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V J Stella

Publications and source records attributed to V J Stella.

At least 19 recordsLinked to original sources
PubMed1992

A kinetic and mechanistic study of the hydrolysis of camptothecin and some analogues.

Quantitative rate and equilibrium constants for the hydrolysis of the lactone (ring E) in camptothecin (1) and analogues (2-5, all substituted in the A ring of 1) at 25 degrees C in aqueous solution were determined by high-performance liquid chromatography with UV-visible detection and by UV-visible spectrophotometry. It was shown that the lactone was converted to the carboxylate in a pH-dependent equilibrium. No major differences were observed in rate and equilibrium constants for 1-5, a result suggesting that the mechanism of lactone hydrolysis is independent of a variety of substituents on the A ring. The conversion of the lactone to its carboxylate form occurred under neutral and basic conditions and appeared to be largely dependent on hydroxide ion. The conversion of the carboxylate to the lactone was observed under neutral and acidic conditions and was pH independent at pH values greater than 5 and dependent on hydronium ion at pH values less than 5. Significant incorporation of oxygen-18 into the lactone ring of 3, a water-soluble analogue of 1, was observed for the ring opening and subsequent ring closing of 3 in H2(18)O. This finding strongly suggests that the mechanism of lactone ring hydrolysis involved acyl cleavage rather than alkyl cleavage. Kinetic solvent isotope effects (kH2O/kD2O, where kH2O and kD2O are the rate constants in H2O and D2O, respectively), obtained over the pH-rate profile for 1, were used to speculate about the nature of the transition states involved in the opening and closing reactions of the lactone ring.

Algorithms↗
PubMed1992

Characterization of sulphoalkyl ether derivatives of beta-cyclodextrin by capillary electrophoresis with indirect UV detection.

A capillary electrophoresis method which characterizes the degrees of substitution of heterogeneous sulphoalkyl ether beta-cyclodextrin derivatives is described. The separation is based on the different electrophoretic mobilities observed from changes in the overall charge of the molecule as a result of substitution. Individual peaks of the electropherogram then provide a measure of each degree of substitution of the present beta-cyclodextrin. Detection of these beta-cyclodextrin derivatives is performed by indirect UV detection.

Benzoates↗
PubMed1992

Synthesis and evaluation of some water-soluble prodrugs and derivatives of taxol with antitumor activity.

The synthesis and evaluation of some 2'- and 7-amino acid derivatives of taxol (1) are reported. Reaction of taxol with N-protected amino acids gave 2'-N-protected amino acid esters of taxol. However, deprotection of the amino group and subsequent isolation of products were complex and only successful when formic acid was used to deprotect a t-BOC protecting group. Esterification of taxol using N,N-dialkylated amino acids gave 2'-amino acid esters of taxol, 2'-(N,N-dimethylglycyl)taxol (4) and 2'-[3-(N,N-diethylamino)propionyl]taxol as its methanesulfonic acid salt (5b), in good yield. The 7-derivatives, 7-(N,N-dimethylglycyl)taxol (9) and 7-L-alanyltaxol (12), were prepared by two alternate methods. In the first approach, the 2'-hydroxyl group was protected using the [(2,2,2-trichloro-ethyl)oxy]carbonyl, or troc, protecting group followed by the esterification of the 7-hydroxyl and subsequent deprotection of the amino and troc groups. In the second approach, taxol was allowed to react with more than 2 molar equiv of the N-protected amino acids or N,N-dialkylated amino acids to give 2',7-diamino acid esters of taxol. For the protected amino acids, the deprotection of the amino group followed by removal of the 2'-substituent gave the 7-amino acid esters of taxol. The methanesulfonic acid salts of both 2'- and 7-amino acid esters showed improved solubility ranging from 2 to greater than 10 mg/mL. The 7-derivatives were effective in promoting microtubule assembly in vitro while 2'-derivatives showed little in vitro activity. The derivatives 2'-(N,N-dimethylglycyl)taxol (4) and 2'-[3-(N,N-diethylamino)propionyl]taxol (5) inhibited proliferation of B16 melanoma cells to an extent similar to that of taxol, while the other derivatives were about 50% as cytotoxic. In a mammary tumor screen, 2'-[3-(N,N-diethylamino)propionyl]taxol showed the greatest antitumor activity compared to the other analogues. The lower activities of the 7-derivatives in inhibiting tumor growth and melanoma cell proliferation (although they were almost as active as taxol in inducing microtubule assembly in vitro) may be due to differences in drug uptake by the cells. The similar cytotoxic and antitumor activities of the 2'-analogues and taxol can be explained by their conversion to taxol or an active taxol metabolite. Therefore, the 2'-analogues appear to behave as prodrugs and have the potential to be developed as chemotherapeutic agents.

