R1 and R2 are groups that permit the nitrogen to be protonated at neutral pH) have access to an additional binding mode of greater kinetic stability. A positive correlation is found between in vivo antitumor activity, selectivity of binding to GC-rich DNAs, and the presence of this fourth, long-lived transient species. We have interpreted our kinetic findings in terms of a molecular model for acridinecarboxamide-DNA complexes that accounts for the appearance of the fourth component. The acridine chromophore is postulated to intercalate from the narrow groove, its major axis lying at an angle to the major axis of the base pairs so that the CH atoms of positions 5 and 6 protrude into the groove. An important feature of the model is a bifurcated hydrogen bond between the O2 oxygen atom of a cytosine base adjacent to the binding site and the NH atoms of the carboxamide and protonated terminal amino functions of the drug molecule. Since the structural features required to form this bonding interaction are necessary, although not sufficient, conditions for in vivo antitumor activity, it is suggested that the model may describe the essential characteristics of the biologically active form of the bound drug. These findings further attest to the value of investigating the kinetics of DNA-drug interaction in studies of the mode of action of antitumor intercalating agents.

Amides↗

PubMed1996

Design, synthesis, and evaluation of nonpeptidic inhibitors of human rhinovirus 3C protease.

The design, synthesis, and biological evaluation of reversible, nonpeptidic inhibitors of human rhinovirus (HRV) 3C protease (3CP) are reported. A novel series of 2,3-dioxindoles (isatins) were designed that utilized a combination of protein structure-based drug design, molecular modeling, and structure-activity relationship (SAR). The C-2 carbonyl of isatin was envisioned to react in the active site of HRV 3CP with the cysteine responsible for catalytic proteolysis, thus forming a stabilized transition state mimic. Molecular-modeling experiments using the apo crystal structure of human rhinovirus-serotype 14 (HRV-14) 3CP and a peptide substrate model allowed us to design recognition features into the P1 and P2 subsites, respectively, from the 5- and 1-positions of isatin. Attempts to optimize recognition properties in the P1 subsite using SAR at the 5-position were performed. In addition, a series of ab initio calculations were carried out on several 5-substituted isatins to investigate the stability of sulfide adducts at C-3. The inhibitors were prepared by general synthetic methods, starting with commercially available 5-substituted isatins in nearly every case. All compounds were tested for inhibition of purified HRV-14 3CP. Compounds 8, 14, and 19 were found to have excellent selectivity for HRV-14 3CP compared to other proteolytic enzymes, including chymotrypsin and cathepsin B. Selected compounds were assayed for antiviral activity against HRV-14-infected HI-HeLa cells. A 2.8 A cocrystal structure of derivative 19 covalently bound to human rhinovirus-serotype 2 (HRV-2) 3CP was solved and revealed that the isatin was situated in essentially the same conformation as modeled.

3C Viral Proteases↗

PubMed1994

Characteristics of antitumor activity of KW-2189, a novel water-soluble derivative of duocarmycin, against murine and human tumors.

Methyl(1S)-1-bromomethyl-7-methyl-5-[(4-methylpiperazinyl)-carb onyloxy]- 3-[(5,6,7-trimethoxy-2-indolyl)-carbonyl]-1,2-dihydro-3H-pyrolo[3, 2-e] indole-8-carboxylate hydrobromide (KW-2189), a novel derivative of duocarmycin B2, was selected for extensive evaluation based on its improved antitumor activity, water solubility, and stability in the culture medium, as compared with duocarmycin B2. Although the in vitro cell growth-inhibitory activity of KW-2189 was less potent than that of duocarmycin B2, it significantly inhibited the growth of five murine solid tumors including Colon 26 adenocarcinoma, Colon 38 adenocarcinoma, and B16 melanoma in vivo. KW-2189 was also effective against murine P388 leukemia and L1210 leukemia not only by local administration (i.p.-i.p. system), but also by systemic administration (i.p.-i.v. or i.v.-i.v. system). The most remarkable feature of KW-2189 was its efficacy against various human xenografts, which was observed in 14 tumors among 16 tested tumors including drug-insensitive tumors by single i.v. administration. Tumor regression was observed in mice bearing LC-6 lung, St-4 and St-40 stomach, Li-7 liver, PAN-2 pancreas, and MX-1 breast carcinomas. In many cases, the activities of KW-2189 were more than those of clinically active agents, mitomycin C, Adriamycin, cisplatin, and cyclophosphamide. Delayed lethal toxicity, which was reported in mice treated with CC-1065 whose structure was similar to KW-2189, was not observed in mice treated with KW-2189. KW-2189 inhibited DNA synthesis more significantly than RNA or protein synthesis, although DNA strand breaks were not observed. KW-2189 was activated by porcine liver esterase, mouse liver homogenate or Hep G2 homogenate, and DU-86-DNA adducts were detected in KW-2189-treated HeLa S3 cells, suggesting that KW-2189 was converted to DU-86 in the cells. These results indicate that KW-2189 is an interesting candidate for further development as a novel antitumor agent.

