Special Issue "Prodrugs"

Abstract: While the mammalian eye is seldom considered an organ of drug metabolism, the capacity for biotransformation is present. Compared to the liver, the metabolic capabilities of the eye are minuscule; however, phase I and phase II metabolic activities have been detected in various ocular structures. The careful consideration of ocular tissue metabolic processes within the eye has important implications for controlling the detoxification of therapeutic agents and for providing the potential for site-specific bio-activation of certain drug molecules, thus enabling significant improvements in drug efficacy and the minimization of side-effect from either local or systemic drug delivery to the eye. Knowledge of these processes is important to prodrug and codrug development and to researchers involved in the design, delivery and metabolism of ophthalmic drugs. This present article reviews the progress in ocular prodrug and codrug design and delivery in light of ocular metabolic activities.

Abstract: With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were characterized in vitro. Stability of the derivatives was studied in aqueous solution, human serum albumin solution, human plasma, and rat liver homogenate at 37°C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 × 10⁴ min at pH 7.4 and 37°C. The carbonate esters were subject to catalysis by plasma esterases except for the t-butyl and acetic acid derivatives, which were stabilized in both human plasma and human serum albumin solutions relative to buffer. In most cases, however, hydrolysis was accelerated in the presence of human serum albumin indicating that the derivatives interacted with the protein, a finding which was confirmed using the p-nitrophenyl acetate kinetic assay. Different human serum albumin binding properties of the phenol model prodrugs with fatty acid-like structure and neutral carbonate esters were observed. In the context of utilizing plasma protein binding in combination with the prodrug approach for optimizing drug pharmacokinetics, the esterase-like properties of human serum albumin towards the carbonate esters potentially allowing the protein to act as a catalyst of parent compound regenerations is interesting.

Abstract: A series of model phenol carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 – 12.5) at 37°C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n-alkyl vs. t-butyl. Hydrolysis of the phenolic carbonate ester 2-(phenoxycarbonyloxy)-acetic acid was increased due to intramolecular catalysis, as compared to the derivatives synthesized from ω-hydroxy carboxylic acids with longer alkyl chains. The carbonate esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further in vitro and in vivo evaluation of the potential of utilizing HSA binding in combination with the prodrug approach for optimization of drug pharmacokinetics.

Abstract: Many drugs suffer from an extensive first-pass metabolism leading to druginactivation and/or production of toxic metabolites, which makes them attractive targets forprodrug design. The classical prodrug approach, which involves enzyme-sensitive covalentlinkage between the parent drug and a carrier moiety, is a well established strategy toovercome bioavailability/toxicity issues. However, the development of prodrugs that canregenerate the parent drug through non-enzymatic pathways has emerged as an alternativeapproach in which prodrug activation is not influenced by inter- and intraindividualvariability that affects enzymatic activity. Cyclization-activated prodrugs have beencapturing the attention of medicinal chemists since the middle-1980s, and reached maturityin prodrug design in the late 1990s. Many different strategies have been exploited in recentyears concerning the development of intramoleculary-activated prodrugs spanning fromanalgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role intwo-step prodrug activation, where an initial enzymatic cleavage step is followed by acyclization-elimination reaction that releases the active drug. This wor

Abstract: Calcium-induced alginate gel bead (Alg-Ca) coated with an alginate hydrolysate(Alg), e.g. the guluronic acid block (GB) was prepared and the model drug, hydrocortisonerelease profiles were investigated under simulated gastrointestinal conditions. Theirmolecular weights were one sixth or one tenth that of Alg and the diffraction patterns of thehydrolysates resembled that of Alg. The drug release rate from Alg-Ca coated with GBapparently lowered than that of Alg-Ca (coating-free) in the gastric juice (pH1.2). And thecoating did not resist the disintegration of Alg-Ca in the intestinal juice (pH 6.8) and thegel erosion accelerated the drug release. On the other hand, for the coated Alg-Cacontaining chitosan, the drug release showed zero-order kinetics without rapid erosion ofAlg-Ca. The drug release rate from Alg-Ca was able to be controlled by the coating andmodifying the composition of the gel matrix.