Alkaloids↗
PubMed1992

Is ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] unusually reactive for an imide?

The hydrolysis of ICRF-187 and two model compounds, 4-methylpiperazine-2,6-dione (4-MP) and 3-methylglutarimide (3-MG), was investigated over the neutral to alkaline pH range at 25 degrees C and an ionic strength of 0.5 (sodium chloride). The purpose of the study was to correlate the influence of molecular changes to the reactivity of these imides. Additionally, an improved chromatographic resolution of all the components of the degradation and NMR confirmation of the identity of the degradation products are presented. Based on the study of 4-MP, which is essentially half of an ICRF-187 molecule, and 3-MG, which has a carbon in place of the piperazine nitrogen, several conclusions can be drawn with regard to the stability of ICRF-187. The tertiary piperazine nitrogen/s of 4-MP and ICRF-187 contributed to the base-catalyzed hydrolysis of these compounds above pH 7 and caused a significant decrease in the pKa values of the imide moiety of ICRF-187 and 4-MP compared with 3-MG. One 2,6-piperazinedione ring of ICRF-187 was shown to affect only minimally the rate of hydrolysis of the second ring. ICRF-187 hydrolyzes by parallel consecutive pathways forming two monoacids with one ring opened and, subsequently, the diacid with both rings hydrolyzed.

Chromatography, High Pressure Liquid↗
PubMed1992

The in vitro enzymic labilities of chemically distinct phosphomonoester prodrugs.

The kinetics of decomposition of phosphomonoesters of hydroxymethyl-5,5-diphenylhydantoin (1), estrone (2), 17 beta-testosterone (3), 1-phenylvinyl alcohol (4), and 17 alpha-testosterone (5) were studied in rat whole blood at 25 and/or 37 degrees C. As the acidity of the leaving hydroxyl group of the phosphomonoester increased, there was a tendency for the rate of hydrolysis to increase, except for the anomalous behavior of 4, which was consistent with its relative rate of hydrolysis in aqueous solutions (1). In addition, the kinetics of hydrolysis of 1-5 and p-nitrophenyl phosphate (p-NPP) were studied in the presence of isolated alkaline phosphatases from a variety of sources. The initial rate of production of 17 alpha- and 17 beta-testosterone from their respective phosphate esters (5 and 3), in the presence of human placental alkaline phosphatase, revealed that 3 was hydrolyzed 5.3-fold more rapidly than 5. This difference in reactivity might have been the result of differences in the stereochemical and/or steric nature of the two isomers. For p-NPP, 1, 2, and 4, the kcat and kcat/Km values determined in the presence of the various alkaline phosphatases showed little variation, whereas for 3, the catalytic constants, kcat and kcat/Km, were found to be dramatically less than those found for p-NPP, 1, 2, and 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗
PubMed1992

Kinetics and mechanism of isomerization of cyclosporin A.

