Current Medicinal Chemistry - Volume 8, Issue 11, 2001

Polyphenolic compounds are abundant throughout the plant kingdom and are found in a wide variety of human foods. The flavonoids, which are the best defined group of polyphenols in the human diet, themselves comprise a large and complex group, all of which contain a three-ring structure with two aromatic centres and a central oxygenated heterocycle. Recent evidence suggests that significant quantities of quercetin and possibly myricetin and kaempferol are absorbed in the gut. A larger fraction probably remains in the lumen, and thus a substantial proportion of the gastrointestinal mucosa is exposed to biologically significant concentrations of these compounds. A substantial body of experimental work has established that flavonoids can suppress carcinogenesis in animal models and there is considerable interest in the biological effects of these compounds at the cellular level. Flavonoids interact with cellular signal pathways controlling the cell cycle, differentiation and apoptosis. Their potentially antineoplastic effects include antioxidant activity, induction of Phase II enzyme activity, inhibition of protein kinases and interactions with Type II estrogen binding sites. Naturally occuring polyphenolic compounds may play a role in the protective effects of fruits and vegetables against cancers in general, and they appear to have considerable potential for pharmaceutical uses as chemopreventive agents against neoplastic changes in the alimentary tract. Future research should therefore focus on the biological effects of flavonoids in the human body, using biomarkers to define their effects at each stage in the onset of neoplasia.

Impairments and defects in the inhibitory neurotransmission in the CNS can contribute to various seizure disorders, i.e., gama-aminobutyric acid (GABA) and glycine as the main inhibitory neurotransmitters in the brain play a crucial role in some forms of epilepsy. Recent advances in deciphering the molecular basis of the GABAergic and glycinergic systems has been achieved by means of cloning techniques and gene targeting strategies in animals, contributing to the understanding of drug action. As well, several anticonvulsive substances emerged which target key molecules of the inhi- bitory systems. Employment of recombinant expression systems, including, but not restricted to the inhibitory circuitry, will further facilitate drug screening and rational approaches to design novel specific antiepileptic drugs, which act highly efficiently to prevent or reduce generation and spread of seizures.

Antiepileptic drugs (AEDs) cover a broad spectrum of pathological conditions ranging from seizures following congenital or acquired brain disorders to behavioural and psychiatric disorders and recently neuropathic pain. The need for novel antiepileptics raises from the expanding field of indications as well as from the fact, that special seizure types are refractory to common AEDs. In addition, many of the conventional antiepileptic drugs exhibit an unfavourable side-effect profile. Since there is growing evidence, that NMDA receptor activation might play a crucial role in epilepsy, NMDA receptor antagonists have become compounds of interest in preventing and treating seizures. This review focuses on NMDA receptor antagonistic compounds, which are already in use for the treatment of epileptic seizures (i. e. MgSO4, felbamate) and compounds in clinical trials (i. e. remacemide, ADCI). Further interest is put on NMDA antagonists in preclinical and biological testing (memantine, dizocilpine, conantokins, Co101244 / PD174494, ifenprodil, arcaine, L-701,324, eliprodil, CGP40116, LY235959, LY233053, MRZ2 / 576, LU73068, 4-Cl-KYN). Some of the latter compounds are predominantely of academic interest (i. e. 4-Cl-KYN), others (i. e. dizocilpine, LY235959, LY233053) might be of therapeutical value when combined with conventional AEDs. In order to reduce adverse effects in antiepileptic medication using NMDA antagonists, special interest will be focused on subtype selective compounds. In this respect, Co101244, a novel potent and selective NR1 / 2B NMDA receptor antagonist might be a lead for therapeutically promising compounds.

The glutamate receptor system is implicated in the development and maintenance of epileptic seizures, and animal studies have disclosed potent anticonvulsant activity of a number of inhibitors of AMPA and / or kainate (KA) receptor activity. These results make such inhibitors potential future antiepileptic drugs. Different series of compounds with inhibitory activity towards AMPA receptors have been developed. Most of these inhibitors are structurally derived from AMPA, quinoxalinedione or 2,3-benzodiazepine. In contrast, only a limited number of inhibitors of KA receptor activity have been developed, most of which contain quinoxalinedione or decahydroisoquinoline skeletons. In spite of promising anticonvulsant activity in various animal model studies, no AMPA / KA receptor inhibitors are in clinical use against epilepsy today. Based on molecular biology studies, AMPA and KA receptors are at present divided into four and five subtypes, respectively, and attempts to develop subtype selective compounds have been initiated. Future studies and development of such compounds will indicate whether AMPA / KA receptor inhibition is a feasible therapeutic strategy for the treatment of epilepsy.

Numbers of biologically active compounds are glycosides. Sometimes, the glycosidic residue is crucial for their activity, in other cases glycosylation only improves pharmacokinetic parameters. Recent developments in molecular glycobiology brought better understanding to the aglycone vs. glycoside activities, and made possible to develop new, more active or more effective glycodrugs based on these findings - very illustrative recent example is the story of vancomycin. This paper deals with an array of glycosidic compounds currently used in medicine but also with biological activity of some glycosidic metabolites of the known drugs. It involves glycosides of vitamins, polyphenolic glycosides (flavonoids), alkaloid glycosides, glycosides in the group of antibiotics, glycopeptides, cardiac glycosides, steroid and terpenoid glycosides etc. The physiological role of the glycosyl and structure-activity relations (SAR) in the glycosidic moiety (-ies) are discussed.