Abstract: 1-Aryl-3-phenethylamino-1-propanone hydrochlorides 1-10, which are potentialpotent cytotoxic agents, were synthesized via Mannich reactions using paraformaldehyde,phenethylamine hydrochloride as the amine component and acetophenone, 4’-methyl-, 4’-methoxy-, 4’-chloro-, 4’-fluoro-, 4’-bromo-, 2’,4’-dichloro-, 4’-nitro-, 4’-hydroxyacetophenone or 2-acetylthiophene as the ketone component. Yields were in the87-98 % range. Of the compounds synthesized, compounds 2, 6-8 and 10 were new. Theoptimum reaction conditions were investigated by changing the mol ratios of the reactants,the solvents and the acidity levels using 1 and 10 as representative targets. It was observedthat the best mol ratio of the ketone, paraformaldehyde and phenethylamine hydrochloridewas 1:1.2:1 (compared with a 2:2.1 ratio), and the most suitable reaction medium wasethanol containing concentrated hydrochloric acid (compared with only ethanol or nosolvent). This study may serve as a guide for the conditions of the reactions to synthesizecompounds having similar chemical structures.

Abstract: Two recently synthesized oxazolidinones: (R)-3-(4-(2-(2-methyltetrazol-5-yl)-pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (DA-7157) and itscorresponding pro-drug (R)-3-(4-(2-(2-methyltetrazol-5-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl) methyl disodium phosphate (DA-7218), have shown very goodactivity against several Gram positive bacteria, including Nocardia and Mycobacterium. Inthe present work we evaluated the therapeutic in vivo effects of DA-7218 on Nocardiabrasiliensis. We first determined the plasma concentration of the prodrug in BALB/c miceusing several doses and then tested its activity in an in vivo experimental actinomycetomamurine model. At the end of treatment, there was a statistically significant differencebetween the three drug receiving groups (25, 12.5 and 5 mg/kg) and the control group(saline solution) (p=0.001), proving that DA-7218 is effective for the treatment of experimental murine actinomycetoma. This compound could be a potential option forpatients affected with mycetoma by Nocardia brasiliensis.

Abstract: Parkinson`s disease (PD) is a progressive, neurodegenerative disorder whichinvolves the loss of dopaminergic neurons of the substantia nigra pars compacta. Currenttherapy is essentially symptomatic, and L-Dopa (LD), the direct precursor of dopamine(DA), is the treatment of choice in more advanced stages of the disease. Substitutiontherapy with LD is, however, associated with a number of acute problems. The peripheralconversion of LD by amino acid decarboxylase (AADC) to DA is responsible for thetypical gastrointestinal (nausea, emesis) and cardiovascular (arrhythmia, hypotension) sideeffects. To minimize the conversion to DA outside the central nervous system (CNS) LD isusually given in combination with peripheral inhibitors of AADC (carbidopa andbenserazide). In spite of that, other central nervous side effects such as dyskinesia, on-offphenomenon and end-of-dose deterioration still remain. The main factors responsible forthe poor bioavailability and the wide range of inter- and intra-patient variations of plasmalevels are the drug’s physical-chemical properties: low water and lipid solubility, resultingin unfavourable partition, and the high susceptibility to chemical and enzymaticdegradation. In order to improve the bioavailability, the prodrug approach appeared to bethe most promising and some LD prodrugs have been prepared in an effort to solve theseproblems. We report here a review of progress in antiparkinson prodrugs, focusing onchemical structures mainly related to LD, DA and dopaminergic agonists.

Abstract: Two-, three- and four-arm, star-shaped poly(ε-caprolactone) andpoly(D,L-lactide) homopolymers, and copolymers of ε-caprolactone with D,L-lactide weresynthesized via ring-opening polymerization of cyclic esters in the presence of glycerol,penthaerythritol and poly(ethylene glycol) as initiators and stannous octoate as a catalyst.Thus obtained oligomers were successfully used in the synthesis of novel macromolecularprodrugs of norfloxacin. The structures of the polymers and prodrugs were elucidated bymeans of MALDI-TOF MS, NMR and IR studies.

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 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.

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 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.

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.

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 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.