The kinetics of isomerization of cyclosporin A to isocyclosporin A were studied in various nonaqueous solvents as a function of temperature and added methanesulfonic acid. The rate of isomerization was found to be acid-catalyzed over the acid concentration range studied. The choice of organic solvent significantly altered the rate of isomerization. For a series of alcohols, the rate was enhanced with increasing dielectric constant of the media, however, this correlation did not hold upon introduction of the dipolar aprotic solvent, tetrahydrofuran. Conversion of cyclosporin A to isocyclosporin A in tetrahydrofuran was found to contain diminished side reactions as compared to alcoholic solvents. The rate of conversion of isocyclosporin A to cyclosporin A was determined in aqueous buffers as a function of pH, buffer concentration, and temperature. The rates of conversion were extremely rapid compared to the forward reaction. Based on the pH dependencies of dilute solution reactivities, isocyclosporin A displayed a kinetically generated pKa value of 6.9 for the secondary amine moiety. From pH 8 to pH 10 the pH-rate profile plot is linear, with a slope approximately equal to unity, indicating apparent hydroxide ion catalysis. The break in pH-rate profile suggests a change in the rate-determining step upon protonation of isocyclosporin A. The rate of isomerization in plasma was comparable with that found in a pH 7.4 buffer solution, indicating that plasma proteins do not significantly alter the isomerization kinetics of isocyclosporin A to cyclosporin A.

Buffers↗
PubMed1992

An unexpected hydrolysis pH-rate profile, at pH values less than 7, of the labile imide, ICRF-187: (+)-1,2-bis-(3,5-dioxopiperazin-1-yl)propane.

The hydrolysis of the cardioprotectant and anticancer agent, ICRF-187 (or ADR-529) and the structurally similar model compound, 4-methylpiperazine-2,6-dione (4-MP), was investigated in the acid to neutral pH range at 25 degrees C and an ionic strength of 0.5 (sodium chloride). Their solution stability was shown to be compromised compared to 3-methylglutarimide (3-MG) and other imides. It appears that the tertiary piperazine nitrogens of ICRF-187 and 4-MP significantly contributed to the instability of these compounds over this pH range. Unexpectedly, bell-shaped curves were observed in the pH-rate profiles. A change in the rate-determining step from tetrahedral intermediate formation in the weakly acidic pH region to breakdown of the tetrahedral intermediate in the more acidic pH regions was proposed as an explanation for the bell-shaped curves. The piperazine nitrogen was implicated in the hydrolytic pathways that occur within these pH regions; the mechanism of involvement was dependent on the state of ionization of the parent molecule and the tetrahedral intermediate.

Drug Stability↗
PubMed1992

The anomalous hydrolytic behavior of 1-phenylvinyl phosphate.

The kinetics of hydrolysis of 1-phenylvinyl phosphate, 1, were studied over a pH range of 1 to 8.3 and over a pD range of 1 to 5.6 at 25 degrees C and mu = 0.5 M with sodium chloride. The hydrolytic behavior of 1 was found to differ, in many respects, from that of alkyl and aryl phosphomonoesters. First, the rates of hydrolysis of 1 were extremely rapid and, in the hydronium ion-catalyzed region, gave a solvent deuterium isotope effect (kH/kD) of 3.20. Also, the 1H-NMR spectrum of acetophenone formed upon complete hydrolysis of 1 in D2O (pD 1.2) revealed that only one deuterium atom was incorporated into the methyl group. Hence, the evidence was consistent with a rate-limiting and nonreversible proton transfer from the solvent to 1. In addition, using an H2 18O labeling study in conjunction with 31P-NMR analysis, the hydrolytic mechanism appeared to involve nucleophilic attack by water at both the alpha-carbon and the phosphorus atom with concurrent C-O and P-O bond fission. Second, in the pH region where the monoanionic species of 1 predominated, buffers had a pronounced catalytic effect on the hydrolysis rate; there appeared to be a normal solvent deuterium isotope effect; and the rate constant, k' o, showed a positive deviation from the established Brønsted relationship. The dissimilarities between 1 and alkyl and aryl phosphomonoesters supported the involvement of an alternate dephosphorylation pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1992

Dissolution of ionizable drugs into unbuffered solution: a comprehensive model for mass transport and reaction in the rotating disk geometry.

