Showing papers in "Medicinal Research Reviews in 1998"

Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle.

Abstract: Tubulin is the biochemical target for several clinically used anticancer drugs, including paclitaxel and the vinca alkaloids vincristine and vinblastine. This review describes both the natural and synthetic agents which are known to interact with tubulin. Syntheses of the more complex agents are referenced and the potential clinical use of the compounds is discussed. This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle. The agents are discussed in relation to the type of binding site on the protein with which they interact. These are the colchicine, vinca alkaloid, rhizoxin/maytansine, and tubulin sulfhydryl binding sites. Also included are the agents which either bind at other sites or unknown sites on tubulin. The literature is reviewed up to October 1997. © 1998 John Wiley & Sons, Inc., Med Res Rev, 18, No. 4, 259–296, 1998.

A review of the plants of the genus Phyllanthus: their chemistry, pharmacology, and therapeutic potential.

Abstract: The plants of the genus Phyllanthus (Euphorbiaceae) are widely distributed in most tropical and subtropical countries, and have long been used in folk medicine to treat kidney and urinary bladder disturbances, intestinal infections, diabetes, and hepatitis B. In recent years, the interest in the plants has increased considerably. Substantial progress on their chemistal and pharmacological properties, as well as a few clinical studies of some Phyllanthus species have been made. This review discusses the current knowledge of their chemistry, the in vitro and in vivo pharmacological, biochemical, and clinical studies carried out on the extracts, and the main active constituents isolated from different species of plants of the genus Phyllanthus. These studies carried out with the extracts and purified compounds from these plants support most of their reported uses in folk medicine as an antiviral, in the treatment of genitourinary disorders, and as antinociceptive agents. However, well-controlled, double-binding clinical trials are lacking. Several compounds including alkaloids, flavonoids, lignans, phenols, and terpenes were isolated from these plants and some of them interact with most key enzymes. Together this data strongly supports the view that the plants belonging to the genus Phyllanthus have potential beneficial therapeutic actions in the management of hepatitis B, nefrolitiase, and in painful disorders.

Camptothecin and taxol: discovery to clinic

Abstract: Camptothecin (CPT) is a pentacyclic alkaloid isolated from wood and bark of Camptotheca acuminata. Initially it was found to be highly active in a number of mouse in vivo cancer assays. Subsequently, CPT was found to uniquely inhibit an enzyme, topoisomerase I, which is involved in DNA replication. A number of CPT analogs are in advanced clinical trial, and two, Topotecan and CPT-11, have been approved for marketing by the FDA. taxol, a taxane alkaloid, was isolated from Taxus brevifolia. Taxol is a highly cytotoxic compound active in several mouse antitumor assays. It was subsequently found to uniquely inhibit tubulin, a protein involved in mitosis. After clinical evaluation, it has become the drug of choice for treatment of ovarian cancer.

Paclitaxel (Taxol®) :A success story with valuable lessons for natural product drug discovery and development

Abstract: The discovery and development of paclitaxel, which covered a time span of some 30 years, has provided some important lessons for those involved in natural product drug discovery and development. These include the adoption of novel screens as they become available, the elucidation of mechanisms of action, and addressing the supply issue at an early stage of development. These issues, as applied to paclitaxel, are illustrated. The development of the NCI human cancer cell line screen, and its application to mechanistic studies through use of COMPARE analyses, are discussed, as is the production of the marine-derived anticancer agent, bryostatin 1, which provides another illustration of a successful approach to solving a supply issue. The history of the development of paclitaxel also illustrates the importance of multidisciplinary collaboration, and the various mechanisms used by the NCI Developmental Therapeutics Program for promoting such collaboration are presented.

Recent advances on bioactive natural products from Chinese medicinal plants.

Abstract: China has accumulated a rich body of empirical knowledge of the use of medicinal plants for the treatment of various diseases throughout its long history. Chemical studies on Chinese medicinal plants provide a valuable material base for the discovery and development of new drugs of natural origin. In this article recent chemical work on various Chinese medicinal plants is reviewed, including Mussaenda pubescens (Rubiaceae), Isatis indigotica (Cruciferae), Euphorbia fischeriana, and E. ebracteolata (Euphorbiaceae), and Stemona species (Stemonaceae). The structural diversity of the medicinal chemical constituents of the above plants is discussed.

Tuberculosis: a search for novel therapy starting with natural products.

