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Molecules, Volume 13, Issue 2 (February 2008), Pages 204-487

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Research

Jump to: Review

Open AccessArticle Trimethyl Lock: A Stable Chromogenic Substrate for Esterases
Molecules 2008, 13(2), 204-211; doi:10.3390/molecules13020204
Received: 19 January 2008 / Accepted: 30 January 2008 / Published: 31 January 2008
Cited by 10 | PDF Full-text (147 KB) | HTML Full-text | XML Full-text
Abstract
p-Nitrophenyl acetate is the most commonly used substrate for detecting thecatalytic activity of esterases, including those that activate prodrugs in human cells. Thissubstrate is unstable in aqueous solution, limiting its utility. Here, a stable chromogenicsubstrate for esterases is produced by the structural [...] Read more.
p-Nitrophenyl acetate is the most commonly used substrate for detecting thecatalytic activity of esterases, including those that activate prodrugs in human cells. Thissubstrate is unstable in aqueous solution, limiting its utility. Here, a stable chromogenicsubstrate for esterases is produced by the structural isolation of an acetyl ester andp-nitroaniline group using a trimethyl lock moiety. Upon ester hydrolysis, unfavorablesteric interactions between the three methyl groups of this o-hydroxycinnamic acidderivative encourage rapid lactonization to form a hydrocoumarin and releasep-nitroaniline. This “prochromophore” could find use in a variety of assays. Full article
(This article belongs to the Special Issue Prodrugs)
Open AccessCommunication Antifouling Metabolites from the Mangrove Plant Ceriops tagal
Molecules 2008, 13(2), 212-219; doi:10.3390/molecules13020212
Received: 28 November 2007 / Revised: 29 January 2008 / Accepted: 29 January 2008 / Published: 31 January 2008
Cited by 19 | PDF Full-text (95 KB) | HTML Full-text | XML Full-text
Abstract
The new diterpene methoxy-ent-8(14)-pimarenely-15-one (1) and three knownmetabolites: ent-8(14)-pimarene-15R,16-diol (2), stigmasterol (3) and β-sitosterol (4), wereisolated from the roots of the mangrove plant Ceriops tagal. Their structures and relativestereochemistry were elucidated by means of extensive NMR, IR and MS analysis.Compounds 1, 2, [...] Read more.
The new diterpene methoxy-ent-8(14)-pimarenely-15-one (1) and three knownmetabolites: ent-8(14)-pimarene-15R,16-diol (2), stigmasterol (3) and β-sitosterol (4), wereisolated from the roots of the mangrove plant Ceriops tagal. Their structures and relativestereochemistry were elucidated by means of extensive NMR, IR and MS analysis.Compounds 1, 2, 3 and 4 exhibited significant antifouling activities against cyprid larvaeof the barnacle Balanus albicostatus Pilsbry, with EC50 values of 0.32 ± 0.01, 0.04 ± 0.00,4.05 ± 0.15 and 18.47 ± 0.40 μg/cm2, respectively, whereas their toxicities towards cypridswere very low, with LC50 values all above 10 μg/cm2. Full article
Open AccessArticle Isolation and Identification of an Anti-tumor Component from Leaves of Impatiens balsamina
Molecules 2008, 13(2), 220-229; doi:10.3390/molecules13020220
Received: 21 December 2007 / Revised: 18 January 2008 / Accepted: 18 January 2008 / Published: 31 January 2008
Cited by 31 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text
Abstract
We have previously shown that ethanol or chloroform extracts of the leaves ofImpatiens balsamina (LIB) have anti-tumor activity against the human hepatocellularcarcinoma cell line HepG2. The ethanol extracts were separated into five fractionsaccording to polarity. An MTT assay indicated that two of [...] Read more.
