The purpose of this study was to determine the in vitro deposition of both drug (albuterol sulfate) and carrier (lactose) particles in relation to each other from a dry powder inhaler formulation using an Andersen cascade impactor (ACI) and time of flight aerosol beam spectromety (TOFABS). In addition, scanning electron microscopy (SEM) combined with X-ray microanalysis was employed to distinguish albuterol surfate from lactose. Drug particles apparently penetrated deeper into the impactor thatnlactose particles contained in the formulation. In some certain stages of impactor, drug particles were separated from lactose particles. Although the TOFABS cannot distinguish between albuterol surfate and lactose, the TOF spectra obtained from the Aerosizer would appear to be partly indicative of the interactions which exist between drug and carrier. One symmetrical TOF peak was obtaind from drug or lactose alone. The TOF peak of the drug was alwys lower than the TOF of lactose. The times obtained for each powder between experiments were hihgly reproducible and typical of material and particle size. The use of SEM-X-ray microanalysis also allowed some qualitative characterization of shape and state of association of the two components.

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A new extension of the Hildebrand solubility approach which describes drug solubility in solvent mixtures showing multiple solubility peaks, the chameleonic effect, is proposed. The experimental solubilities of oxolinic acid were measured at 25°C in solvent mixtures of ethanol-water and ethanol-ethyl acetate. A plot of the mole fraction of the drug against the solubility parameter (δ) of the solvent mixtures displays two peaks at δ=30.78 MPa^1/2 (80% v/v of ethanol in water) and atδ=20.90 MPa^1/2 (30% v/v of ethanol in ethyl acetate). The new extension proposed reproduces two solubiliyt peaks. The thermogrms of the solid phase before and after equilibration with the solvent mixtures did not show significant changes. The new extension was also tested with experimental data previously reported for drugs showing two solubility peaks of different height. The accuracy of other published models for describing two solubility maxima is also compared.

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The modified extended Hansen method was tested for the first time to determine partial solubility parameters of non-polymeric pharmaceutical excipients. The method was formerly tested with drug molecules, and is based upon a regression analysis of the logarithm of the mole fraction solubility of the solute against the partial solubility parameters of a series of solvents of different chemical classes. Two monosaccharides and one disaccharide (lactose mononydrate, saccharose and mannitol) were chosen. The solubility of these compounds was de-termined in a series of solvents ranging from nonolar to polar and covering a wide range of the solubility parameter scale. Sugars do not absorb at the UV-vis region, and the saturated solutions were assayed with a recent chromatographic technique coupled to an evaporatiev light scattering detector. This technique was suitable to determine the concentration dissolved in most solvents. The modified extended Hansen method provided better results than the original approach.The best model was the four parameter equation, which includes the dispersion δ_d, dipolar δ_p, acidic δ_a and basic δ_b partial solubility parameters. The partial solubility parameters obtained, expressed as MPa^1/2, were δ_d=17.6, δ_p=28.7, δ_h=19, δ_b=14.5, δ_b=12.4, δ_T=32.8 for lactose, δ_d=16.2, δ_p=24.5, δ_h=14.6, δ_a=8.7, δ_b=12.2, δ_T=32.8 for mannitol and δ_d=17.1, δ_P=18.5, δ_h=13, δ_a=11.3, δ_b=7.6, δ_T=28.4 for saccharose. The high total solubility total solubility parameters δ_T obtained agree with the polar nature of the sugars. The dispersion parametes δ_d are quite similar for the three sugars indicating that the polar δ_p and hydrogen bonding parameters (δ_h, δ_a, δ_b) are responsible for the variation in the total solubility parameters δ_T obtained, as also found for drugs. The results suggest that the method could be extended to determine the partial solubility parameters of other non-polymeric pharmaceutical excipients.

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Various compounds were synthesized by combining three components at positions P₁, P_1' and P_2'. Of these, N-(trans-4-aminomethylcyclohexanecarbonyl)-Tyr(O-2-bromobenzyloxycarbonyl)-octylamide inhibited plasmin selectively with IC₅₀ values of 0.80 and 0.23 μM towards S-2251 and fibrin, respectively. THis compound also inhibited plasma kallikrein, urokinase, thrombin and trypsin with IC₅₀ values of 10, >50, >50 and 1.6 μM, rspectively.