The histamine H3 receptor is considered a potential target for novel drugs as it regulates the activity of various neurotransmitters in the peripheral and the central nervous system. Particularly H3-receptor agonists have been suggested to become valuable drugs for the treatment of several CNS disorders, inflammatory and acid related diseases. Due to its strong basicity and polarity the highly potent and selective histamine H3-receptor agonist (R)-alpha-methylhistamine hardly penetrates biological membranes and is furthermore rapidly inactivvated in vivo. Thus, lipophilic, non-basic azomethine prodrugs of (R)-alpha-methylhistamine have been developed to overcome its pharmacokinetic disadvantages. This bioreversible derivatization decreased its basicity, increased its lipophilicity and reduced its metabolization. As a result the biological half-life was prolonged and oral absorption as well as penetration into the brain were significantly increased. By systematic variation of the pro-moiety we were able to optimize the pharmacokinetic properties which allow for both peripheral and central delivery of the parent amine. The azomethine prodrugs described herein display satisfactory stability to be orally administered while being adequately labile to deliver (R)-alpha-methylhistamine at sufficient concentrations in vivo. At present, these azomethines not only serve as valuable tools for pharmacological studies related to the histamine H3 receptor, but also represent a promising approach to achieve therapeutic application of the histamine H3-receptor agonist (R)-alpha-methylhistamine.Currently the parent compound of the prodrugs is under clinical development phase II.

The oxime formation reaction of therapeutical progestogen (levonorgestrel, levonorgestrel acetate, norethisterone), androgen (methyltestosterone, testosterone phenylpropionate) and anabolic (nortestosterone phenylpropionate) Delta 4-3-ketosteroids has been investigated. The ketosteroid-hydroxylamine reaction was monitored by reversed phase HPLC system. It was established, that under the experimental conditions applied the oxime formation was complete within 2 h. The reaction leads to the formation of Z and E oxime isomers. The isomers of norgestimate (levonorgestrel 17-acetate oxime) and other Delta 4-3-ketosteroid oximes have been separated by a new normal phase HPLC method. The identification (elution order assignation) and determination of the formation ratio of the isomers have been performed by 1H NMR spectroscopy on the basis of the chemical shift differences of 4-H signals. The on-line CD and UV spectra of the pure oxime isomers were recorded and then molar ellipticities and absorbances of the isomers were calculated in the wavelength range of 200-300 nm via parameter estimation method.

In the late 20th century, the treatment of cancer began to include its prevention. Today, compounds exist that will lower the risk of developing certain types of cancer. This has been demonstrated in studies where chemically induced tumor growth has been slowed or reversed. Anti-inflammatory compounds having chemopreventive activity are piroxicam, sulindac, aspirin, celecoxib and curcumin. The selective estrogen receptor modulators, tamoxifen and raloxifene, are beneficial in the prevention of estrogendependent tumors. Retinoids, vitamin A derivatives, such as targretin and fenretinide are useful in the prevention of tumors. Compounds containing sulfur, such as sulforaphane and oltipraz, are even useful as radioprotective agents. The steroid dehydroepiandosterone can inhibit experimental carcinogenesis. All of these chemical classes provide a start for the medicinal chemist to design more effective chemopreventive agents. The biomarkers used to determine the chemopreventive activity of new compounds are quite often activities of enzymes. The identification of those individuals at high risk is still in its infancy and presents a troubling dilemma.

Podophyllotoxin derivatives like etoposide 7a, etophos 7b, and teniposide 7c are used clinically as potent chemotherapeutic agents for a variety of tumors including small cell lung carcinoma, testicular cancer, and malignant lymphoma.These compounds derived from a series of modifications which converted podophyllotoxin 1a from an entity that interacted with tubulin and blocks mitosis to one that induced a block in late S or early G2 by interacting with topoisomerase II.Synthetic studies on podophyllotoxin derivatives can be divided in four general approaches (the oxo-ester route, the dihydroxy acid route, the tandem conjugate addition route and the Diels-Alder route). Albeit a number of synthetic sequences afforded products with excellent enantiopurities, the low overall yields still disqualify synthesis as an alternative for naturally produced materials.An alternative route based on the enzyme-catalyzed cyclization of synthetic intermediates to analogues of the podophyllotoxin family is being explored.Synthetic dibenzylbutanolides, which were revealed by biosynthetic studies to be the precursors of aryltetralin lignans, have been treated with enzymes derived from cell cultures of Podophyllum peltatum, Catharanthus roseus, Nicotiana sylvestris and Cassia didymobotrya. The ciclyzation process afforded however compounds with a different stereochemistry in the C ring. The obtainment of a novel compound with a benzylidenebenzylbutirolactone structure still leaves considerable scope for exploring biotransformations in order to obtain podophyllotoxin analogues via a combination of synthetic chemistry and biotechnological methods.