Animals↗

PubMed1992

Nonlinearities in amoxycillin pharmacokinetics. I. Disposition studies in the rat.

Several features of amoxycillin pharmacokinetics in man are not well known in spite of the extensive clinical use of the antibiotic. In this paper it is demonstrated that amoxycillin disposition kinetics in rats is clearly nonlinear, and that this may be due mainly to its elimination mechanisms. At different intravenous bolus dose levels, and in steady-state perfusion studies, the most striking feature is an increased renal clearance as dose increases (from 3.5 to 7.0 mg kg-1 for intravenous bolus, and from 4.6 to 20.0 micrograms min-1 for intravenous perfusions). This phenomenon has been attributed to a saturation of the active renal tubular reabsorption of the antibiotic. When the intravenous dose is substantially increased (28.0 mg kg-1 bolus), plasma clearance tends to stabilize, probably because saturation of the active tubular secretion of amoxycillin takes place at these doses. Extrarenal clearance seems to remain linear throughout the entire dose range. On the basis of these observations and a review of selected bibliography, an interpretation of the kinetic disposition behaviour of amoxycillin in man is attempted.

Amoxicillin↗

PubMed1995

Proposed cation-pi mediated binding by factor Xa: a novel enzymatic mechanism for molecular recognition.

Factor Xa (FXa) is an important serine protease in the blood coagulation cascade. Small synthetic competitive inhibitors of FXa are under development as potential anticoagulants. To better understand FXa structural features and molecular recognition mechanisms, we have constructed three dimensional models of FXa-inhibitor complex structures via a new search approach that samples conformational space and binding space simultaneously for DABE and DX-9065a, two bis amidinoaryl derivatives that are among the most potent and selective FXa inhibitors reported to date. We find the most probable binding modes for the two inhibitors to be a folded conformation, with one distal amidino group extending into the S1 pocket, forming a salt-bridge with FXa Asp-189, and the other positively charged group fitting into the S4 subsite, and stabilized by a cation-pi interaction. We propose as a hypothesis that the cavity-like S4 subsite formed by the three pi-faces of the aromatic residues Tyr-99, Phe-174 and Trp-215 is sufficiently rich in pi electrons that it is not only a hydrophobic pocket, but also forms a cation recognition site. This proposed cation-pi binding mechanism is one of the first proposed for enzymatic molecular recognition, and for which experimental verification can be obtained without any complicating charge compensation mechanism. Our models provide plausible explanations of the structure-activity relationships observed for these inhibitors, and suggest that cation-pi interactions may provide a novel mechanism for molecular recognition.

Amino Acid Sequence↗

PubMed1997

The foldability landscape of model proteins.