Abstract: The reemergence of tuberculosis and closely related diseases as significant public health problems is briefly reviewed with particular emphasis on the exacerbating role of AIDS and multiple drug resistance. Screening methods available for discovering new chemical entities active against resistant strains are discussed and their use in screening extracts and compounds for activity is illustrated with a number of newly discovered structures being presented. In particular, the properties of the potent and structurally novel indoloquinazolinone alkaloid, tryptanthrin, is described. Many analogs of this lead structure were synthesized by combinatorial and multiple parallel synthetic techniques and evaluated in vitro and in vivo for their potential in the chemotherapy of human infections.

Signals mediating nuclear targeting and their regulation: Application in drug delivery

Abstract: The recent progress with respect to understanding the signals mediating the transport of proteins in both directions through the NPC, and cellular proteins interacting with these signals to effect the transport process has made possible a number of advances in terms of the use of this information in a clinical setting. In particular, our knowledge of the mechanism of regulation of the process, and of how we may exploit the cellular transport machinery itself in a therapeutic situation, especially where there may be transport pathways specific to particular viruses, has advanced considerably. In this context, this review expounds current understanding of the signals conferring targeting to the nucleus, and their practical and potential use in delivering molecules of interest to the nucleus in a clinical context. It also deals with targeting signals conferring nuclear protein export/shuttling between nuclear and cytoplasmic compartments as well as with those conferring nuclear or cytoplasmic retention, and with the specific mechanisms regulating the activity of these signals, and in particular those regulating signal-dependent nuclear protein import. Detailed understanding of the processes of signal-mediated nuclear protein import/export and its regulation enables the considered application and optimization of approaches to target molecules of interest, such as plasmid DNA or toxic molecules, efficiently to the nucleus according to need in a clinical or research context, and enhance the expression or efficiency of their action, respectively. The use of nuclear targeting signals in this context is reviewed, and future possibilities in terms of the application of our growing understanding of nuclear transport and its regulation are discussed. © 1998 John Wiley & Sons, Inc. Med. Res. Rev., 18, No. 4, 189–223, 1998.

Review of pharmacodynamics, pharmacokinetics, and therapeutic properites of sulodexide

Abstract: Due to various side effects of heparin, such as heparin-induced thrombocytopenia type I or type II, alternative anticoagulants are in clinical development to optimize the anticoagulant regimes in patients requiring low or high anticoagulation dosages. Sulodexide is a highly purified preparation containing a fast-moving heparin fraction as well as dermatansulfate. The pharmacological effects of sulodexide differ substantially from unfractionated heparin and are mainly characterized by a prolonged half-life and reduced effect on global coagulation and bleeding parameters. The lipolytic activity of sulodexide is increased in comparison to unfractionated heparin. Clinical studies demonstrate the safety and efficacy of sulodexide. Specially, oral administration leads to fibrinolytic activities in contrast to oral administration of other glycosaminoglycans. Thus, sulodexide releases tissue plasminogen activator and decreases fibrinogen levels as well as HDL and total cholesterol levels and blood viscosity. Clinical efficacy is demonstrated in peripheral arterial disease, cardiovascular events, in postphlebitic syndrome and on albuminuria in nephropathy.

The search for orally active medications through combinatorial chemistry

Abstract: The literature of combinatorial chemistry is reviewed with particular attention paid to considerations of absorption, distribution, metabolism and excretion in the design and evaluation of libraries containing drug-like molecules. Published libraries are evaluated in particular for the likelihood that the products would possess oral bioavailability. © 1998 John Wiley & Sons, Inc. Med. Res. Rev., 18, No. 3, 149–185, 1998.

Noncariogenic intense natural sweeteners

Abstract: There is a definite relationship between the dietary consumption of sucrose and the incidence of dental caries. Noncaloric sucrose substitutes for use in the sweetening of foods, beverages, and medicines may be either synthetic compounds or natural products. In the United States, four potently sweet artificial sweeteners are approved, namely, saccharin, aspartame, acesulfame potassium, and sucralose. Highly sweet plant constituents are used in Japan and some other countries, including the diterpene glycoside stevioside and the protein thaumatin. Recent progress in a research project oriented towards the discovery and evaluation of novel potentially noncariogenic sweeteners from plants has focused on substances in the sesquiterpenoid, diterpenoid, triterpenoid, steroidal saponin, and proanthocyanidin structural classes. The feasibility of using Mongolian gerbil electrophysiological and behavioral assays to monitor the sweetness of plant extracts, chromatographic fractions, and pure isolates has been investigated. An in vivo cariogenicity study on the commercially available natural sweeteners stevioside and rebaudioside A has been carried out.