We have previously shown that ethanol or chloroform extracts of the leaves ofImpatiens balsamina (LIB) have anti-tumor activity against the human hepatocellularcarcinoma cell line HepG2. The ethanol extracts were separated into five fractionsaccording to polarity. An MTT assay indicated that two of the fractions had anti-tumoractivity and that the petroleum ether fraction (PEF) was the most active. But the availablequantities of both the PEF and chloroform fractions (CHF) were limited, precluding furtherstudy. The chloroform extract (CHE) shared almost all the same spots with the PEF andCHF and was plentiful enough to carry out further separations. Thus, the CHE was furtherseparated into six sub-fractions (CHE1~6) by column chromatography. A MTT assayshowed that only the CHE2 fraction had a strong tumor inhibition ratio (IC50 = 6.47±0.05mg/L), which was superior to that of curcumin (IC50 = 13.95±0.11 mg/L). However, TLCrevealed that CHE2 was not pure and still contained two more components. After furtherseparation and purification, followed by TLC and MTT assay confirmation, the final activecomponent was isolated and identified as 2-methoxy-1,4-naphthoquinone by m.p., UV, MSand 13C- and 1H-NMR data. This is the first report demonstrating that2-methoxy-1,4-naphthoquinone has intensive in vitro anti-tumor activity against HepG2cells. Full article
Open AccessArticle New Benzoyl Glucosides and Cytotoxic Pterosin Sesquiterpenes from Pteris ensiformis Burm.
Molecules 2008, 13(2), 255-266; doi:10.3390/molecules13020255
Received: 18 January 2008 / Revised: 4 February 2008 / Accepted: 4 February 2008 / Published: 5 February 2008
Cited by 28 | PDF Full-text (96 KB) | HTML Full-text | XML Full-text
Abstract
Three new compounds: 2R,3R-pterosin L 3-O-β-D-glucopyranoside (1), β-Dxylopyranosyl(1→2)-7-O-benzoyl-β-D-glucopyranoside (2) and 4-O-benzoyl-β-D-xylopyranosyl(1→2)-7-O-benzoyl-β-D-glucopyranoside (3), together with nine knowncompounds, were isolated from the ethyl acetate extract of Pteris ensiformis. 5-[2-Hydroxyethylidene]-2(5H)-furanone (4), which had been synthesized, was isolated fromnatural sources for the first time. The structures [...] Read more.
Three new compounds: 2R,3R-pterosin L 3-O-β-D-glucopyranoside (1), β-Dxylopyranosyl(1→2)-7-O-benzoyl-β-D-glucopyranoside (2) and 4-O-benzoyl-β-D-xylopyranosyl(1→2)-7-O-benzoyl-β-D-glucopyranoside (3), together with nine knowncompounds, were isolated from the ethyl acetate extract of Pteris ensiformis. 5-[2-Hydroxyethylidene]-2(5H)-furanone (4), which had been synthesized, was isolated fromnatural sources for the first time. The structures of all isolated compounds were determinedon the basis of mass and spectroscopic evidence. Compound 1 and pterosin B (5) showcytotoxicity against HL 60 cells (human leukemia) with the IC50 values of 3.7 and 8.7μg/mL, respectively. Full article
Open AccessCommunication Two New Constituents from Artemisia capillaris Thunb.
Molecules 2008, 13(2), 267-271; doi:10.3390/molecules13020267
Received: 26 November 2007 / Revised: 2 February 2008 / Accepted: 4 February 2008 / Published: 5 February 2008
Cited by 8 | PDF Full-text (66 KB) | HTML Full-text | XML Full-text
Abstract Two new compounds, 6′-O-caffeoyl-p-hydroxyacetophenone-4-O-β-D-glucopyranoside(1) and 6-amino-9-[1-(3,4-dihydroxyphenyl)ethyl]-9H-purine (2) wereisolated from the aerial parts of Artemisia capillaris Thunb. The structures wereestablished on the basis of spectral data. Full article
Open AccessArticle 1,2-Diaryl(3-pyridyl)ethanone Oximes. Intermolecular Hydrogen Bonding Networks Revealed by X-ray Diffraction
Molecules 2008, 13(2), 301-318; doi:10.3390/molecules13020301
Received: 30 December 2007 / Revised: 1 February 2008 / Accepted: 4 February 2008 / Published: 7 February 2008
Cited by 6 | PDF Full-text (362 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The synthesis of a set of 1-aryl-2-aryl(3-pyridyl)ethanones 1-5 and thecorresponding ketoximes 6-9 is reported. Structural studies of oximes 6, 7 and 9 wereperformed in solution using 1H-NMR and in the solid state by X-ray crystallography,providing evidence of H-bonding networks. The crystal [...] Read more.