Molecular evolution may be considered as a walk in a multidimensional fitness landscape, where the fitness at each point is associated with features such as the function, stability, and survivability of these molecules. We present a simple model for the evolution of protein sequences on a landscape with a precisely defined fitness function. We use simple lattice models to represent protein structures, with the ability of a protein sequence to fold into the structure with lowest energy, quantified as the foldability, representing the fitness of the sequence. The foldability of the sequence is characterized based on the spin glass model of protein folding. We consider evolution as a walk in this foldability landscape and study the nature of the landscape and the resulting dynamics. Selective pressure is explicitly included in this model in the form of a minimum foldability requirement. We find that different native structures are not evenly distributed in interaction space, with similar structures and structures with similar optimal foldabilities clustered together. Evolving proteins marginally fulfill the selective criteria of foldability. As the selective pressure is increased, evolutionary trajectories become increasingly confined to "neutral networks," where the sequence and the interactions can be significantly changed while a constant structure is maintained.

Amino Acid Sequence↗

PubMed1997

The relevance of neural architecture to visual performance: phylogenetic conservation and variation in Dipteran visual systems.

In cyclorrhaphan flies, giant tangential neurons in the lobula plate are supplied by isomorphic arrays of evolutionarily conserved achromatic elementary motion detecting circuits originating in the retina. The arrangements among giant tangential neurons is characteristic of a taxon and can differ between taxa having different visual performances. Observations of 12 brachyceran and 4 nematoceran species have identified different behaviors associated with visually stabilized flight. Neuroanatomical comparisons between closely related species having different behaviors and phylogenetically distant species that have similar behaviors suggest that such differences relate to differences of giant tangential cell architecture in the lobula plate. These functionally related differences contrast to anatomical features that reflect phylogenetic affinities. For example, the lobula plates of robber flies, typified by ballistic flight behavior, all differ from other taxa in lacking cyclorrhaphan-type vertical motion-sensitive neurons; instead, they possess an extra complement of horizontal cells in their place. The results suggest that, although circuits that compute elementary motion are conserved across the Diptera, selective pressure has resulted in modifications of their target neurons, thus contributing to the wide variety of visual behaviors observed within this group of insects.

Animals↗

PubMed1998

Evaluation of biodegradable rifampicin-bearing microsphere formulations using a stability-indicating high-performance liquid chromatographic assay.

The validation of a rapid and selective stability-indicating high-performance liquid chromatographic procedure for the determination of rifampicin (RIF) and its decomposition products in aqueous solution is described. Direct injection and column switching HPLC procedures have been compared and, owing to the increased sensitivity and precision, the latter has been applied to the study of RIF stability in the presence of isoascorbic acid at pH 7.4. The time-dependent hydrolytic decomposition of RIF to 3-formyl rifamycin SV (RSV) was found to be biexponential. Log concentration versus time plots of RIF and RSV decomposition were found to be parallel, indicating a pseudo equilibrium decomposition process. This feature allowed corrections for the amounts lost to secondary reactions to be calculated when the assay was applied to the determination of release characteristics of RIF from biodegradable poly-d, l-lactide-co-glycolide microspheres.

Antibiotics, Antitubercular↗

PubMed1996

Protein secondary structural types are differentially coded on messenger RNA.

Tricodon regions on messenger RNAs corresponding to a set of proteins from Escherichia coli were scrutinized for their translation speed. The fractional frequency values of the individual codons as they occur in mRNAs of highly expressed genes from Escherichia coli were taken as an indicative measure of the translation speed. The tricodons were classified by the sum of the frequency values of the constituent codons. Examination of the conformation of the encoded amino acid residues in the corresponding protein tertiary structures revealed a correlation between codon usage in mRNA and topological features of the encoded proteins. Alpha helices on proteins tend to be preferentially coded by translationally fast mRNA regions while the slow segments often code for beta strands and coil regions. Fast regions correspondingly avoid coding for beta strands and coil regions while the slow regions similarly move away from encoding alpha helices. Structural and mechanistic aspects of the ribosome peptide channel support the relevance of sequence fragment translation and subsequent conformation. A discussion is presented relating the observation to the reported kinetic data on the formation and stabilization of protein secondary structural types during protein folding. The observed absence of such strong positive selection for codons in non-highly expressed genes is compatible with existing theories that mutation pressure may well dominate codon selection in non-highly expressed genes.

Bacterial Proteins↗

PubMedDate not supplied

Theoretical studies of cis-Pt(II)-diammine binding to duplex DNA.