Glyceryl-ether monooxygenase [EC 1.14.16.5]. A microsomal enzyme of ether lipid metabolism.

Abstract: The history, biological, and medical aspects of glyceryl ethers, as well as their chemical syntheses, biosynthesis, and their chemical and physical properties are briefly reviewed as background information for appreciating the importance of the enzyme glyceryl-ether monooxygenase, and for embarking on new studies of this enzyme. The occurrence, isolation and general properties of the microsomal, membrane-bound, glyceryl-ether monooxygenase from rat liver are described. Radiometric, nonradiometric, and coupled and direct spectrophotometric assays for this enzyme are detailed. The effects of detergents on the kinetics of this enzyme are described together with the stoichiometry and the effects of inhibitors. The structure-activity relationships of pterin cofactors and of ether lipid substrates, including their stereospecificities, have been summarized from enzyme kinetic data which are also tabulated. The mechanism of enzymic hydroxylation of glyceryl ethers and a model for the active site of glyceryl-ether monooxygenase are proposed from these apparent kinetic data. Notes on useful future studies of this monooxygenase have been made.

Review, reevaluation, and new results in quantitative structure-activity studies of anticonvulsants.

Abstract: This paper reviews and reevaluates all of the published QSAR treatments of anticonvulsants and extends them to a new relationship. This reveals that in almost all cases, the Clog P relationship plays a significant part in the QSAR relationship whether the data stems from receptor to whole animal studies. In some cases the steric factors (B5, B1, and L) are important and, in one case, the log VW relationship is of marginal importance. Electronic effects, except for the Hammett's constant σ, are comparatively unimportant. This suggests that the receptors involved possess a special stereochemical and electronic feature: The aromatic ring and the nitrogen moieties (e.g., an amide group) are the primary binding groups. The study shows that log P, as calculated by the Clog P program, is suitable for this form of QSAR study. Log Po of 2 was found to be ideal for passive penetration of these agents into the CNS. © 1998 John Wiley & Sons, Inc., Med Res Rev, 18, No. 2, 91–119, 1998.

Molecular simulation of the primary and secondary structures of the Aβ(1‐42)‐peptide of Alzheimer's disease

Abstract: The major protein constituent of the deposits of Alzheimer's disease is the so-called amyloid beta-peptide (Abeta) which was derived from proteolysis of a large transmembrane amyloid precursor protein. Some physicochemical and biological properties of the Abeta(1-42) peptide are described in this paper. Three functional areas of the soluble Abeta(1-42) peptide were found: (i) a lipophilic region in the middle of the peptide (Lys16 to Ala21), (ii) a second lipophilic core at the end (Lys28 to Val40), and (iii) polarized and charged, solvent-exposed areas. Using molecule coordinates found experimentally by NMR-solution spectroscopy, subsequent Gasteiger-MM+ geometry optimization led to the result that the first lipophilic core has an alpha-helical structure which is stabilized by intramolecular hydrogen-bonding forces. The result is a loop-like molecule. The second lipophilic core has a beta-sheet structure, and is able to form long-ranged, noncovalent, mainly hydrophobic forces with other beta-sheets of Abeta peptides. The beta-strands run in an antiparallel direction. The aggregates are highly stable and ordered. The negatively charged, solvent-exposed residues are potential sites for a crosslinking with membrane-bound receptors. A perspective in drug research is the development of drugs that bind to individual beta-sheets by noncovalent interactions, blocking the associations between the individual Abeta peptides and preventing the formation of amyloid aggregates.

Modern drug development from traditional medicinal plants using radioligand receptor-binding assays.

Abstract: Traditional medicinal plants in various countries, particularly in India have been used for centuries for various ailments; however, there has been little scientific effort to validate these anecdotal uses mentioned in the literature. A number of these traditionally used plant extracts and various "Ayurvedic medicines" that are highly valued in Ayurveda, the traditional system of medicine in India for antiaging, memory-enhancing, nerve tonic, anxiolytic, anti-inflammatory and immunopotentiation, have been screened using National Institutes of Mental Health (NIMH) Synthetic Screening Program for scientific validation and the development of new leads of psychotherapeutic compounds using Radioligand Receptor Binding Assays (RRA). Crude methanolic extracts of plants are screened using approximately 40 different in vitro RRA (primarily from rat brain homogenates) and 6 enzyme assays including acetylcholine esterase, choline acetyltransferase, and monoamine oxidase (MAO), A and B. The total crude extracts of many of these plants showed potent selectivity to various receptors, especially gamma-Amino Butyric Acid (GABA(A)), N-Methyl-D-Aspartic Acid (NMDA), and MAO receptors, which are presumed to be involved in mental disorders. The focus was on plants showing the highest displacement of GABA, cholecystokinin (CCK), NMDA, MAO, and benzodiazopines. Bioassay guided fractionation of the most active extracts resulted in pure compounds which retained the original activity of the crude extract validating the folkloric use. A bioactivity-guided fractionation of Terminalia bellerica fruit extract led to the isolation of several pure compounds which retained the original activity of the crude extract for CCK and GABA receptors, with the exception of compound B3EA-6, which exhibited high affinity for Neurokinin receptor (Substance K approximately NK-1). The absolute structure of B3EA-6 has been established by x-ray crystallography.