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 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).

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 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.

Abstract: The purpose of this work is to review the published strategies for the productionof prodrugs of amines. The review is divided in two main groups of approaches: those thatrely on enzymatic activation and those that take advantage of physiological chemicalconditions for release of the drugs. A compilation of the most important approaches ispresented in the form of a table, where the main advantages and disadvantages of eachstrategy are also referred.

Abstract: Recently, World Health Organization (WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people, mainly in developing countries, die each year from infectious diseases. From 1975 to 1999, 1393 new drugs were approved yet only 1% were for the treatment of neglected diseases [3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas’ disease (American trypanosomiasis), sleeping sickness (African trypanosomiasis), malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis.

Abstract: We report the synthesis and total NMR characterization of 5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-[[[(4’’-nitrophenoxy)carbonyl]oxy]-methyl]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (5), a new cephalosporinderivative. This compound can be used as the carrier of a wide range of drugs containingan amino group. The preparation of the intermediate product, 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (6), as well as the synthesis of the antimalarial primaquine prodrug 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]- 5-dioxide (7) are alsodescribed, together with their total ¹H- and ¹³C-NMR assignments.

Abstract: Curative radiation therapy of pelvic malignancies, frequently results in doselimitingtoxicities such as serous, mucoid, or more rarely, bloody diarrhea. Several studieshave evaluated the cytoprotective effects of amifostine in preventing rectal mucositisassociated with radiation treatment. We searched Medline for published comparativestudies that evaluated the use of amifostine to reduce radiation-induced toxicity associatedwith pelvic irradiation. In ten studies there was an evidence-based cytoprotection (P less than 0.05)by amifostine. Although results are variable, current evidence suggests that amifostine mayhave a radioprotective effect in the rectal mucosa, particularly when administeredintrarectally. Significant improvements were seen in both symptomatic and objective(rectosigmoidoscopy) end points. There is a need to conduct well-designed clinical trialswith sufficient numbers of participants to confirm these findings together with a costbenefitstudy. Objective measurements using rectosigmoidoscopy are superior tosubjective measures such as WHO or RTOG/EORTC toxicity grading scales.

Abstract: This review describes specific strategies for targeting to the central nervoussystem (CNS). Systemically administered drugs can reach the brain by crossing one of twophysiological barriers resistant to free diffusion of most molecules from blood to CNS: theendothelial blood-brain barrier or the epithelial blood-cerebrospinal fluid barrier. Thesetissues constitute both transport and enzymatic barriers. The most common strategy fordesigning effective prodrugs relies on the increase of parent drug lipophilicity. However,increasing lipophilicity without a concomitant increase in rate and selectivity of prodrugbioconversion in the brain will result in failure. In these regards, consideration of theenzymes present in brain tissue and in the barriers is essential for a successful approach.Nasal administration of lipophilic prodrugs can be a promising alternative non-invasiveroute to improve brain targeting of the parent drugs due to fast absorption and rapid onsetof drug action. The carrier-mediated absorption of drugs and prodrugs across epithelial andendothelial barriers is emerging as another novel trend in biotherapeutics. Several specifictransporters have been identified in boundary tissues between blood and CNScompartments. Some of them are involved in the active supply of nutrients and have been used to explore prodrug approaches with improved brain delivery. The feasibility of CNSuptake of appropriately designed prodrugs via these transporters is described in detail.

Abstract: Prodrugs are biologically inactive derivatives of an active drug intended to solve certain problems of the parent drug such as toxicity, instability, minimal solubility and non-targeting capabilities. The majority of drugs for cardiovascular diseases undergo firstpass metabolism, resulting in drug inactivation and generation of toxic metabolites, which makes them appealing targets for prodrug design. Since prodrugs undergo a chemical reaction to form the parent drug once inside the body, this makes them very effective in controlling the release of a variety of compounds to the targeted site. This review will provide the reader with an insight on the latest developments of prodrugs that are available for treating a variety of cardiovascular diseases. In addition, we will focus on several drug delivery methodologies that have merged with the prodrug approach to provide enhanced target specificity and controlled drug release with minimal side effects.

