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Biomedical subjects

R M Kellogg

Publications and source records attributed to R M Kellogg.

At least 19 recordsLinked to original sources
PubMed2001

Diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide.

The highly diastereoselective addition of allylzinc bromide to imines derived from (R)-phenylglycine amide is reported. Homoallylamines with high enantiomeric purity are obtained from the adducts in three steps on removal of the chiral auxiliary by means of a nonreductive protocol. Removal of the auxiliary by hydrogenation leads to the saturated amines, also in high enantiomeric purity. [reaction: see text]

Journal Article↗
PubMed2001

Asymmetric strecker synthesis of alpha-amino acids via a crystallization-induced asymmetric transformation using (R)-phenylglycine amide as chiral auxiliary.

[reaction: see text]. Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and can be isolated in 76-93% yield and dr > 99/1. The diastereomerically pure alpha-amino nitrile obtained from pivaldehyde (R1 = t-Bu, R2 = H) was converted in three steps to (S)-tert-leucine in 73% yield and >98% ee.

Amides↗
PubMed2001

Synthesis, analysis and reduction of 2-nitropropyl starch.

Granular 2-nitropropyl potato starch was synthesized by reaction with 2-nitropropyl acetate in an aqueous suspension. Nitroalkylation occurs preferentially with the amylose fraction of potato starch, as was confirmed by leaching experiments and digestion of the modified starch with alpha-amylase. The 2-nitropropyl substituent is a mixture of the nitroalkane and nitronic acid tautomer. Some grafting occurs and to a lesser extent additional reactions (formation of carbonyls and oximes) of the nitro group take place. After catalytic hydrogenation of water soluble 2-nitropropyl starch only a small amount of the nitro functionality was reduced to the corresponding amine. Reduction of granular 2-nitropropyl starch with sodium dithionite did not go to completion and led to a complex mixture of starting material, several intermediates and side products (for example sulfamates).

Amylose↗
PubMed2001

Highly enantioselective and regioselective biocatalytic azidolysis of aromatic epoxides.

[figure: see text] The halohydrin dehalogenase from Agrobacterium radiobacter AD1 catalyzed the highly enantioselective and beta-regioselective azidolysis of (substituted) styrene oxides. By means of kinetic resolutions the remaining epoxide and the formed azido alcohol could be obtained in very high ee. In a large scale conversion, the decrease in yield and selectivity due to the uncatalyzed chemical side reaction could be overcome by slow addition of azide.

Azides↗
PubMed2000

Fluorescent-labeled ligands for the benzodiazepine receptor. Part 1: Synthesis and characterization of fluorescent-labeled benzodiazepines.

Because radioactive labeled ligands in receptor assays have several disadvantages, we synthesized a number of fluorescent-labeled benzodiazepines. Several fluorophores were attached at different positions of 1,4-benzodiazepine molecules in order to assess the impact of the fluorophores and their coupling position on the affinity for the benzodiazepine receptor. Besides the 1,4-benzodiazepines, the 1,2-annelated 1,4-benzodiazepines were also used for labeling. A metabolite of flumazenil (18), desethylflumazenil (Ro15-3890, 19), was labeled with the fluorophore 4-bromomethyl-7-methoxycoumarin, with and without the incorporation of a spacer chain, yielding the methyl-methoxycoumarin (Mmc) derivatives Mmc-Ro15-3890 (20a) and Mmc-O-CO-(CH2)3-Ro15-3890 (20b), respectively. After the synthesis, the fluorescent-labeled benzodiazepines were purified by HPLC, using an analytical RP-C18 column. For the purification of 20b, the chromatographic system was optimized, using multi-criteria decision making (MCDM) techniques. The binding affinities for the benzodiazepine receptor and the fluorescence characteristics were determined for the resulting products.

Animals↗
PubMed1999

Design and synthesis of reagents for phage display screening of dehalogenases.

Bifunctional molecules containing both a biotin and a substrate unit have been designed and synthesized for phage display screening of mutant libraries of haloalkane dehalogenase enzymes. The molecules were assembled using a convergent modular synthetic strategy. One molecule was synthesized to evaluate the concept of covalent capture and a second for screening of phage libraries for enantioselectivity.

Alkyl and Aryl Transferases↗
PubMed1998

Cross-linking of starch with bifunctional precursors of nitroalkenes.