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From the stem-bark of Juglans mandshurica, two new naphthalenyl glucopyranosides, 1, 4, 8-trihydroxy-nahthalene 1-O-[α-L-arabinofuranosyl-(1→6)-β-D-glucopyranoside] (1) and 1, 4, 8-trihydroxynaphthalene 1-O-β-D[6'-O-(3", 5"-dihydroxy-4"-methoxybenzoyl)]glucopyranoside (4), and two new α-tetralonyl glucopyranosides, 4α, 5, 8-trihydroxy-α-tetralone 5-O-β-D-[6'-O-(3", 5"-dihydroxy-4"-methoxybenzoyl)glucopyranoside (7) and 4α, 5, 8-trihydroxy-α-tetralone 5-O-β-D-[6'-O-(3", 4", 5"-trihydroxybenzoyl)glucopyranoside (8), were isolated together with three known naphthalenyl glucopyranosides (2, 3 and 5), one α-tetralonyl glucopyranoside (6), four flavonoids (9-12), and two gaalloyl glucopyranosides (13, 14).Amongst the isolated compounds, 1, 2, 6-trigalloylglucopyranose (13) and 1, 2, 3, 6-tertagalloylglucopyranose (14) exhibited the most potent inhibition of reverse transcriptase (RT) activity with IC₅₀ values of 0.067 and 0.040 μM, respectively, while the latter compound also inhibited ribonuclease H (RNase H) activity with an IC₅₀ of 39 μM, comparable in potency to illimaquinone used as a positive contorl. 1, 4, 8-Trihydroxy-naphthalene 1-O-β-D-glucopyranoside (2), 1, 4, 8-trihydroxynaphthalene 1-O-β-D-[6'-O-(4"-hydroxy-3", 5"-dimethoxybenzoyl)]glu-copyranoside (3) and 8 showed moderate inhibition against both enyzme activities, and inhibitory potency of 2 against RNase H activity (IC₅₀=156 μM) was slightly greater than that against the RT activity (IC₅₀=290 μM).The inhibitory potencies of 4α, 5, 8-trihydroxy-α-tetralone 5-O-β-D-[6'-O-4"-hydroxy-3", 5"-dimethoxybenzoyl)] glucopyranoside (6), 7 and 8 against RT activity increased accompanied by an increase in the number of free hydroxyls on the galloyl residues, as represented by the IC₅₀ values of >500, 330 and 5.8 μM, respectively.

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Seven new monoterpene glycoside esters related to paeoniflorin were isolaetd from Paeniae Radix, together with polymeric proanthocyanidins, polygalloylglucoses and 48 known compounds (a benzoylsucrose, seven aromatic acids, adenosine, nine monoterpene glycosids, eight flavan-3-ols, a catechin dimeer formed by oxidation, seven proanthocyanidins, three galloylsucroses, five galloylglucoses, and six ellagitannins). The structures of the new compounds were determined by spectral investigation including two-dimensional NMR techiniques. In addition, increased water solubility of polymeric proanthocyanidin in the presence of paeoniflorin was examined by n-octanol-water partition and ¹H-NMR spectral experiments.

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A heat conduction microcalorimeter was used to evaluate the isothermal transitionin water from anhydrate to monohydrate at 298 K. Sulfaguanidine (SGN) anhydrate was used as a model compound for the measurement of hydration kinetics in water. It is the well-known that SGN is very slighty soluble in water and capable of existing as the anhydrate or monohydrate form in the solid state. The transition rates of SGN anhydrate to monohydrate in tablets and granules were investigated. The hydration kinetics of tablets with controlled surface areas, obatined by coating the side with paraffin in aqueous solution, followed an apparent zero-order mechanism. Onthe other hand, the transision mechanism of the granules involved a phase boundary-controlled contracting interface reaction.

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A new approach for the synthesis of 4-oxo-3-quinolinecarboxylic acid derivtives is described. This methodology involves the C-acylation of the anions of appropriate β-keto esters with novel N-hydroxysuccinimide esters of anthranilic acids. The intermediate C-acylation products 3 are spontaneously cyclized to afford 3-ethoxycarbonyl-4-oxoquinoline derivatives 4. The introduction of a variety of substituents at positins 1 and 2 of the quinoline ring is feasible with the selection of suitable anthranilic acids and β-keto esters. The structure of the obtained 2-substituted 3-ethoxycarbonyl-4-oxoquinolines was confirmed by IR and NMR spectral data.