A model has been developed to describe the mass transport and reaction of ionizable compounds where mass transfer is caused by convection and diffusion from a rotating disk. Dissolution rates of benzoic acid, 2-naphthoic acid, and indomethacin in aqueous solutions of high ionic strength (I = 0.5 with potassium chloride) at 25 degrees C were investigated. The model includes the effects of diffusion, convection, and simultaneous acid/base reaction at all points in the region adjacent to the dissolving solid. The solution of the transport equations is obtained numerically with an iterative algorithm which uses (a) closure of all material balances and (b) equilibria at the solid/liquid surface as constraints. The model solution yields both the flux of the dissolving acid and the concentration profile of each component. Reduced values of all reaction rate constants are used in the region adjacent to the dissolving surface to allow convergence of the computation. Although nonequilibrium concentration values are calculated, it is shown that the theoretical dissolution rate determined as the solution of the model is insensitive to the magnitude of the rate constants as their maximum useable values are approached. Comparisons of the model results with experimentally determined fluxes show close agreement and confirm that the transport mechanisms in the model formulation are consistent with the measured values. Further, the inclusion of convection allows accurate calculations without utilization of an arbitrary boundary layer thickness. Accurate dissolution rates can be determined using this technique under a wide range of conditions, except at low pH.

Acids↗
PubMed1991

Experimental determinations of diffusion coefficients in dilute aqueous solution using the method of hydrodynamic stability.

Diffusion coefficients were experimentally determined in dilute aqueous solution at 25 +/- 0.1 degrees C, ionic strength 0.5 M, using Taylor's method of hydrodynamic stability. The methodology described is accurate enough to show significant differences in diffusion coefficients between the various ionic forms of the same species as a function of degree of ionization. In Taylor's method, diffusion coefficients were measured by allowing two solutions of differing solute concentration to contact in a capillary tube, forming a stable, measurable concentration gradient. The solute diffusion coefficient is a function of the gradient, the solution viscosity, the solution density, and some capillary dimensions. Viscosity was maintained constant across experiments and values of sufficient accuracy were available in the literature. Solution densities were measured with a tuning fork densimeter. Compounds studied were o-aminobenzoic acid, benzoate anion, the four forms of phosphate and citrate, and the zwitterionic forms of glycine, diglycine, and triglycine. Based on the results for the four forms of phosphate and citrate, experimental diffusivity values vary with the ionic state of the diffusant, presumably because of the altered state of hydration as charge varies. For the glycine series, the diffusivity showed an unexpected dependency on molecular weight (size).

Aminobenzoates↗
PubMed1991

Stability, compatibility, and plasticizer extraction of taxol (NSC-125973) injection diluted in infusion solutions and stored in various containers.

The stability of taxol (NSC-125973) in various diluents and containers was determined, and the extent of leaching of di(2-ethylhexyl) phthalate (DEHP) from polyvinyl chloride (PVC) bags caused by the taxol formulation was measured. A taxol formulation consisting of a 6-mg/mL solution of taxol in 50% polyoxyethylated castor oil and 50% dehydrated ethanol was added to 50- and 100-mL glass bottles, PVC infusion bags, and polyolefin containers containing 5% dextrose injection or 0.9% sodium chloride injection to give initial nominal taxol concentrations of 0.3, 0.6, 0.9, and 1.2 mg/mL. The containers were maintained at 20-23 degrees C for 12-24 hours. Samples were assayed by stability-indicating high-performance liquid chromatography, and clarity was determined visually. An experiment was run to ascertain whether DEHP would leach from a PVC administration set during a simulated infusion. There was no substantial loss of taxol over 24 hours. Filtration through a membrane resulted in no loss of taxol. All the solutions initially appeared hazy. Solutions stored in PVC bags became more hazy with time than solutions stored in glass or polyolefin containers. The haze seen in PVC bags was traced to leaching of DEHP. Agitation had no effect on the extent of leaching. Leaching was also seen during simulated delivery through PVC administration sets. No DEHP was detected when solutions were stored in glass or polyolefin containers and infused through polyethylene-lined sets. At the dilutions studied, taxol was visually and chemically stable for up to 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1990

Mechanism of hydrolysis and structure-stability relationship of enaminones as potential prodrugs of model primary amines.