The binding of cis-Pt(II) diammine (cis-DP) to double-stranded DNA was studied with several kinked conformations that can accommodate the formation of a square planar complex. Molecular mechanics (MM) calculations were performed to optimize the molecular fit. These results were combined with quantum mechanical (QM) calculations to ascertain the relative energetics of ligand binding through water vs direct binding of the phosphate to the ammine and platinum, and to guide the selection of DNA conformations to model complex formation. Based on QM and MM calculations, models are proposed that may be characterized by several general features. A structure involving hydrogen bonding between each ammine and distinct adjacent phosphate groups, referred to as closed conformation (CC), has already been reported. This is also found in the crystal structure of small dimers. We report alternative conformations that may be important in platination of duplex DNA. They are characterized by an intermediate conformation (IC), involving hydrogen bonding between one ammine and phosphate group, and an open conformation (OC), without ammine phosphate hydrogen bonding. The IC and OC can be stabilized by water bridges in the space between the ammine and the phosphate groups. Sugar puckers alternate from the type C(2')-endo or C(1')-exo (S), to the type C(3')-endo or C(2')-exo (N), with intermediate types near O(1')-endo (O). In general, the sugar puckers alternate from S to N to S through the platinated region (3'-TpG*pG*p-5'), with the complexed strand exhibiting, (3')-S*-N*-S-(5') alternation, while the complementary strand shows either (3')-S*-N*-S-(5') or (3')-S*-N*-O-(5') alternation. In both the OC and IC, a hydrogen bond is found between the ammine and O4(T) on thymine (T) at the (3') end, adjacent to the complex site. There is a continuous range of backbone conformations through the platinated region which relate the OC to the IC. The models presented suggest that the dynamics of the binding of the cis-Pt(II)-diammines to adjacent N7(G) in double-stranded DNA may encompass several conformational possibilities, and that water bridges may play a roll in supporting open and intermediate conformations. Proton-proton distances are reported to assist in the experimental determination of conformations.

Cisplatin↗

PubMed1986

Proposals for the mu-active conformation of the enkephalin analog Tyr-cyclol(-N gamma-D-A2-bu-Gly-Phe-Leu-).

The conformational behavior of the sterically restricted cyclic peptide Tyr-cyclo(-N gamma-D-A2-bu-Gly-Phe-Leu-), proposed recently as an enkephalin analog with high opiate activity, is examined by theoretical investigations. The method used allows the search of conformational energy minima associated with cyclic structures fitting a hypothetical opiate pharmacophore. The results obtained show that, despite the fact that many cyclic structures of low conformational energy can be found for this compound, only one of them can be retained as a conformer presenting the characteristic features of the imposed pharmacophore. This conformation is stabilized by an intramolecular H-bond between the D-A2bu-carbonyl and the Leu NH group so that a beta-turn is formed. This structure also presents a high mobility of the Tyr1 side-chain which can fit the tyramine moiety of rigid opiates with minor loss of conformational energy. A two-step binding mechanism is proposed for the interactions of this cyclic peptide with its receptor which could be an intermediate between the "zipper" model proposed for flexible linear peptides and the "lock-and-key" model adapted to rigid molecules. The selectivity of enkephalin analogs for mu and delta opioid receptors is discussed in light of the present theoretical investigations.

Enkephalin, Leucine↗

PubMed1992

Stability of septohippocampal neurons following excitotoxic lesions of the rat hippocampus.