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A novel synthesis of a radioactive compound of 1α-hydroxyvitamin D₃ (1α OHD₃) (1) and its pharmacokinetics are described. Radioactive 1αOHD₃ tritiated at 22 and 23 positions ([22, 23-³H₄]1αOHD₃) (5) was prepared via key reactions of the reduction of acetylenic side chain in the ketone (12) with tritium gas in the presence of palladium-charcoal and the subsequent Wittig reaction with the A-ring synthon (16). [22, 23-³H₄]1αOHD₃ (5) showed high specific radioactivity (111.5 Ci/mmol) and was used successfully in pharmacokinetics studeies with rats. In the pharmacockinetics studies, the plasma concentration level of the active form of vitamin D₃, 1α, 25-dihydroxyvitamin D₃ [1α, 25(OH)₂D₃], after oral or intravenous administration of [22, 23-³H₄]1αOHD₃ (5), showed longer half-life, lower maximum concentration, and lower area under the curve than those after treatment of 1α, 25(OH)₂D³ tritiated at 26 and 27 positions (4). These results might suggest a beneficial therapeutic utility of 1αOHD₃ (1) over the treatment of 1α, 25(OH)₂D₃ (2).

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Diethylaminosulfur trifluoride reacted with cyclic ketoximes bearing substituent(s) that can stabilize a carbocation to cause fluorinative fragmentation, affording fluorinated carbonitrile. Ketoximes lacking such substituents afforded complex mixtures. However, the intorduction of a sulfur functionality, which can stabilize a carbocatin and can be easily removed from teh reaction products, into the ketoxime was effective for producing the fluorinative fragmentation.

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The superoxide dismutase (SOD) activity of iron(II) tetrakis-N, N, N', N' (2-pyridylmethyl)ethylenediamine complex (Fe-TPEN) was reexamined using a pulse radiolysis mehtod. In our previous study (J. Biol. Chem., 264, 9243-9249 (1989)), we reportd that this complex has a potent SOD activity in a cyt. c (cytochrome c)-based system (IC₅₀=0.8 μM) and protects E. coli cells against paraquat toxicity . The present pulse radiolysis experiment revealed that Fe(II)TPEN reacts stoichiometrically with superoxide to form Fe(III)TPEN with a second-order rate constant of 3.9×10⁶M^-1s^-1 at pH 7.1, but superoxide did not reduce Fe(III)TPEN to Fe(II)TPEN. The reaction of Fe(III)TPEN and superoxide was biphasic. In the fast reaction, an adduct (Fe(III)TPEN-superoxide complex) was formed at the second-order rate constant of 8.5×10⁵_M^-1_S^-1 at pH 7.4. In the slow one, the adduct reacted with another moleculre of the adduct, regenerating Fe(III)TPEN. In the cyt. c method with catalase, this Fe(III)TPEN-superoxide complex showed cyt.c oxidation activity, which had led to overstimation of its SOD activity. Based on the titration data, the main species of complex in aqueous media at neutral pH was indicated to be Fe(III)TPEN(OH^-). A spectral chagne after the reduction with hydrated electron indicates that the OH^- ion coordinates directly to Fe(III) by displacing one of the pyridine rings. The X-ray analysis of [Fe(II)TPEN]SO₄ supported this structure. From the above results we propose a novel reaction mechanism of FeTPEN and superoxide which resembles a proton catalyzed dismuting process, involving Fe(III)TPEN-superoxide complex.

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Chlorpheniramine (CPM) maleate was prepared as a series of resinates by the batch method. The several resinates were investigated by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and infrared (IR) spectrometry. The results from DSC and XRPD showed that the molecular state of the entrapped drug changed from the crystalline to amorphous state. IR spectra indicated that only CPM species was entrapped in the resinates. Moreover, it also showed that the positively charged amine group of the drug interacted with the sulfonate groups of the resin by ionic association. The dissolution of the drug and resinates was also studied where it was found that the dissolution of the resinates was retarded by their corsslinked structure and markedly affectd by the quantity of resin.

