Intestinal Absorption of Acyclovir β-Glucoside: Comparative Study with Acyclovir,Guanosine, and Kinetin β-Glucoside

Purpose. To characterize the intestinal absorption of a -glucose conjugate of acyclovir (9-[(2-hydroxyethoxy) methyl] guanine, ACV) and compare it to ACV and its analogues in terms of stability and transport by Na⁺/glucose cotransporter (SGLT1). Methods. ACVglc was enzymatically synthesized using cellulase. Intestinal absorption experiments were performed with rat everted small intestine. Conformation of the glucose moiety was analyzed by NMR spectroscopy. Results. The ACVglc was stable on the mucosal side, and was transported to the serosal side in all regions of the small intestine. However, significant contribution of SGLT1 to the transport of ACVglc was not observed. NMR spectroscopic analysis indicated that the glucose conformation of ACVglc was the ⁴C₁ chair form, identical to (-glucose or SGLT1-transportable -glucosides reported previously. Therefore, other factors such as molecular size and charge due to aglycone may cause no transport of ACVglc by SGLT1. On the other hand, the hydrophilicity of ACVglc was much higher than of ACV, suggesting water solubility-derived improvement of intestinal absorption of ACV. Conclusions. ACVglc is stable and absorbable, but it is not transported by SGLT1. No involvement of SGLT1 in the ACVglc transport is not due to glucose conformation.     

Synthesis and β-Adrenergic Activities of R-Fluoronaphthyloxypropanolamine

Purpose. Many biogenic amines where an aromatic proton is substituted with fluorine have exhibited pharmacological properties that are dependent on the position of fluorine on the aromatic ring. For example, 6-fluoroepinephrine is selective for -adrenergic receptors whereas the 2-fluoroisomer is selective for -receptors. Aryloxypropanolamines are -receptor agonists or antagonists, depending on the aryl group and its substituents. We therefore hypothesized that fluorine substitution on the aromatic ring could lead to significant biological effects in this class. A target with fluorine on naphthyl group of a known -antagonist was chosen for investigation. Methods. Synthesis of the target compound began with fluoronaphthalene and involved introduction of 4-hydroxy group by Friedel-Crafts acylation followed by Baeyer Villiger oxidation. The side chain was introduced stereoselectively using the chiral synthon (2R)-glycidyl 3-nitrobenzenesulfonate, a Sharpless epoxidation technique. The epoxide was opened with t-butyl amine. HPLC methods were used to characterize %ee of the enantiomer. Results. The target compound was synthesized in several hundred milligram quantity, and in good yield and high enantiomeric excess, showing practicality of the synthetic scheme. It exhibited potent binding activities on -adrenergic receptors, and was found to be two times selective for ₂-receptors over ₁. Conclusions. The current report demonstrates that aromatic fluorine substitution on -adrenergic ligands can be achieved, and that such can be used to obtain binding selectivity between receptors.     

Synthesis and Characterization of a Cytotoxic Cationic Polyvinylpyrrolidone–Curcumin Conjugate

Curcumin has been studied as a potential drug for many diseases including cancer. One of the serious limitations projected on curcumin is its poor water solubility and the substantially low bioavailability. With a view to enhance the aqueous solubility of curcumin, we synthesized polyvinylpyrrolidone–curcumin conjugates. Polyvinylpyrrolidone was used for the conjugation considering its long history of safe usage as a biomaterial for various medical applications. The drug conjugates self-assembled in aqueous solution to form nanosized micellar aggregates. The formation of micellae stabilized curcumin against hydrolytic degradation. Another interesting feature of the conjugate was its cationic nature. The net zeta potential in the pH range from 3 to 7.4 was +25 to +20 mV, reflecting the potential stability of the conjugate micellae at physiological pH. We quantified cytotoxic potential of the conjugate by the MTT assay, using L929 fibroblast cells. The results showed that the conjugate had higher cytotoxicity than that of the free curcumin. It is expected that the relative enhanced cytotoxicities are the result of enhanced aqueous solubility and polymer-mediated drug internalization. The conjugate has the potential to circumvent limitations of curcumin and thereby to extrapolate further its applications as an effective anticancer drug.     

The Physicochemical Properties,Plasma Enzymatic Hydrolysis,and Nasal Absorption of Acyclovir and Its 2′-Ester Prodrugs

A series of 2-(O-acyl) derivatives of 9-(2-hydoxyethoxymethyl)guanine (acyclovir) was synthesized by acid anhydride esterification. Aqueous solubilities in isotonic phosphate buffer (pH 7.4), partition coefficients in 1-octanol/phosphate buffer, and hydrolysis kinetics in rat plasma were determined. The ester prodrugs showed consistent increases in lipophilicity with corresponding decreases in aqueous solubility as a function of side-chain length. The bioconversion kinetics of the prodrugs appear to depend on both the apolar and the steric nature of the acyl substituents. When perfused through the rat nasal cavity using the in situ perfusion technique, acyclovir showed no measurable loss from the perfusate. Nasal uptake of acyclovir prodrugs, on the other hand, were moderately improved. Furthermore, the extent of nasal absorption appears to depend on the lipophilicity of the prodrugs in the descending order hexanoate > valerate > pivalate > butyrate. Simultaneous prodrug cleavage by nasal carboxylesterase was also noted in the case of hexanoate.     