The synthesis of a set of 1-aryl-2-aryl(3-pyridyl)ethanones 1-5 and thecorresponding ketoximes 6-9 is reported. Structural studies of oximes 6, 7 and 9 wereperformed in solution using 1H-NMR and in the solid state by X-ray crystallography,providing evidence of H-bonding networks. The crystal packing was controlled byhomomeric intermolecular oxime···oxime H-bond interactions for 6 and cooperativeoxime···N(pyridyl) and CH/π interactions for 7 and 9. Full article
Open AccessArticle A Facile Route to Diastereomeric Phosphorus Ylides. Chemoselective Synthesis of Dialkyl (E)-2-[1-(2-Oxocyclopentylidene)ethyl]-2-butenedioates
Molecules 2008, 13(2), 331-339; doi:10.3390/molecules13020331
Received: 24 December 2007 / Revised: 21 January 2008 / Accepted: 21 January 2008 / Published: 7 February 2008
Cited by 9 | PDF Full-text (87 KB) | HTML Full-text | XML Full-text
Abstract 2-Acetylcyclopentanone undergoes a smooth reaction with triphenylphosphineand dialkyl acetylenedicarboxylates to produce dialkyl 2-(1-acetyl-2-oxocyclopentyl)-3-(1,1,1-triphenyl-λ5-phosphanylidene)succinates. These compounds undergo intramolecularWittig reactions in boiling benzene to produce highly strained spirocyclobutenederivatives, which spontaneously undergo ring-opening reactions to produce dialkyl (E)-2-[1-(2-oxocyclopentyliden)ethyl]-2-butenedioates. Full article
(This article belongs to the Special Issue Spiro Compounds)
Open AccessArticle Michael Additions of Amines to Methyl Acrylates Promoted by Microwave Irradiation
Molecules 2008, 13(2), 340-347; doi:10.3390/molecules13020340
Received: 30 December 2007 / Revised: 1 February 2008 / Accepted: 2 February 2008 / Published: 7 February 2008
Cited by 23 | PDF Full-text (74 KB) | HTML Full-text | XML Full-text
Abstract A simple and efficient protocol has been developed for the Michael addition ofamines to α,β-unsaturated esters under microwave irradiation. Under these conditions therewas a significant decrease in the reaction time, increases in the yields and increased purityof the products. Full article
Open AccessArticle Synthesis and Properties of a New Water-Soluble Prodrug of the Adenosine A2A Receptor Antagonist MSX-2
Molecules 2008, 13(2), 348-359; doi:10.3390/molecules13020348
Received: 29 January 2008 / Revised: 11 February 2008 / Accepted: 11 February 2008 / Published: 12 February 2008
Cited by 21 | PDF Full-text (103 KB) | HTML Full-text | XML Full-text
Abstract The compound L-valine-3-{8-[(E)-2-[3-methoxyphenyl)ethenyl]-7-methyl-1-propargylxanthine-3-yl}propyl ester hydrochloride (MSX-4) was synthesized as an aminoacid ester prodrug of the adenosine A2A receptor antagonist MSX-2. It was found to bestable in artificial gastric acid, but readily cleaved by pig liver esterase. Full article
(This article belongs to the Special Issue Prodrugs)
Open AccessArticle Synthesis, Molecular Structure and Spectral Properties of Quaternary Ammonium Derivatives of 1,1-Dimethyl-1,3-propylenediamine
Molecules 2008, 13(2), 379-390; doi:10.3390/molecules13020379
Received: 30 January 2008 / Revised: 12 February 2008 / Accepted: 12 February 2008 / Published: 15 February 2008
Cited by 8 | PDF Full-text (159 KB) | HTML Full-text | XML Full-text
Abstract
1,1-Dimethyl-3-oxo-1,4-diazepan-1-ium chloride (1) and 1,1-dimethyl-1-carboxymethyl-3-aminopropyl ammonium hydrochloride (2) have been obtained by thereactions of 1,1-dimethyl-1,3-propylenediamine with ethyl chloroacetate and chloroaceticacid, respectively. The products have been characterized by FTIR, Raman and NMRspectroscopy. B3LYP calculations have also been carried out. The screening constants for [...] Read more.