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In order to clarify the mechanism of action for the antioxidative activity of fluvastatin sodium (FLV, (±)-sodium (3RS, 5RS, 6E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3, 5-dihydroxy-6-heptanoate) and its derivatives, reaction of the corresponding methyl ester of FLV with di-tert-butyl diperoxyxalate was examined, and the corresponding keto derivative was isolated from the reaction mixture. On the basis of this result, it was concluded that the active site is the allylic carbon conjugated with the indole ring.

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A "trimethyl lock" system has been known to facilitate lactonization reactions through what has been termed a stereopopulation contorl mechanism. We have found that a similar trimethyl lock system can also facilitate cyclic ether formation with the concomitant release of a carboxylic acid in the presence of anhydrous tetrabutylammonium fluoride. To study this base-mediated trimethyl lock-facilitated cyclic ether formation, we synthesized fifteen model compounds. All model compounds underwent base-mediated cyclic ether formation in high yields at 0°C to room temperature (r.t.) with the concomitant release of the attached carboxylate. Such a system potentially could be used for the development of a two-dimensional linker for solid phase peptide and organic synthesis.

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A series of [2-(ω-phenylalkyl)phenoxy]alkylamines was synthesized and thir receptor binding affinity was examined in vitro. These compounds showed an affinity for serotonin-2 (5-HT₂) and dopamine-2 (D₂) receptors. [2-(2-phenylethyl)phenoxy]alkylamine derivatives with a pyrrolidine or piperidine moiety in the structure showed higher affinity for 5-HT₂ receptors but lower affinity for D₂ receptors. Among these compounds, (S)-2-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]1-methylpyrrolidine, (S)-27, exhibited the most potent and selective affinity for 5-HT₂ receptors. Furthermore, (S)-27 was effective in inhibiting 5-HT-induced vasoconstriction in vitro and platelet aggregation both in vitro and ex vivo.

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Structural features of fluorescent methoxycoumarins were examined from the viewpoint of substituent effect and ring structure in connection with intramolecular charge-transfer (ICT). The fluorescence of methoxycoumarins depended primarily upon the ICT from a C₆-electron-donating group to the substituents at the C₃-position of the coumarin ring. Furthermore, the presence of a lactone ring itself, including a carbonyl group, cyclic ether oxygen and ethylenic bond as parital ring structures, was found to be essential for fluorescing in methoxycoumarins according to the fluorescent behaviors of chemically deformed model compounds.

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The inhibitory effects of various endogenous and synthetic compounds on the nitration and oxidation of L-tyrosine by peroxynitrite were examined. Nitrating and oxidizing activities were monitored by the formation of 3-nitrotyrosine and dityrosine with a HPLC-UV-fluorescence detector system, respectively. Glutathione, seroninand synthetis sulfur- and selenium-containing compounds inhibited both the nitration and oxidation reaction of L-tyrosine effectively. However, 5-methosytryptamine, melatonin and α-lipoic acid only inhibited the nitration reaction, and enhanced the formation of an oxidation product. This is important evidence that there are different intermediates in the nitrating and oxidizing reactions of L-tyrosine by peroxynitrite. It was suggested that 5-methoxytryptamine, melatonin and α-lipoic acid reacted only with the nitrating intermediate of peroxynitrite and inhibited nitration of L-tyrosine. Actually, the DNA stand breakage, which is believed to be a typical reaction of hydroxyl radical-like species, caused by peroxynitrite was not effectively ionhibited by 5-methoxytryptamine. 5-Methoxytryptamine, melatonin and α-lipoic acid were viewed as useful reagents for investigating the mechanisms of damage by peroxynitrite in vitro.

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THe synthesis of the new complexes of 1-phenylacetyl-4-phenyl-3-thiosemicarbazide (H₂papts) and 1-phenoxyacetyl-4-phenyl-3-thiosemicarbazide (H₂p_xapts); [Ru(HL)₂(H₂O)₂], [Rh(HL)₃], [Ag(H₂L)(H₂O)₂](NO₃), trans [UO₂(HL)(bipy)(AcO)(H₂O₂)] (H₂L=H₂papts, H₂p_xapts; bipy=2, 2'-bipyridyl), [Ag(H₂papts)(bipy)]⁺ and [Pd-(Hpapts)(bipy)]⁺ is described. Characterization of these complexes by IR, electronic and ¹H-NMR sectra, conductometric titrations and thermal analysis is included. The complexes [Ru(HL)₂(H₂O)₂] were found to be efficient catalysts for the oxidation of primary alcohols to aldehydes and acids, secondary alcohols to ketones and aryl halides to aldehydes and acids in the presence of NaIO₄ as co-oxidant.