The present study examined the effects of removing hippocampal nerve growth factor (NGF)-producing neurons upon cholinergic and noncholinergic septohippocampal projecting neurons. To deplete septal/diagonal band neurons of their intrinsic source of NGF, rats received unilateral intrahippocampal injections of ibotenic acid and were sacrificed 2-24 weeks later. Choline acetyltransferase and parvalbumin immunohistochemistry failed to reveal changes in the number of cholinergic or gamma-aminobutyric acid-containing neurons, respectively, within the septal/diagonal band region ipsilateral to the hippocampal lesion at any time point examined. Additionally, immunocytochemical localization of nonphosphorylated and phosphorylated neurofilament proteins did not reveal abnormal staining characteristics within the septal/diagonal band complex, suggesting that this lesion does not alter cytoskeletal features of neurons which project to the hippocampus. Selected rats received unilateral hippocampal lesions and 3 months later were injected with fluorogold into the remaining hippocampal remnant and with wheat germ agglutinin conjugated to horse radish peroxidase into the intact contralateral hippocampus. Both retrograde tracers were predominantly transported to their respective ipsilateral septum and vertical limb of the diagonal band. This indicates that following the lesion, septal/diagonal band neurons still project ipsilaterally and sprouting to the NGF-rich contralateral side does not occur. RNA blot analysis revealed a decrease in NGF mRNA expression within the lesioned hippocampus with a maximum reduction of approximately 70%. In contrast, no change in NGF mRNA expression was observed within the ipsilateral septum relative to the contralateral side. The present study demonstrates that removal of hippocampal target neurons does not alter the number, morphology, or projections of both cholinergic and noncholinergic septal/diagonal band neurons.

Animals↗

PubMed1986

Differential features of ribosomes and of poly(U)-programmed cell-free systems derived from sulphur-dependent archaebacterial species.

The properties of poly(U)-directed cell-free systems developed from the sulphur-dependent, thermophilic archaebacteria Desulfurococcus mobilis, Thermoproteus tenax, Sulfolobus solfataricus, Thermococcus celer and Thermoplasma acidophilum have been compared. All systems are truly thermophilic in requiring incubation at temperatures close to the physiological optimum for cell growth. Under optimized conditions the error frequency in tRNA selection is less than 0.4% at 80 degrees C, and synthetic efficiencies (Phe residues polymerized per ribosome in 40 min) span from 4 for Tp. tenax, to 10 for Tc. celer, to 20-25 for D. mobilis and T. acidophilum and to 40 for S. solfataricus. According to requirements for polypeptide synthesis and to degree of stability of the ribosomal subunits' association, sulphur-dependent thermophiles cluster into two groups. Group I organisms (D. mobilis, Tp. tenax, S. solfataricus) harbour 70-S monomers composed of weakly associated subunits, whose poly(Phe)-synthesizing capacity is totally dependent on added spermine while being drastically inhibited by monovalent cations. Group II organisms (Tc. celer and T. acidophilum) contain 70-S particles composed of tightly bonded subunits, whose synthetic capacity is independent of spermine while being totally dependent on monovalent cations. Spermine promotes poly(Phe) synthesis on ribosomes of group I organisms by converting the peptidyltransferase center into an active conformation, while monovalent cations are inhibitory by preventing the interaction between the free ribosomal subunits. The closeness between Tc. celer and T. acidophilum ribosomes provides new insight on the phylogenetic placement of Thermococcaceae.

Archaea↗

PubMed1990

General features in the stoichiometry and stability of ionophore A23187-cation complexes in homogeneous solution.

Existing literature describing the stoichiometry and stability of complexes between A23187 and divalent cations in solution has been extended to include additional transition series cations, the heavy-metal cations Cd2+ and Pb2+, plus seven lanthanide series trivalent cations. Stability constants of 1:1 complexes between the ionophore and the divalent cations vary by 6.2 orders of magnitude between Cu2+ and Ba2+ which are the strongest and weakest complexes, respectively. Considering alkaline-earth and first-series transition cations together, the pattern of stability constants obeys the extended Irving-Williams series as is seen with many nonionophorous liganding agents. Cd2+ and Pb2+ are bound with an affinity similar to those of Mn2+ and Zn2+, whereas the lanthanides are bound with little selectivity and slightly higher stability. Titration of the ionophore in the 10(-5) M concentration range with di- and trivalent cations gives rise first to complexes of stoichiometry MA2 and subsequently to MA as the metal concentration is increased. The second stepwise stability constants for formation of the MA2 species exceeds the first constant by approximately 10-fold. With lanthanides, heavy metals, and transition-metal cations, OH-, at near physiological concentrations, competes significantly with free ionophore for binding to the 1:1 complexes. This competition is not apparent when Ca2+ or Mg2+ are the central cations. Possible implications of the 1:1 complex selectivity pattern, the ionophore-hydroxide competitive binding equilibria, and potential ternary complexes involving 1:1 ionophore:cation complexes and other anions present in biological systems are discussed with respect to the ionophore's transport selectivity and biological actions.