Granular starch was cross-linked with 1,3-di-O-acetyl-2-nitro-1,3-propanediol (1), 1,3-di-O-pivaloyl-2-nitro-1,3-propanediol (2), 2-nitro-3-O-pivaloyl-1-propene-3-ol (3), 1,3-di-O-acetyl-aci-2-nitro-1, 3-propanediol (4), 1,3-di-O-pivaloyl-aci-2-nitro-1,3-propanediol (5) and 1,6-di-O-acetyl-2,5-dinitro-1,6-hexanediol (6). The bifunctional precursors for the nitro-alkenes 1, 2, 3, and 4 were readily synthesized in high yields from nitromethane, paraformaldehyde and acetic anhydride (1, 3) or pivaloyl chloride (2, 4), respectively. The reaction rate for the cross-linking was very high, and for 1 and 3, the reaction reached completion within 1 h (at room temperature). The swelling capacities of the products obtained when starch was cross-linked with precursors for the nitroalkenes 1-4 and 6 were lower in comparison to epichlorohydrin cross-linked starch. These results indicate a high reaction efficiency at low degrees of substitution. Cross-linked 2-nitroalkyl starch ethers were synthesized in a one-pot synthesis by addition of 1 or 3 and 2-nitroalkyl acetates to granular suspensions of starch.

Alkylation↗
PubMed1995

Synthesis and cytotoxicity of novel lignans.

In this study the syntheses of 11 novel lignans are described. Their cytotoxicities are studied in GLC4, a human small cell lung carcinoma cell line, using the microculture tetrazolium (MTT) assay. Ten of these compounds were substituted with a menthyloxy group on the 5-position of the lactone. These compounds can easily be prepared in (novel) 'one-pot', three- or four-step syntheses. In addition, methods for controlling the stereogenic centers are described. Furthermore, five naturally occurring podophyllotoxin-related compounds were tested. The cytotoxicities of all lignan compounds, and of three non-lignan intermediates originating from the syntheses, were compared with the clinically applied anticancer agents etoposide, teniposide, and cisplatin. Most compounds showed moderate to high activities against GLC4, and two of the compounds containing a menthyloxy group showed activities comparable to the reference cytotoxic agents.

Antineoplastic Agents↗
PubMed1992

Low molecular weight proteins as carriers for renal drug targeting. Preparation of drug-protein conjugates and drug-spacer derivatives and their catabolism in renal cortex homogenates and lysosomal lysates.

Low molecular weight proteins (LMWPs) are known to be reabsorbed and catabolized primarily by the proximal tubular cells of the kidneys. As such, LMWPs might serve as drug carriers that release drugs site-specifically in the kidney. We tested this concept in vitro by coupling different drugs to the LMWP lysozyme both directly (amide bond) and via different spacers: oligopeptides (amide bond), (poly-)alpha-hydroxy acids (ester bond), and a pH sensitive cis-aconityl spacer (amide bond). The capability of the kidney to release the parent drug from such drug-spacer derivatives and drug-LMWP conjugates by enzymatic or chemical hydrolysis of the bond was tested by incubation experiments in renal cortex homogenates and lysosomal lysates. Directly coupled conjugates of terminal carboxyl group containing drugs and lysozyme were catabolized to single amino acids, but did not result in release of the parent drug. The amide bond between the drug and the final amino acid (lysine) appeared to be stable in the incubation milieu. Different oligopeptide spacers coupled to the drugs showed similar results: the oligopeptide itself was cleaved but the amide bond between the drug and different single amino acids remained untouched. Only amide bonds of derivatives of carboxylic drugs with peptide structures themselves were cleaved. Some of the directly coupled conjugates of terminal amino drugs and oligopeptides showed clear release of the parent drug whereas others were stable. Terminal amino drugs were rapidly released from an acid-sensitive cis-aconityl spacer. Terminal carboxyl group containing drugs were enzymatically released from their glycolic and lactic ester spacers at different rates. These kinds of drugs were also released as parent drug from LMWP conjugates with ester spacers like L-lactic acid. Increasing spacer length by intercalating a tetra(L-lactic acid) molecular between the drug and the protein further increased the extent and rate of drug release, indicating increased accessibility of the bond to the enzymes. Terminal amino group containing drugs were rapidly generated as parent drug from LMWP conjugates using an acid-sensitive spacer. In addition the conjugates were found to be adequately stable in plasma, considering their rapid clearance from the bloodstream. It is concluded that LMWPs may indeed be of use as carriers for specific renal delivery of drugs, since renal cortex homogenates and lysosomal lysates are able to catabolize the protein and generate the parent drug from drug-LMWP conjugates bearing suitable spacers. The option of enzymatic release is limited by the narrow specificity of the lysosomal enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed1985

Continuous-flow techniques for platelet concentrate collection: a step toward standardization and yield predictability.

This study chronicles leukocyte- and erythrocyte-depleted platelet concentrate collection by a dual stage channel in which three variables: 1) donor peripheral blood platelet concentration, 2) total blood processed, and 3) collection volume were statistically correlated with platelet yield as determined by a multiple regression analysis of single variables. Platelet concentration in the final yield was related to donor precount and collection rate, and could be varied as indicated for individual applications. Total blood processed was established by procedure time, which in turn was defined by citrate-induced calcium changes in the donor. Reduction in peripheral blood platelet concentration averaged 24% for a mean platelet yield of 3.8 X 10(11). An average of 40% of transfused platelet concentrates were recovered in recipient peripheral blood 1 hr posttransfusion and were hemostatically effective, as determined by correction of bleeding time. Platelet yields and patient response were sustained during current collection procedures, verifying the principles described during the investigative period.