Synthesis and antidiabetic activity of β-acetamido ketones

This paper reports the use of trifluoroacetic acid as a catalyst in the Dakin–West reaction for the synthesis of β-acetamido ketones. The method has several advantages such as requiring only mild conditions and a low concentration of catalyst. Screening of 19 β-acetamido ketones for antidiabetic activity in vitro showed that their activity as peroxisome proliferator-activated receptor (PPAR) agonists and as dipeptidyl peptidase 4 (DPP-IV) inhibitors was fairly weak.     

PEG–Ursolic Acid Conjugate: Synthesis and In Vitro Release Studies

A highly water-soluble macromolecular compound of ursolic acid with monomethoxypoly(ethylene glycol) (mPEG) was prepared. The physicochemical properties and stabilities under different conditions were investigated. By PEG conjugation, greatly increased water solubility was obtained, and the results showed that this conjugate was a potential prodrug for the oral delivery of ursolic acid.     

Synthesis and cytotoxic activity of new β-carboline derivatives

On the basis of harmine and 1-methoxy-canthin-6-one chemical structures, a series of novel 1,4-disubstituted and 1,4,9-trisubstituted β-carbolines and tetracyclic derivatives were designed and synthesized. Cytotoxic activities of these compounds in vitro were investigated in a human tumor cell line panel. Almost all compounds demonstrated interesting cytotoxic activities in particular against prostate cancer cells PC-3 with IC50 in the low micromolar range. Compound X was found to be the most potent one with IC50 value of 8.0 μM; this suggests further studies with models of prostate cancer.     

Synthesis of β-hydroxy-propenamide derivatives and the inhibition of human dihydroorotate dehydrogenase

Novel beta-hydroxy propenamides as analogues of the active metabolite of leflunomide (A 771726) were synthesized and evaluated for their inhibitory activity on dihydroorotate dehydrogenase (DHODH) in an investigation into their immunosuppressive activity. Compounds 2a, 3a, and 3h were approximately 4-40 times more potent than leflunomide in their activity while they were-less active than A 771726.     

Synthesis and antitumor efficacy of a β-glucuronidase-responsive albumin-binding prodrug of doxorubicin

In this paper we describe the synthesis and biological evaluation of the first β-glucuronidase-responsive albumin-binding prodrug designed for the selective delivery of doxorubicin at the tumor site. This prodrug leads to superior antitumor efficacy in mice compared to HMR 1826, a well-known glucuronide prodrug of doxorubicin that cannot bind covalently to circulating albumin. Furthermore, this compound inhibits tumor growth in a manner similar to that of doxorubicin while avoiding side effects induced by the free drug.     

Synthesis and Evaluation of a Well-defined HPMA Copolymer–Dexamethasone Conjugate for Effective Treatment of Rheumatoid Arthritis

Purpose  To develop a pH-sensitive dexamethasone (Dex)-containing N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate with well-defined structure for the improved treatment of rheumatoid arthritis (RA). Methods  A new pH-sensitive Dex-containing monomer (MA–Gly–Gly–NHN=Dex) was synthesized and copolymerized with HPMA using reversible addition–fragmentation transfer (RAFT) polymerization. The structure of the resulting HPMA copolymer–Dex conjugate (P-Dex) was analyzed and its therapeutic efficacy was evaluated on adjuvant-induced arthritis (AIA) rats. Results  P-Dex was synthesized with controllable molecular weight and polydispersity index (PDI). The Dex content can be controlled by the feed-in ratio of MA–Gly–Gly–NHN=Dex. The P-Dex used for in vitro and in vivo evaluation has a average molecular weight (M _w) of 34 kDa and a PDI of 1.34. The in vitro drug-release studies showed that the Dex release from the conjugate was triggered by low pH. Clinical measurements, endpoint bone mineral density (BMD) test and histology grading from the in vivo evaluation all suggest that newly synthesized P-Dex has strong and long-lasting anti-inflammatory and joint protection effects. Conclusions  A HPMA copolymer–dexamethasone conjugate with a well-defined structure has been synthesized and proved to be an effective anti-arthritis therapy. It may have a unique clinical application in the treatment of rheumatoid arthritis. Xin-Ming Liu and Ling-Dong Quan have contributed equally to this work.     