Biological Transport↗

PubMed1996

Analysis and suppression of DNA polymerase pauses associated with a trinucleotide consensus.

We have studied a novel class of DNA sequences that cause DNA polymerases to pause. These sequences have the central consensus Py-G-C and are not necessarily adjacent to hairpins in the DNA template. Since most consensus sequences do not cause pauses under standard conditions, additional template features must exist that make it difficult to incorporate nucleotides at these positions. We believe that these pauses result from constraints that make the conformation change involved in nucleotide selection more difficult. These pauses can obscure parts of DNA sequencing ladders and prevent DNA amplification by the polymerase chain reaction. The addition of betaine, and some related compounds, relieves these pauses.

Bacteriophage T7↗

PubMed1988

Specific killing of human endothelial cells by antibody-conjugated glucose oxidase.

Conjugates of antibody with glucose oxidase obtained via the carbohydrate moiety of the enzyme via oxidation with periodate are suggested as a tool for selective killing of the target cell. The conjugate was separated from uncoupled enzyme by repeated precipitation with ammonium sulfate (42% saturation). Purity of the conjugate was estimated by gel filtration on Toya Pearl TP-65. The glucose oxidase conjugated with rabbit antibody against mouse IgG bound specifically to plastic-adsorbed mouse immunoglobulins and to cultured human endothelial cells pretreated with mouse anti-endothelial antiserum. Glucose oxidase targeted to the cells generates hydrogen peroxide in the presence of glucose. This hydrogen peroxide killed the endothelial cells even in the absence of a halide-peroxidase system and in the presence of catalase. Features of the conjugate (specificity, effective cytotoxicity, high stability) make it suitable for prospective in vivo application and for immunoselective segregation of heterogeneous cell populations.

Animals↗

PubMed1980

Transmission and scanning electron microscopy of whole glioma cells cultured in vitro.

Twenty-six lines of malignant glioma cells have been established in our laboratories. The cell lines have all been derived from low-differentiated human astrocytomas which did not differ in their histopathological classification. A representative selection of these lines was cultured on formvar-covered, carbon stabilized, gold, EM grids. After glutaraldehyde and osmium fixation, they were dehydrated, critical-point dried and studied as whole-cell preparations in the transmission electron microscopy (TEM) mode. The specimens were then coated with 10-nm of a gold/palladium alloy and the same cells identified and examined in the scanning electron microscopy (SEM) mode. This combined TEM and SEM method makes it possible to relate intracellular structures to surface details, such as ruffles, endocytotic vacuoles, filopodia and microvilli. The study also revealed a large spectrum of dissimilarities between the studied lines, which underlines the fact that no essential structural features of a tumor type can be drawn from studies on occasional lines of cells derived from it.

Astrocytoma↗

PubMed1986

Aniridic glaucoma: the results of gonio-surgery to prevent and treat this problem.

Repetitive gonioscopy of children with congenital aniridia confirms the presence of an angle abnormality which can be progressive and cause glaucoma. This abnormality features obstruction of the trabecular meshwork by variable mixtures of anterior migration of the peripheral iris and thickening of the uveal meshwork associated with a vascular net over exposed trabecular meshwork adjacent to the anterior edge of the iris. Preliminary results of prophylactic gonio-surgery in 28 eyes of 16 children with an average age of 4 years was reported. This surgery was performed without complication and produced a permanent exposure of the trabecular meshwork to the anterior chamber for an average of 8 circumferential hours, if two procedures were performed. Preliminary results suggest a stabilization of eye pressures at least through childhood and encourage the continuation of these prophylactic operations on selected eyes with congenital aniridia. Therapeutic goniotomy for established acquired glaucoma in congenital aniridia cannot be relied on, but may be a benefit for early detected cases or for glaucoma associated with aniridia in infancy.

Child↗