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Syntheses of (S)-chroman-2-carboxaldehyde congener 1 and (S)-chiral isoprene unit 3 were achieved based on the enzymatic acetylation of (±)-chroman-2-methanol 6 and (±)-(2, 3)-anti-2-methyl-3-(p-methoxyphenyl)-1, 3-propane diol 12, respectively. Synthesis of the side-chain part corresponding to (3R, 7R)-3, 7, 11-trimethyldodecan-1-ol 27 was achieved by the couping reaction of (S)-3 and (R)-3, 7-dimethyloctyl iodide 4. The Witting reaction of (3R, 7R)-phosphonium salt 2 derived from (3R, 7R)-27 and (S)-1 gave the olefin 28 which was subjected to cat-alytic hydrogenation to afford (2R, 4' R, 8' R)-α-tocopherol.

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A novel isoxazole derivative, O-(5-isoxazolyl)-L-serine (OIS, 1), was synthesized by a Mitsunobu reaction of isoxazolin-5-one (4) with N-Boc-L-serine tert-butyl ester (5) and subseaquent deprotection of the coupling product. Its structure was elucidated by sectroscopic analyses. The pharmacological activity of 1 was also examined with cloned glutamate receptors and transporters using a Xenopus oocyte-expressing system showing substrate activity on an excitatory amino acid carrier 1 (EAAC 1) as a glutamate transporter.

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Three flavonol triglycosides kaempferol 3-[2^Gal-(4-acetylrhamnosyl)robinobioside], kaempferol 3-(2^Gal-rhamnosylrobinobioside) and quercetin 3-(2^G-rhamnosylrutinoside) have been isolated from a methanolic extract of Galega officinalis aerial parts. They are reported for the first time in the genus Galega; moreover, the acetylated triglycoside is a new natural product.

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The effect of excipients on the protein stability during lyophilization as well as the storage stability of lyophilized bilirubin oxidase (BO) andβ-galactosidase (GA) formulations were studied using four polymer excipients : dextran, polyvinylalcohol (PVA), poly(acrylic acid) (PAA), and α, β-poly(N-hydroxyehyl)-L-aspartamide (PHEA). Denaturation of BO and GA during lyophilization largely depended on the excipient used. Dextran appeared to cause severe damage to proteins, whereas PHEA protected proteins effectively from denaturation. Storage stability of BO and GA formulatinas also depended on the excipients. such that the formulations containing dextran and PAA were relatively unstable. Storage stability was improved by absorption of a small amount of water for all the formulations studied. Absorption of a larger amount of water, however, decreased the storage stability of the formulatins containing PVA, PAA or PHEA. In contrast, the storage stability of formulations containing dextran did not decrease noticeably with increasing water. This may be because formulations containing dextran have a higher glass transition temperature than formulations containing PVA, PAA or PHEA when a large amount of water is absorbed.

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A new oleanene glucuronide called melilotus-saponin O₂ (1) was isolated together with three known ones (soyasaponin i, astragaloside VIII, wistariasaponin D) form the aerial parts of Melilotus officinalis (L>) PALLAS (Leguminosae). The structure of 1 was determined to be 3-O-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranosyl-(1→2)-β-D-glucuronopyranosyl melilotigenin by spectroscopic and chemical methods.

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An efficient one-pot procedure for the preparation of diazadioxime was described. Treatment of ketooximes with alkyldiamine followed by NaBH₄ by in dry ethanol afforded the correspponding d, l-diazadioximes in 56-74% yield without isolation of the intermediates.

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Two new cardiac blycosides called cheiranthosides VI (2) and VII (3) were isolated together with a known one, glucoerysimoside (1) from the seeds of Erysimum cheiranthoides. Based on spectroscopic data, the structures of 2 and 3 were charcterized as periplogenin 3-O-β-D-glucopyranosyl(1→4)-β-D-fucopyranoside and peirplogenin 3-O-β-D-glucopyranosyl(1→4)-β-D-antiaropyranoside, respectively.