Abstract: Polyanionic macromolecules are extremely abundant both in the extracellular environment and inside the cell, where they are readily accessible to many proteins for interactions that play a variety of biological roles. Among polyanions, heparin, heparan sulfate proteoglycans (HSPGs) and glycosphingolipids (GSLs) are widely distributed in biological fluids, at the cell membrane and inside the cell, where they are implicated in several physiological and/or pathological processes such as infectious diseases, angiogenesis and tumor growth. At a molecular level, these processes are mainly mediated by microbial proteins, cytokines and receptors that exert their functions by binding to HSPGs and/or GSLs, suggesting the possibility to use polyanionic antagonists as efficient drugs for the treatment of infectious diseases and cancer. Polysulfated (PS) or polysulfonated (PSN) compounds are a heterogeneous group of natural, semi-synthetic or synthetic molecules whose prototypes are heparin and suramin. Different structural features confer to PS/PSN compounds the capacity to bind and inhibit the biological activities of those same heparin-binding proteins implicated in infectious diseases and cancer. In this review we will discuss the state of the art and the possible future development of polyanionic drugs in the treatment of infectious diseases and cancer.

Abstract: Prodrug design for brain delivery of small- and medium-sized neuropeptides was reviewed, focusing on thyrotropin-releasing hormone and structurally related peptides as examples. We have summarized our most important advances in methodology, as well as assessed the benefits and limitations of bioreversible chemical manipulation techniques to achieve targeting of the parent molecules into the central nervous system. The value of prodrug-amenable analogues as potential drug-like central nervous systems agents was highlighted.

Abstract: Alfacalcidol (1α-hydroxyvitamin D₃) has been widely used since 1981 as a prodrug for calcitriol (1α,25-dihydroxyvitamin D₃) in the treatment of hypocalcemia, chronic renal failure, hypoparathyroidism and osteoporosis. More recently, doxercalciferol (1α-hydroxyvitamin D₂) has been used since 1999 as a prodrug for 1α,25-dihydroxyvitamin D₂ for the treatment of secondary hyperparathyroidism. Currently, six forms of vitamin D are known. They range from vitamin D₂ to vitamin D₇ and are distinguished by their differing side chains. Only vitamin D₂ and vitamin D₃ have been found to be biologically active based on the elucidation of activation pathways. Alfacalcidol and osteoporosis/doxercalciferol and secondary hyperparathyroidism are discussed, with a new look at old compounds including their practical syntheses.

Abstract: Two different types of soft alkyl ether prodrugs incorporating ethyleneoxy groups into the promoiety have been synthesized for a model phenol (acetaminophen, APAP): alkyloxycarbonyloxymethyl type (AOCOM) and N-alkyl-N-alkyloxycarbonyl-aminomethyl type (NANAOCAM). The solubilities in isopropyl myristate, S_IPM, and water, S_AQ, partition coefficients between IPM and pH 4.0 buffer, K_IPM:4.0, and the delivery of total species containing APAP through hairless mouse skin from IPM, J_MMIPM, have been measured for the prodrugs. The J_MMIPM values were accurately predicted by the Roberts-Sloan (RS) equation. Only modest increases in JMMIPM were realized (about 1.4 times) by each type. The only prodrug that was more water soluble and more lipid soluble than APAP did not improve J_MMIPM of APAP. This result may be due to the strong association of water molecules with the ethyleneoxy groups, and especially the triethyleneoxy derivative, which dramatically increases the molecular weight and depresses J_MMIPM.

Abstract: Gene directed enzyme prodrug therapy (GDEPT) of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV), cytosine deaminase (CD) from bacteria or yeast with 5-fluorocytodine (5-FC), and bacterial nitroreductase (NfsB) with 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), and their respective derivatives.

Abstract: Proteins and peptides in mammals are based exclusively on L-amino acids. Recent investigations show that D-amino acids exhibit physiological effects in vivo, despite of their very small quantities. We have investigated the hepatoprotective effects of the Land D-enantiomers of α-melanocortin peptide (α-MSH). The results showed that peptideenantiomerism is related to the protective effects of melanocortin peptides in vivo. L-α-MSH exhibited potent hepatoprotective effect in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice, while its D-mirror image was inefficient. Furthermore, the antibody to the L-peptide did not recognize the D-structure. The results indicate that the opposite peptide configuration may be used to modulate its function and metabolism in vivo and in vitro.