Synthesis of a New pH-Sensitive Folate–Doxorubicin Conjugate and its Antitumor Activity In Vitro

Folate–aminocaproic acid–doxorubicin (FA–AMA–DOX) was synthesized and characterized by H NMR spectroscopy and mass spectrometry. Cytotoxicity and cellular uptake experiments were performed in KB and HepG2 cells, which express folic acid receptor, and the cell line A549, which does not express folic acid receptor. Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cellular uptake was monitored using fluorescence microscopy. The amount of DOX released from FA–AMA–DOX was much greater at pH 5.0 than that at pH 6.5 or 7.4. The cytotoxicity of FA–AMA–DOX toward KB and HepG2 cells was greater than that of DOX or AMA–DOX at the same concentrations, and cytotoxicity could be attenuated by FA in a dose-dependent manner. On the contrary, the cytotoxicity of FA–AMA–DOX and AMA–DOX toward A549 cells was lower than that of DOX at the same concentration, and cytotoxicity could not be reduced by FA. Compared with FA–AMA, FA–AMA–DOX increased the intracellular accumulation of DOX in KB cells. These results suggested that FA–AMA–DOX have suitable attributes for the active targeting of folate-receptor-positive tumor cells and for releasing the chemotherapeutic agent, DOX, in situ; it therefore has potential as a novel cancer therapeutic. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:530–540, 2013     

Synthesis of β-amino carbonyl derivatives of coumarin and benzofuran and evaluation of their biological activity

A series of β-amino carbonyl compounds containing coumarin (4a–h) and benzofuran (6a–i) moieties was synthesized by a three component Mannich reaction of 3-acetyl-2H-chromen-2-one (1) or 1-(1-benzofuran-2-yl) ethanone (5) with p-substituted aromatic aldehydes (2a–g) and aromatic amines (3a–b) in the presence of cerric ammonium nitrate as a catalyst. The newly synthesized compounds were screened for antimicrobial and antioxidant activities. Compounds 4b, 4e, 4f, 6f, 6g, and 6i showed microbial inhibition with minimal inhibition concentration ranging between 0.040 and 0.500 mg/mL, compounds 4b, 4c, 6c, 6e, and 6i showed promising free radical scavenging activity and compounds 4b, 4f, 6c, 6d, and 6h showed good chelating ability with Fe²⁺ ions. The synthesized compounds were studied for docking on the enzyme, glucosamine-6-phosphate synthase to predict the binding affinity and orientation at the active site of the receptor.     

Acetaminophen Intoxication and Length of Treatment: How Long Is Long Enough?

The currently recommended dosing scheme for treating acetaminophen overdose in the United States consists of a loading dose of oral N-acetylcysteine 140 mg/kg, followed by 70 mg/kg every 4 hours for 17 doses, for a total of 72 hours of oral N-acetylcysteine therapy. This protocol has been both effective and safe. We critically evaluated the evidence that supports reducing the course of N-acetylcysteine therapy from 72 hours to 24 or 36 hours. This shorter regimen offers important benefits for both the patient and the patient's family, such as increased drug tolerability and reduced hospital stay. Patients who intentionally ingested acetaminophen with harmful intent could receive appropriate psychosocial treatment more quickly. In addition, shorter courses of N-acetylcysteine therapy have positive financial ramifications by reducing the hospital stay by 1 or 2 days. Clearly, a shorter treatment regimen would not be appropriate for all patients, particularly those who seek treatment late (> 24 hrs after ingestion) and those with evidence of organ toxicity. In order to provide the necessary evidence to support a change in accepted clinical practice, further investigation on the safety and efficacy of a shorter N-acetylcysteine regimen should be conducted by clinical researchers in a controlled manner.     

Synthesis and antimicrobial activities of highly functionalised novel β-lactam and thiazolidine-grafted tetrahydrobenzothiophenes

A series of biologically active N-(3-chloro-2-oxo-4-phenylazetidin-1-yl)/3-N-(4-oxo-2-arylthiazolidin-3-yl)-2-(methylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamides derivatives have been synthesised in good yield. The structures of compounds have been established on the basis of IR, ¹H, ¹³C NMR, and elemental analysis. The structure–activity relationships have been studied by screening of antimicrobial activity over a representative panel of bacterial and fungal strains using two-fold serial dilution method. All these synthesised compounds exhibited significant activities against all bacterial and fungal strains.     

Benzisothiazoles and β-adrenoceptors: Synthesis and pharmacological investigation of novel propanolamine and oxypro-panolamine derivatives in isolated rat tissues

In an attempt to examine the ability of benzisothiazole-based drugs to interact with beta-adrenoceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the beta-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the beta1- and beta3-adrenoceptor-mediated responses, respectively. None of these products showed any beta-adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl, tert-butyl, benzyl, and piperonyl derivatives 2a-d and 3a-d elicited surmountable inhibition of the isoprenaline-induced chronotropic effects in the atria, suggesting competitive antagonism at the beta1-recognition site. The pA2 values revealed tert-butyl 3b and the isopropyl substituted piperonyl derivatives 3a to be the most effective. Remarkably, many of the 2-substituted propanolamines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound 3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the beta3-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the beta-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac beta1-adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.     

Synthesis and Cardiac Imaging of 18F-Ligands Selective for β1-Adrenoreceptors

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