1,1-Dimethyl-3-oxo-1,4-diazepan-1-ium chloride (1) and 1,1-dimethyl-1-carboxymethyl-3-aminopropyl ammonium hydrochloride (2) have been obtained by thereactions of 1,1-dimethyl-1,3-propylenediamine with ethyl chloroacetate and chloroaceticacid, respectively. The products have been characterized by FTIR, Raman and NMRspectroscopy. B3LYP calculations have also been carried out. The screening constants for 13C- and 1H- atoms have been calculated by the GIAO/B3LYP/6-31G(d,p) approach andanalyzed. The FTIR and NMR spectra of the investigated compounds 1 and 2 are inexcellent agreement with the structures optimized by Density Functional Theory (DFT)calculations. Full article
Open AccessArticle Spirowallichiione: A Rearranged Multiflorane from Euphorbia wallichii Hook F. (Euphorbiaceae)
Molecules 2008, 13(2), 405-411; doi:10.3390/molecules13020405
Received: 11 January 2008 / Revised: 4 February 2008 / Accepted: 4 February 2008 / Published: 18 February 2008
Cited by 8 | PDF Full-text (73 KB) | HTML Full-text | XML Full-text
Abstract Euphorbia wallichii of the family Euphorbiaceae yielded a new rearrangedpentacyclic triterpene of the multiflorane class which we have named spirowallichiione.The structure of this natural spirocompound was elucidated with the aid of modernspectroscopic techniques, including 2D-NMR. Full article
(This article belongs to the Special Issue Spiro Compounds)
Open AccessArticle Synthesis and Antimalarial Evaluation of Cyclic β-Amino Acid-Containing Dipeptides
Molecules 2008, 13(2), 432-443; doi:10.3390/molecules13020432
Received: 31 January 2008 / Revised: 11 February 2008 / Accepted: 15 February 2008 / Published: 18 February 2008
Cited by 8 | PDF Full-text (105 KB) | HTML Full-text | XML Full-text
Abstract
This paper describes an efficient synthesis and the antiparasitic evaluation ofcyclic β-amino acid-containing dipeptides 3.1-3.6 and 4.1-4.5. The antimalarial propertiesof all these dipeptides have been evaluated in vitro against Plasmodium falciparum and invivo against Plasmodium berghai. Compounds 4.4 and 4.5 have been [...] Read more.
This paper describes an efficient synthesis and the antiparasitic evaluation ofcyclic β-amino acid-containing dipeptides 3.1-3.6 and 4.1-4.5. The antimalarial propertiesof all these dipeptides have been evaluated in vitro against Plasmodium falciparum and invivo against Plasmodium berghai. Compounds 4.4 and 4.5 have been found to be veryeffective in this respect, with IC50 values of 3.87 and 3.64 μg/mL in the in vitro test, while4.5 has also been found to be active in the in vivo evaluation. Full article
Open AccessArticle The First Guaian-12-oic Acid Glucopyranosyl Ester and Other Constituents from Picris rhagadioloides (L.) Desf. (Asteraceae)
Molecules 2008, 13(2), 444-451; doi:10.3390/molecules13020444
Received: 8 February 2008 / Revised: 15 February 2008 / Accepted: 15 February 2008 / Published: 19 February 2008
Cited by 4 | PDF Full-text (56 KB) | HTML Full-text | XML Full-text
Abstract
The first guaian-12-oic acid glucopyranosyl ester was isolated from the roots ofPicris rhagadioloides (L.) Desf. (Asteraceae), in addition to five costuslactone-typeguaianolides, four germacranolides and three phenolic compounds. This is the first timethat the known phenolics syringaldehyde and syringaresinol, as well as the [...] Read more.
The first guaian-12-oic acid glucopyranosyl ester was isolated from the roots ofPicris rhagadioloides (L.) Desf. (Asteraceae), in addition to five costuslactone-typeguaianolides, four germacranolides and three phenolic compounds. This is the first timethat the known phenolics syringaldehyde and syringaresinol, as well as the knownsesquiterpene lactones glucozaluzanin C, cichorioside C and hypochoeroside A have beendescribed from a Picris species. The compounds were characterized on the basis ofphysicochemical, 1D- and 2D-NMR spectroscopic, and mass spectrometric data. Full article
Open AccessArticle Effects of Anonaine on Dopamine Biosynthesis and L-DOPA-Induced Cytotoxicity in PC12 Cells
Molecules 2008, 13(2), 475-487; doi:10.3390/molecules13020475
Received: 30 January 2008 / Revised: 22 February 2008 / Accepted: 25 February 2008 / Published: 27 February 2008
Cited by 8 | PDF Full-text (141 KB) | HTML Full-text | XML Full-text
Abstract
The effects of anonaine, an aporphine isoquinoline alkaloid, on dopaminebiosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Anonaineat concentration ranges of 0.01-0.2 μM showed a significant inhibition of dopaminecontent at 24 h, with an IC50 value of 0.05 μM. Anonaine [...] Read more.