The objective of this work was to investigate the chemistry and the structure-stability relationship of enaminones (a class of enamines formed between a primary amine and a 1,3-dicarbonyl compound) and to evaluate their potential usefulness as prodrugs of primary amines. The acid-catalyzed degradation of the enaminones was found to be very sensitive to minor differences in the structure of the 1,3-dicarbonyl compound used to form the enaminone, but relatively insensitive to changes in the amine portion of the enaminones. A correlation was found between the rate of enaminone hydrolysis and the pKa of the 1,3-dicarbonyl compound, suggesting that the rate-controlling step in the hydrolysis of the enaminones was the proton addition to the vinyl carbon of the enaminone. Enaminones formed with cyclic 1,3-dicarbonyl compounds were significantly more stable than those formed with structurally similar acyclic compounds. Based on chemical stability considerations alone, enaminones do not appear to be good candidates as prodrugs of primary amines. Evidence is presented, however, that enaminones formed between amines and 1,3-ketoesters or lactones may be subject to enzyme-catalyzed degradation. Further research on the design of enaminones destabilized by a triggering enzymatic event that results in the loss of conjugation (e.g., ester or lactone hydrolysis or an oxidation/reduction event) may prove worth pursuing.

Amines↗
PubMed1990

Chemical stability of pentostatin (NSC-218321), a cytotoxic and immunosuppressant agent.

Pentostatin, an unusual nucleoside of natural origin, has been used for the treatment of hairy cell leukemia, as an immunosuppressant agent, and as an inhibitor of adenosine deaminase. The studies of the physicochemical properties and solution stability of pentostatin are important to the development of a parenteral formulation for extensive preclinical and clinical testing. Pentostatin displayed apparent pKa values at 25 +/- 0.1 degree C and ionic strength of 0.15 M of 2.03 +/- 0.03 and 5.57 +/- 0.14 (spectrophotometric) and 5.50 +/- 0.02 (potentiometric) for N1 and the amidine nitrogen in the seven-membered ring, respectively, which are the most likely protonation sites. The rates of degradation of pentostatin were determined as a function of pH, buffer concentration, and temperature. In the pH range 1.0-4.0, pentostatin undergoes acid-catalyzed glycosidic cleavage leading to the formation of the base compound, and 2-deoxyribose. A carbonium ion mechanism in which C-N bond cleavage was the rate-determining step was consistent with the data. In the pH range 6.5-10.5, the imine bond at C5 position in pentostatin is hydrolyzed to form the corresponding formamide. Pentostatin hydrolysis in this pH range was independent of pH. At pH greater than 11, pentostatin decomposes to nonchromophoric products probably through multiple-step base-catalyzed hydrolytic mechanisms. Pentostatin appears to be quite stable after reconstitution of a lyophilized experimental dosage form. Care must be taken if pentostatin is extensively diluted with 5% dextrose in water, as pentostatin stability is compromised at pH values less than 5.

Buffers↗
PubMed1989

The role of calcium ions and bile salts on the pancreatic lipase-catalyzed hydrolysis of triglyceride emulsions stabilized with lecithin.