Abstract: New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition.

Abstract: Oligo(ε-caprolactone) and oligolactide were synthesized via ring-opening polymerization of cyclic esters in the presence of creatinine as initiators. Thus obtained oligomers were successfully used in the synthesis of novel polyurethane conjugates of norfloxacin. The structures of the polymers and conjugates were elucidated by means of MALDI-TOF MS, NMR and IR studies.

Abstract: Research over the past decade has indicated that melanocortin peptides are potent inhibitors of inflammation and a promising source of new anti-inflammatory and cytoprotective therapies. The purpose of the present paper is to compare protective effects of α-, β-, and γ-melanocyte stimulating hormone on acetaminophen induced liver lesions in male CBA mice. Acetaminophen was applied intragastrically in a dose of 150 mg/kg, and tested substances were applied intraperitoneally 1 hour before acetaminophen. Mice were sacrificed after 24 hours and intensity of liver injury was estimated by measurement of plasma transaminase activity (AST and ALT) and histopathological grading of lesions. It was found that α-, β-, and γ-MSH decrease intensity of lesions by both criteria in a dose-dependent manner.

Abstract: Reduced glutathione (GSH) is the most abundant non-protein thiol in mammalian cells and the preferred substrate for several enzymes in xenobiotic metabolism and antioxidant defense. It plays an important role in many cellular processes, such as cell differentiation, proliferation and apoptosis. GSH deficiency has been observed in aging and in a wide range of pathologies, including neurodegenerative disorders and cystic fibrosis (CF), as well as in several viral infections. Use of GSH as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties. Several reports have provided evidence for the use of GSH prodrugs able to replenish intracellular GSH levels. This review discusses different strategies for increasing GSH levels by supplying reversible bioconjugates able to cross the cellular membrane more easily than GSH and to provide a source of thiols for GSH synthesis.

Abstract: A series of benzimidazolylbenzenesulfonamide compounds containing electron-releasing and electron-withdrawing substituents were synthesized and tested for their in vitro antibacterial activity. Two BZS compounds showed strong antibacterial activity against methicillin-resistant Staphylococcus aureus and Bacillus subtilis. Quantitative studies of their structure-activity relationship using a simple linear regression analysis were applied to explore the correlation between the biological activity and the charges on acidic hydrogen atoms in the synthesized compounds.

Abstract: Thymidine 5´-bis[3-acetyloxy-2-cyano-2-(2-phenylethylcarbamoyl)propyl]phosphate (1) has been prepared and the removal of phosphate protecting groups by hog liver carboxyesterase (HLE) at pH 7.5 and 37 °C has been followed by HPLC. The first detectable intermediates are the (R_P)- and (S_P)-diastereomers of the monodeacetylated triester 14, which subsequently undergo concurrent retro-aldol condensation to diester 4 and enzyme-catalyzed hydrolysis to the fully deacetylated triester 15. The former pathway predominates, representing 90% of the overall breakdown of 14. The diester 4 undergoes the enzymatic deacetylation 700 times less readily than the triester, but gives finally thymidine 5´-monophosphate as the desired main product. To elucidate the potential toxicity of the electrophilic 2-cyano-N-(2-phenylethyl)acrylamideby-product 17 released upon the deprotection, the hydrolysis of 1 has also been studied in the presence of glutathione (GSH).