The effects of anonaine, an aporphine isoquinoline alkaloid, on dopaminebiosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Anonaineat concentration ranges of 0.01-0.2 μM showed a significant inhibition of dopaminecontent at 24 h, with an IC50 value of 0.05 μM. Anonaine at 0.05 μM inhibited tyrosinehydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) activities to 38.4-40.2% and 78.4-90.2% of control levels at 12-24 h and 3-6 h, respectively. TH activity wasmore influenced than AADC activity. Anonaine also decreased intracellular cyclic AMPlevels, but not intracellular Ca2+ concentrations. In addition, anonaine (0.05 μM) reducedL-DOPA (50 μM and 100 μM)-induced increases in dopamine content at 24 h. However,anonaine (0.05 μM) did not enhance L-DOPA (50 μM and 100 μM)-induced cell death 476after 24 h. These results suggest that anonaine inhibits dopamine biosynthesis by mainlyreducing TH activity without aggravating L-DOPA-induced cytotoxicity in PC12 cells. Full article
(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)

Review

Jump to: Research

Open AccessReview Cholesterylbutyrate Solid Lipid Nanoparticles as a Butyric Acid Prodrug
Molecules 2008, 13(2), 230-254; doi:10.3390/molecules13020230
Received: 4 January 2008 / Revised: 31 January 2008 / Accepted: 1 February 2008 / Published: 1 February 2008
Cited by 25 | PDF Full-text (155 KB) | HTML Full-text | XML Full-text
Abstract
Cholesterylbutyrate (Chol-but) was chosen as a prodrug of butyric acid.Butyrate is not often used in vivo because its half-life is very short and therefore too largeamounts of the drug would be necessary for its efficacy. In the last few years butyric acid'santi-inflammatory [...] Read more.
Cholesterylbutyrate (Chol-but) was chosen as a prodrug of butyric acid.Butyrate is not often used in vivo because its half-life is very short and therefore too largeamounts of the drug would be necessary for its efficacy. In the last few years butyric acid'santi-inflammatory properties and its inhibitory activity towards histone deacetylases havebeen widely studied, mainly in vitro. Solid Lipid Nanoparticles (SLNs), whose lipid matrixis Chol-but, were prepared to evaluate the delivery system of Chol-but as a prodrug and totest its efficacy in vitro and in vivo. Chol-but SLNs were prepared using the microemulsionmethod; their average diameter is on the order of 100-150 nm and their shape is spherical.The antineoplastic effects of Chol-but SLNs were assessed in vitro on different cancer celllines and in vivo on a rat intracerebral glioma model. The anti-inflammatory activity wasevaluated on adhesion of polymorphonuclear cells to vascular endothelial cells. In thereview we will present data on Chol-but SLNs in vitro and in vivo experiments, discussingthe possible utilisation of nanoparticles for the delivery of prodrugs for neoplastic andchronic inflammatory diseases. Full article
(This article belongs to the Special Issue Prodrugs)
Open AccessReview Progress in the Studies on Rutaecarpine
Molecules 2008, 13(2), 272-300; doi:10.3390/molecules13020272
Received: 1 January 2008 / Revised: 1 February 2008 / Accepted: 2 February 2008 / Published: 6 February 2008
Cited by 52 | PDF Full-text (258 KB) | HTML Full-text | XML Full-text
Abstract
Rutaecarpine is an indolopyridoquinazolinone alkaloid isolated from Evodiarutaecarpa and related herbs, which has shown a variety of intriguing biological propertiessuch as anti-thrombotic, anticancer, anti-inflammatory and analgesic, anti-obesity andthermoregulatory, vasorelaxing activity, as well as effects on the cardiovascular andendocrine systems. Recent progress in [...] Read more.