Lecithin-stabilized triglyceride emulsions are subject to hydrolysis by pancreatic lipase. The time profiles of these reactions are characterized by a lag-phase and a zero-order phase. Lag phases are more pronounced with long-chain triglycerides. Ca2+ is effective in reducing the lag-phase and activating lipase. Kinetic analysis of the reactions suggests that, like previous findings by others, taurodeoxycholate (TDC) micellar solutions combine with the lipase-colipase complex to form another catalytically active enzyme form. This enzyme form exhibits reduced activity in the absence of Ca2+. In the presence of Ca2+ the mixed micelle-lipase complex becomes more active and opens a new pathway for lipolysis. It is suggested that this enzyme form can bind more easily to interfaces with different physicochemical properties. Under these conditions, Ca2+ activates the lipolysis of short-, medium-, and long-chain triglycerides by a similar mechanism. Maximum activities were measured in the presence of approximately 6 mM TDC and 30 mM Ca2+. The experimental conditions approximate the physiological conditions in the gastrointestinal tract since all of the factors studied here have been reported to be necessary for in vivo lipolysis and/or absorption of triglycerides. A mechanistic model for lipolysis in the presence of Ca2+ and the bile salt TDC is proposed which accounts for most of the experimental observations in a quantitative manner.

Bile Acids and Salts↗
PubMed1989

Pancreatic lipase-catalyzed hydrolysis of esters of hydroxymethyl phenytoin dissolved in various metabolizable vehicles, dispersed in micellar systems, and in aqueous suspensions.

Lipase-catalyzed hydrolysis of fatty acid esters of 3-hydroxymethyl phenytoin was studied in various triglyceride and ethyl oleate emulsions, dispersed in micellar solutions, and suspended in an aqueous buffered solution. Phenytoin release from ethyl oleate emulsions of the prodrugs show apparent first-order kinetics with the pentanoate to nonanoate derivatives and sigmoidal kinetics with the long-chain fatty acid derivatives (stearate and oleate). A transition in the kinetic behavior, between the short- and the long-chain acyl prodrugs, was observed with the decanoate derivative. These observations are accounted for by a proposed kinetic model. Phenytoin release from the solid prodrugs follows zero-order kinetics and is independent of the total amounts of suspended material but directly proportional to the lipase concentration. Lipolysis of the solid suspended prodrugs was dependent on the length of the acyl side chain of the prodrug, with maxima for the pentanoate and the octanoate derivatives. The short-chain derivatives, acetate and propionate, as well as the long-chain prodrug, stearate, showed the slowest lipolysis rate when present as solid dispersions. The zero-order rate is qualitatively correlated with the melting point of the prodrugs. This result might be expected if the melting point is taken as a measure of the cohesivity or packing of the molecules at the surface of a crystal.

Catalysis↗
PubMed1987

Mechanistic investigation of the degradation of sulfamic acid 1,7-heptanediyl ester, an experimental cytotoxic agent, in water and 18oxygen-enriched water.

The hydrolytic degradation of sulfamic acid 1,7-heptanediyl ester was carried out in water and 18O-enriched water at 47 degrees C. The degradation of 1 was also studied at various pH values in the range of 2.5 to 8.0 at constant ionic strength (0.15 M) and temperature (25 degrees C). The hydrolysis was first order and independent of pH with a mean (+/- SD) observed rate constant (kobs) of 2.38 +/- 0.6 X 10(-3) h-1. No significant buffer catalysis was observed. From TLC, HPLC, and mass spectral studies, 1 initially degraded to sulfamic acid 1,7-heptanemonoyl ester and subsequently to 1,7-heptanediol. The site of bond cleavage was assessed by mass spectrometry of the 18O-enriched water reaction mixtures. Exclusive C--O bond fission was observed. Several mechanistic pathways for the degradation of 1 could be postulated. The results from 18O-labeling studies, the pH-rate profile and buffer studies, and kinetic solvent isotope effect (KSIE) studies were consistent with an SN2 mechanism with an early transition state (reactant-like transition state) where no appreciable bond had developed between the incoming nucleophile, water, and the carbon atom of 1. Although an SN1 mechanism was unlikely, based on the need to postulate the formation of a primary carbocation, this mechanism could not be totally ruled out.

Antineoplastic Agents↗