Adult↗
PubMed1983

Mononuclear cell (MNC) collection by continuous-flow centrifugation (CFC).

Mononuclear cell separation and collection by continuous-flow centrifugation relates to centrifugal acceleration, total blood processed, peripheral blood concentration, and probable mobilization from extravascular sites during the procedure. At low-G forces, 70-80% of mononuclear cells are cleared. As G forces are increased, 95-100% of mononuclear cells can be cleared, but excessive platelet depletion occurs. An average of three billion cells were harvested from 2-3 liters of blood, rising to nine billion when 6 liters were processed. The total blood processed is defined by citrate infusion rates and ionized calcium changes. Large quantities of mononuclear cells were collected from normal donors without any significant depletion. If the objective of harvesting mononuclear cells is depletion, intensive schedules may be needed.

Blood Component Removal↗
PubMed1982

Bioorganic modelling stereoselective reactions with chiral neutral ligand complexes as model systems for enzyme catalysis.

In terms of the reporting of accomplished chemistry this review can do no more than give an indication of the rapid progress in the branch of bioorganic modelling based on the use of macrocyclic compounds that (usually) act as complexing agents. What remains to be done, however, is to point out problems that have not been satisfactorily solved and to suggest other profitable areas of investigation. From the material accumulated in this review one can draw the conclusion that especially crown (or cryptate) systems offer special advantages in bioorganic modelling because such compounds can - enzyme like - complex a potential substrate. On the basis of quite simple binding considerations, coupled with an analysis of steric interactions, accurate predictions of the stereochemistry of the complex can be made. The inclusion of catalytic groups in the crown (or cryptate) system and reactive functional groups in the substrate is then done in such a fashion that the stereoelectronic arrangement is compatible with the predicted geometry of the complex. However, the good complexing ability of the ligand is paradoxically often its greatest failing in terms of developing a system in which the functionalized ligand acts truly as a catalyst. As seen from much of the chemistry discussed in this review the ligand is incapable of the double task of complexing substrate but releasing product in an enzymic fashion, i.e. that turnover occurs. How is this problem to be solved? Induced conformational changes are an obvious approach although the design of proper systems remains a challenge for which few suggestions outside of unlimited ingenuity can be given. Much of the solution to such problems will lie also in a much better understanding than we now have of non-covalent interactions and the stereochemistry of such interactions. The assembly and disassembly of large molecular aggregates by the making and dissolution of non-covalent bonds is an art at which chemists are still relative amateurs. A better understanding of non-covalent interactions may also provide the key to achieving also the twin goals of both speed and selectivity in bioorganic modelling. As far as enantioselectivity is concerned it is clear that this can be achieved fairly effectively by the use of relatively small, but appropriately placed, groups that force the substrate to complex in an enantioselective step with the ligand. In other words, the problem of enantioselectivity can be solved at the stage of complex forming, which is kinetically rapid. The p]roblem of rate enhancement lies in the mentarity with the transition state of the reaction being catalyzed. Again the achievement of this goal lies in ingenuity of design. Potential areas of applications of chiral crown ether (or cryptate) ligand systems in bioorganic modelling lie in, for example, the formation of carbon-carbon bonds, development of oxidative processes (i.e...

Chemical Phenomena↗
PubMed1981

Cross cellular contamination in plateletpheresis, leukapheresis and plasma exchange.

Continuous flow cell separation procedures in the IBM-2997 single stage and dual stage channels allow collection of components for replacement transfusions and therapeutic exchange of plasma or depletion of leukemic leukocytoses or thrombocytoses. Minimal cross cellular contamination with red cells and lymphocytes is achieved for platelets collected in the dual stage channel through blood path design. A reduction in cross cellular contamination is minimized in the single stage channel by procedural guidelines which reflect the principles of whole blood response to centrifugal acceleration in this system

Blood Transfusion↗
PubMed1979

Principles of blood separation and component extraction in a disposable continuous-flow single-stage channel.

A single-stage disposable channel and seal that provides for leukocyte and granulocyte collection by continuous-flow cell separation (CFCS) has been designed by the IBM Corporation. This paper describes (1) the separation characteristics of whole blood as it responds to varying gravitational (G) forces and flow rates through the channel; (2) the mechanism by which the buffy coat accumulates and is extracted; (3) the efficiency of extraction; (4) those donor and procedural variables that contribute to the final yield; (5) posttransfusion increment response in patients; and (6) the functional integrity of the cells collected.

Blood Cells↗