Thymidylate synthase inhibition: A structure‐based rationale for drug design

Abstract: Thymidylate synthase (TS) is a very interesting target in antiproliferative diseases. Its inhibition causes thimineless death of the cells and compounds inhibiting TS are widely used in anticancer therapy. The classical antifolate TS inhibitors are structural analogs of the folate cofactor; they often share the same metabolic pathways and this causes the development of resistance inside the cells. A detailed analysis of the available x-ray crystal structures of the complexes of the enzyme with different substrates and inhibitors support the finding of a structural basis of their biological activity. TS inhibitors nonstructural analog of folate, non-analog antifolate inhibitors (NAAI), are welcome as a new interesting research topic. Among the most recent and interesting ones, compounds from Agouron related to the indole structure, are independent on the folate metabolism, highly active and specific for human TS. Other compounds, phthalein derivatives, can inhibit TS enzymes from various sources and show an interesting biological activity profile: they inhibit better bacterial and fungal TS than human TS. The x-ray crystal structures of some of these inhibitors with TS show that they bind in a different binding site from that of the classical folate TS inhibitors. This indicates a potential allosteric binding site useful for future drug discovery studies. © 1998 John Wiley & Sons, Inc. Med Res Rev,18, No. 1, 21-42, 1998.

Prospecting for potentially new pharmaceuticals from natural sources

Abstract: Many new natural product-derived pharmaceutically active compounds and compositions, each effective in treating an array of diseases and maladies including various tumors and HIV, have been reportedly isolated from different sources of vegetation, including the bark of yew trees, needles, leaves, fungi, and cell culture of many different species; vegetables such as West African yams; and Chinese and Indian herbs. Other sources include vegetation from South American rainforests. Many of the sources of such natural products are historical in nature and/or are known from folklore. Recent studies have provided potentially new biodiverse pharmaceutical compounds such as paclitaxel, which is obtainable from several species, including various portions of T. brevifolia, the Western yew tree, and other yew species such as T. baccata, T. cuspidata, T. wallichiana, T. media, T. canadensis, T. chinensis and T. yunnanensis as well as from T. wardii, T. capitata, T. brownii, T. gem, T. globosa, T. floridana, T. hicksii, T. densiformis, and T. darkgreen spreader, in addition to cultured plant cells and fungi. The novel compounds and their semisynthetic brominated and chlorinated analogs prepared from T. yunnanensis extract show strong activity against several types of tumors.

Education of medicinal chemists in departments of Medicinal Chemistry (U.S.A.)

Abstract: The present state of faculties, student bodies, and curricula in departments of medicinal chemistry have been surveyed by questionnaire and analyzed in the context of perceptions of quality and content The results reveal a healthy diversity of educational objectives and a broader range of educational objectives than those uncovered in previous surveys of the perceived needs of industrial departments of medicinal chemistry in their search for drug discovery personnel

Prevention of cancer and cardiovascular diseases : A common strategy?

Abstract: Cancer and cardiovascular diseases are two pathological states involving uncontrolled proliferation of either tumor or vascular smooth muscle cells. Interestingly, both types of disease can be prevented by the same type of chemical agent, such as marine polyunsaturated fatty acids, sulfur-containing compounds present in garlic, and wine polyphenols, among others, which seem to be fairly effective in the prevention of certain types of cancer and cardiovascular diseases. This is supported by numerous epidemiological studies and laboratory experiments involving animal models. It is therefore suggested that the mode of action of these compounds interfering with the development of these pathological states share some common trends. This could be taken into consideration in future studies related to the molecular mechanisms leading to these diseases as well as with the chemopreventive potential of some dietary components. © John Wiley & Sons, Inc. Med. Res. Rev., 18, No. 3, 139–148, 1998.