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New 1, 2-di-substituted carbocyclic nucleosides with 6-chloropurine, adenine and hypoxanthine bases were synthesized by construction of purine on the primary amino group of (±)-trans-2-aminocyclopentylmethanol. AM1 calculations showed close correspondence between the positions of the heteroatoms in the adenine derivative and dideoxyadenosine. The most active of the new compounds in antiviral assays and antitumoral assays against L1210/0, MOLT4/C8 and CEM/0 cells was the 6-chloropurine derivative.

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Easily accessible Ac-(Z)-ΔPhe-NHMe was photoisomerized to so far unknown Ac-(E)-ΔPhe-NHMe. Some parameters of the process leading to a diastereomeric mixture of ratio 90(Z) : 10(E) have been tested and the photoisomerization has been carried out on a preparative milligram scale. The isomers were separated via crystallization followed by preparative HPLC.

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The surface tension of aqueous solutions of simple cyclic, heterocyclic and aromatic amines was measurd with a Du Nouy tensiometer at 25°C and the results discussed in terms of structure-aggrgation relationships.The simple compounds used in this study were piperazine, piperidine, morpholine 3-methylpyridine, cyclohexylamine and benzylamine, with carbon numbers ranging from four to seven.Piperazine, piperidine and morpholine did not form micellr associatins but cyclohexylamine, benxylamine and 3-methylpyridine did, indicating that more than six-carbons are necessary to form micellar associations, at least for compounds having a six-membered ring.

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Two new azadirachtin-type limonoids, 1-methacrylyl-3-acetyl-11-methoxymeliacarpinin (1) and 1-(2-methylpropanoyl)-3-acetyl-11-methoxymeliacarpinin (2), together with the known compounds, melicarpinin D (3), melianin B (4) and 2β, 3β-dihydroxy-5α-pregn-17(20)-(Z)-en-16-one (5), were isolated from the roots of Melia azedarch. The structures of 1 and 2 were elucidated by analysis of spectroscopic data and comparison of their NMR data with those of 3. Compounds 1 and 5 exhibited significant activity in the brine shrimp lethality test (BST).

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Lipase-catalyzed transesterification of acemic 4-substituted 4-hydroxybutyramides with succinic anhydride proceeded enantioselectively to afoord (S)-succinic acid monoester and unreacted (R)-4-hydroxybutyramide derivative, which were separated easily by treatment with an alkaline solution. Both enantiomers were convereted easily to opitcally active γ-substituted γ-butyrolactones.

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A one-pot, convenient method for the preparation of optically active homoallylic alcohols from allyl halides was developed. Allyltrichlorosilanes were generated in situ from allyl halides and trichlorosilane in the presence of cuporous chloride and tertiary amine. Without isolation of the allyltrichlorosilanes, benzaldehyde and chiral biquinoline N, N'-dioxide were introduced into the same flask, producing the corresponding homoallylic alcohols with good to high enantioselectivities.

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Peptides mimicking chemokne receptor CCR5 were synthesized and their anti-HIV-1 activities evaluated. Prepared compounds, especially a sulfated derivatievs, showed significant anti-HIV-1 activities. Furthermore, a hybrid molecule linked to an N-carbomethoxycarbonyl-prolyl-phenylalanine (CPF) moiety had a greater effect.

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Synthesis of J-111, 347 (1), a new 1β-methylcarbapenem with broad-spectrum antibacterial activity including that against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, was achieved via diastereoselective preparationo f a side-chain thiol 3 from an optically active (R)-3, 4-dihydroxybutanal 4.

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We have designed and synthesized estrogen antagonists bearing dicarba-closo-dodecaborane (carborane) as a hydrophobic pharmacophore based on the structure of 1-(4-hydroxyphenyl)-1, 12-dicarba-closo-dodecaborane, a potent estrogen agonist that we reported previously. Compounds with a long alkyl chain bearing an amide moiety on the carborane skeleton (6, 7) showed estrogen antagonistic activity in a luciferase reporter gene assay using COS-1 cells tranfected with a rat ERα-espression plasmid and as an appropriate reporter plasmid.

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