Abstract: A novel series of succinyl derivatives of three curcuminoids were synthesized as potential prodrugs. Symmetrical (curcumin and bisdesmethoxycurcumin) and unsymmetrical (desmethoxycurcumin) curcuminoids were prepared through aldol condensation of 2,4-pentanedione with different benzaldehydes. Esterification of these compounds with a methyl or ethyl ester of succinyl chloride gave the corresponding succinate prodrugs in excellent yields. Anticolon cancer activity of the compounds was evaluated using Caco-2 cells. The succinate prodrugs had IC₅₀ values in the 1.8–9.6 μM range, compared to IC₅₀ values of 3.3–4.9 μM for the parent compounds. Curcumin diethyl disuccinate exhibited the highest potency and was chosen for stability studies. Hydrolysis of this compound in phosphate buffer at pH 7.4 and in human plasma followed pseudo first-order kinetics. In phosphate buffer, the k_obs and t_1/2 for hydrolysis indicated that the compound was much more stable than curcumin. In human plasma, this compound was able to release curcumin, therefore our results suggest that succinate prodrugs of curcuminoids are stable in phosphate buffer, release the parent curcumin derivatives readily in human plasma, and show anti-colon cancer activity.

Abstract: In this study the solvolysis of newly synthesized fluocinolone acetonide C-21 esters was analysed in comparison with fluocinonide during a 24-hour period of time. The solvolysis was performed in an ethanol-water (90:10 v/v) mixture using the excess of NaHCO₃. The solvolytic mixtures of each investigated ester have been assayed by a RP-HPLC method using isocratic elution with methanol-water (75:25 v/v); flow rate 1 mL/min; detection at 238 nm; temperature 25 °C. Solvolytic rate constants were calculated from the obtained data. Geometry optimizations and charges calculations were carried out by Gaussian W03 software. A good correlation (R = 0.9924) was obtained between solvolytic rate constants and the polarity of the C-O2 bond of those esters. The established relation between solvolytic rate constant (K) and lipophilicity (cLogP) with experimental anti-inflammatory activity could be indicative for topical corticosteroid prodrug activation.

Abstract: Aminolevulinic acid (ALA) is an endogenous metabolite normally formed in the mitochondria from succinyl-CoA and glycine. Conjugation of eight ALA molecules yields protoporphyrin IX (PpIX) and finally leads to formation of heme. Conversion of PpIX to its downstream substrates requires the activity of a rate-limiting enzyme ferrochelatase. When ALA is administered externally the abundantly produced PpIX cannot be quickly converted to its final product - heme by ferrochelatase and therefore accumulates within cells. Since PpIX is a potent photosensitizer this metabolic pathway can be exploited in photodynamic therapy (PDT). This is an already approved therapeutic strategy making ALA one of the most successful prodrugs used in cancer treatment.

Abstract: The development of resistance to current antifungal therapeutics drives the search for new effective agents. The fact that several acetophenone-derived Mannich bases had shown remarkable antifungal activities in our previous studies led us to design and synthesize some acetophenone-derived Mannich bases, 1-8 and 2-acetylthiophene-derived Mannich base 9, 1-aryl-2-dimethylaminomethyl-2-propen-1-one hydrochloride, to evaluate their antifungal activities. The designed chemical structures have α,β-unsaturated ketone moieties, which are responsible for the bioactivities of the Mannich bases. The aryl part was C₆H₅ (1); 4-CH₃C₆H₄ (2); 4-CH₃OC₆H₄ (3); 4-ClC₆H₄ (4); 4-FC₆H₄ (5); 4-BrC₆H₄ (6); 4-HOC₆H₄ (7); 4-NO₂C₆H₄ (8); and C₄H₃S(2-yl) (9). In this study the designed compounds were synthesized by the conventional heating method and also by the microwave irradiation method to compare these methods in terms of reaction times and yields to find an optimum synthetic method, which can be applied for the synthesis of Mannich bases in further studies. Since there are limited number of studies reporting the synthesis of Mannich bases by microwave irradiation, this study may also contribute to the general literature on Mannich bases. Compound 7 was reported for the first time. Antifungal activities of all compounds and synthesis of the compounds by microwave irradiation were also reported for the first time by this study. Fungi (15 species) were used for antifungal activity test. Amphotericin B was tested as an antifungal reference compound. In conclusion, compounds 1-6, and 9, which had more potent (2–16 times) antifungal activity than the reference compound amphotericin B against some fungi, can be model compounds for further studies to develop new antifungal agents. In addition, microwave irradiation can be considered to reduce reaction period, while the conventional method can still be considered to obtain compounds with higher reaction yields in the synthesis of new Mannich bases.