Rutaecarpine is an indolopyridoquinazolinone alkaloid isolated from Evodiarutaecarpa and related herbs, which has shown a variety of intriguing biological propertiessuch as anti-thrombotic, anticancer, anti-inflammatory and analgesic, anti-obesity andthermoregulatory, vasorelaxing activity, as well as effects on the cardiovascular andendocrine systems. Recent progress in the studies on the isolation, synthesis, structureactivityrelationship studies, biological activities and metabolism of rutaecarpine arereviewed. Full article
(This article belongs to the Special Issue Alkaloids: Novel Therapeutic Perspectives)
Open AccessReview Nitroalkanes as Central Reagents in the Synthesis of Spiroketals
Molecules 2008, 13(2), 319-330; doi:10.3390/molecules13020319
Received: 8 January 2008 / Revised: 2 February 2008 / Accepted: 4 February 2008 / Published: 7 February 2008
Cited by 15 | PDF Full-text (89 KB) | HTML Full-text | XML Full-text
Abstract
Nitroalkanes can be profitably employed as carbanionic precursors for theassembly of dihydroxy ketone frameworks, suitable for the preparation of spiroketals. Thecarbon-carbon bond formation is carried out exploiting nitroaldol and Michael reactions,while the nitro to carbonyl conversion (Nef reaction) ensures the correct introduction [...] Read more.
Nitroalkanes can be profitably employed as carbanionic precursors for theassembly of dihydroxy ketone frameworks, suitable for the preparation of spiroketals. Thecarbon-carbon bond formation is carried out exploiting nitroaldol and Michael reactions,while the nitro to carbonyl conversion (Nef reaction) ensures the correct introduction of theketo group. Several spiroketal systems endowed with considerable biological activity canbe prepared using this synthetic strategy. Full article
(This article belongs to the Special Issue Spiro Compounds)
Open AccessReview Design, Synthesis and Applications of Hyaluronic Acid-Paclitaxel Bioconjugates†
Molecules 2008, 13(2), 360-378; doi:10.3390/molecules13020360
Received: 29 January 2008 / Revised: 11 February 2008 / Accepted: 11 February 2008 / Published: 12 February 2008
Cited by 20 | PDF Full-text (114 KB) | HTML Full-text | XML Full-text
Abstract
Paclitaxel (1a), a well known antitumor agent adopted mainly for the treatmentof breast and ovarian cancer, suffers from significant disadvantages such as low solubility,certain toxicity and specific drug-resistance of some tumor cells. To overcome theseproblems extensive research has been carried out. Among [...] Read more.
Paclitaxel (1a), a well known antitumor agent adopted mainly for the treatmentof breast and ovarian cancer, suffers from significant disadvantages such as low solubility,certain toxicity and specific drug-resistance of some tumor cells. To overcome theseproblems extensive research has been carried out. Among the various proposed strategies,the conjugation of paclitaxel (1a) to a biocompatible polymer, such as hyaluronic acid(HA, 2), has also been considered. Coupling a bioactive compound to a biocompatiblepolymer offers, in general, many advantages such as better drug solubilization, betterstabilization, specific localization and controlled release. Hereafter the design, synthesisand applications of hyaluronic acid-paclitaxel bioconjugates are reviewed. An overview ofHA-paclitaxel combinations is also given. Full article
(This article belongs to the Special Issue Prodrugs)
Open AccessReview Novel Prodrugs for Targeting Diagnostic and Therapeutic Radionuclides to Solid Tumors
Molecules 2008, 13(2), 391-404; doi:10.3390/molecules13020391
Received: 6 February 2008 / Revised: 15 February 2008 / Accepted: 15 February 2008 / Published: 18 February 2008
Cited by 7 | PDF Full-text (640 KB) | HTML Full-text | XML Full-text
Abstract
Most cancer therapeutics (chemo, radiation, antibody-based, anti-angiogenic)are at best partially and/or temporarily effective. In general, the causes for failure can besummarized as: (i) poor diffusion and/or nonuniform distribution of drug/prodrugmolecules in solid tumors; (ii) high drug concentration and retention in normal tissues(leading [...] Read more.
Most cancer therapeutics (chemo, radiation, antibody-based, anti-angiogenic)are at best partially and/or temporarily effective. In general, the causes for failure can besummarized as: (i) poor diffusion and/or nonuniform distribution of drug/prodrugmolecules in solid tumors; (ii) high drug concentration and retention in normal tissues(leading to side effects); (iii) requirement for plasma-membrane permeability and/orinternalization of drug/prodrug molecules; (iv) low uptake of drug by tumor; (v) lack ofretention of drug within tumor (most have gradient-driven reversible binding); and (vi)multidrug resistance. We are developing an innovative technology that aims to surmountthese problems by actively concentrating and permanently entrapping radioimaging andradiotherapeutic prodrugs specifically within solid tumors. The approach will enablenoninvasive sensing (imaging) and effective therapy of solid tumors, allowing tumordetection, diagnosis, and treatment to be closely coupled (personalized medicine). Full article
(This article belongs to the Special Issue Prodrugs)
Open AccessReview Structure and Catalytic Properties of Carboxylesterase Isozymes Involved in Metabolic Activation of Prodrugs
Molecules 2008, 13(2), 412-431; doi:10.3390/molecules13020412
Received: 14 December 2007 / Revised: 9 February 2008 / Accepted: 11 February 2008 / Published: 18 February 2008
Cited by 105 | PDF Full-text (634 KB) | HTML Full-text | XML Full-text
Abstract
Mammalian carboxylesterases (CESs) comprise a multigene family whose geneproducts play important roles in biotransformation of ester- or amide-type prodrugs. Theyare members of an α,β-hydrolase-fold family and are found in various mammals. It has beensuggested that CESs can be classified into five major [...] Read more.
Mammalian carboxylesterases (CESs) comprise a multigene family whose geneproducts play important roles in biotransformation of ester- or amide-type prodrugs. Theyare members of an α,β-hydrolase-fold family and are found in various mammals. It has beensuggested that CESs can be classified into five major groups denominated CES1-CES5,according to the homology of the amino acid sequence, and the majority of CESs that havebeen identified belong to the CES1 or CES2 family. The substrate specificities of CES1 andCES2 are significantly different. The CES1 isozyme mainly hydrolyzes a substrate with asmall alcohol group and large acyl group, but its wide active pocket sometimes allows it toact on structurally distinct compounds of either a large or small alcohol moiety. In contrast,the CES2 isozyme recognizes a substrate with a large alcohol group and small acyl group,and its substrate specificity may be restricted by the capability of acyl-enzyme conjugateformation due to the presence of conformational interference in the active pocket. Sincepharmacokinetic and pharmacological data for prodrugs obtained from preclinicalexperiments using various animals are generally used as references for human studies, it isimportant to clarify the biochemical properties of CES isozymes. Further experimentationfor an understanding of detailed substrate specificity of prodrugs for CES isozymes and itshydrolysates will help us to design the ideal prodrugs. Full article
(This article belongs to the Special Issue Prodrugs)
Open AccessReview Application of Prodrugs to Inflammatory Diseases of the Gut
Molecules 2008, 13(2), 452-474; doi:10.3390/molecules13020452
Received: 26 January 2008 / Revised: 20 February 2008 / Accepted: 21 February 2008 / Published: 27 February 2008
Cited by 18 | PDF Full-text (152 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
Abstract
Oral delivery is the most common and preferred route of drug administrationalthough the digestive tract exhibits several obstacles to drug delivery including motilityand intraluminal pH profiles. The gut milieu represents the largest mucosal surfaceexposed to microorganisms with 1010-12 colony forming bacteria/g [...] Read more.
Oral delivery is the most common and preferred route of drug administrationalthough the digestive tract exhibits several obstacles to drug delivery including motilityand intraluminal pH profiles. The gut milieu represents the largest mucosal surfaceexposed to microorganisms with 1010-12 colony forming bacteria/g of colonic content.Approximately, one third of fecal dry matter is made of bacteria/ bacterial components.Indeed, the normal gut microbiota is responsible for healthy digestion of dietary fibers(polysaccharides) and fermentation of short chain fatty acids such as acetate and butyratethat provide carbon sources (fuel) for these bacteria. Inflammatory bowel disease (IBD)results in breakage of the mucosal barrier, an altered microbiota and dysregulated gutimmunity. Prodrugs that are chemically constructed to target colonic release or aredegraded specifically by colonic bacteria, can be useful in the treatment of IBD. Thisreview describes the progress in digestive tract prodrug design and delivery in light of gutmetabolic activities. Full article

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