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Showing papers in "Current Medicinal Chemistry in 2001"


Journal ArticleDOI
TL;DR: Delineation of the profile of oxidative damage in each disease will provide clues to how the specific neuronal populations are differentially affected by the individual disease conditions.
Abstract: The age-related neurodegenerative diseases exemplified by Alzheimerhs disease (AD), Lewy body diseases such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntingtonhs disease are characterized by the deposition of abnormal forms of specific proteins in the brain. Although several factors appear to underlie the pathological depositions, the cause of neuronal death in each disease appears to be multifactorial. In this regard, evidence in each case for a role of oxidative stress is provided by the finding that the pathological deposits are immunoreactive to antibodies recognizing protein side-chains modified either directly by reactive oxygen or nitrogen species, or by products of lipid peroxidation or glycoxidation. Although the source(s) of increased oxidative damage are not entirely clear, the findings of increased localization of redox-active transition metals in the brain regions most affected is consistent with their contribution to oxidative stress. It is tempting to speculate that free radical oxygen chemistry plays a pathogenetic role in all these neurodegenerative conditions, though it is as yet undetermined what types of oxidative damage occur early in pathogenesis, and what types are secondary manifestations of dying neurons. Delineation of the profile of oxidative damage in each disease will provide clues to how the specific neuronal populations are differentially affected by the individual disease conditions.

612 citations


Journal ArticleDOI
TL;DR: Assessment of oxidative stress status (OSS) may help in designing newer modes of male factor infertility treatment by suitable antioxidants because a balance between ROS generation and antioxidant capacity plays a critical role in the pathophysiology of disease state.
Abstract: Impairment of normal spermatogenesis and sperm function are the most common causes of male factor infertility. Abnormal sperm function is difficult to evaluate and treat. There is a lack of understanding of the factors contributing to normal and abnormal sperm function leading to infertility. Many recent studies indicate that oxygen-derived free radicals induce damage to spermatozoa. The excessive generation of these reactive oxygen species (superoxide, hydroxyl, nitric oxide, peroxide, peroxynitrile) by immature and abnormal spermatozoa and by contaminating leukocytes associated with genitourinary tract inflammation have been identified with idiopathic male infertility. Mammalian spermatozoa membranes are rich in polyunsaturated fatty acids. This makes them very susceptible to oxygen-induced damage, which is mediated by lipid peroxidation. In a normal situation, the antioxidant mechanisms present in the reproductive tissues and their secretions are likely to quench these reactive oxygen species (ROS) and protect against oxidative damage to gonadal cells and mature spermatozoa. During chronic disease states, aging, toxin exposure, or genitourinary infection/inflammation, these cellular antioxidant mechanisms downplay and create a situation called oxidative stress. Thus, a balance between ROS generation and antioxidant capacity plays a critical role in the pathophysiology of disease state. Recent efforts towards the development of new reliable assays to evaluate this oxidative stress status have resulted in the establishment of ROS-TAC score. Such assessment of oxidative stress status (OSS) may help in designing newer modes of male factor infertility treatment by suitable antioxidants.

580 citations


Journal ArticleDOI
TL;DR: Evidence clearly indicates to the potential health promoting properties of these citrus flavonoids.
Abstract: Citrus flavonoids encompass a diverse set of structures, including numerous flavanone and flavone O- and C-glycosides and methoxylated flavones. Each of these groups of compounds exhibits a number of in vitro and in vivo anti-inflammatory and anticancer actions. These biological properties are consistent with their effects on the microvascular endothelial tissue. Evidence suggests that the biological actions of the citrus flavonoids are possibly linked to their interactions with key regulatory enzymes involved in cell activation and receptor binding. The citrus flavonoids show little effect on normal, healthy cells, and thus typically exhibit remarkably low toxicity in animals. The citrus flavonoids extend their influence in vivo through their induction of hepatic phase I and II enzymes, and through the biological actions of their metabolites. Evidence clearly indicates to the potential health promoting properties of these dietary compounds.

555 citations


Journal ArticleDOI
TL;DR: An array of glycoside compounds currently used in medicine but also with biological activity of some glycosidic metabolites of the known drugs are dealt with.
Abstract: 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.

420 citations


Journal ArticleDOI
TL;DR: Important molecules discussed include Vincristine, Vinblastine, Colchicine, Ellipticine and Lepachol along with Flavopiridol, a semi-synthetic analogue of the chromone alkaloid Rohitukine from India, a pyridoindole alkaloids from leaves of Ochrosia species and many more.
Abstract: Natural Products have long been a fertile source of cure for cancer, which is projected to become the major causes of death in this century. However, there is a continuing need for development of new anticancer drugs, drug combinations and chemotherapy strategies, by methodical and scientific exploration of enormous pool of synthetic, biological and natural products. There are at least 250,000 species of plants out of which more than one thousand plants have been found to possess significant anticancer properties. While many molecules obtained from nature have shown wonders, there are a huge number of molecules that still either remains to be trapped or studied in details by the medicinal chemists. The article reviews many such structures and their related chemistry along with the recent advances in understanding mechanism of action and structure-function relationships of nature derived anti-cancer agents at the molecular, cellular and physiological levels. Taxol, one of the most outstanding agents, has been found beneficial in treatment of refractory ovarian, breast and other cancers. Another prominent molecule includes Podophyllotoxin. Synthetic modification of this molecule led to the development of Etoposide, known to be effective for small cell cancers of the lungs and testes. Camptothecin isolated from Camptotheca acuminata also have been extensively studied. Other important molecules discussed include Vincristine, Vinblastine, Colchicine, Ellipticine and Lepachol along with Flavopiridol, a semi-synthetic analogue of the chromone alkaloid Rohitukine from India, a pyridoindole alkaloid from leaves of Ochrosia species and many more. The review also deals with the lesser-known plants of sub-Himalayan region.

414 citations


Journal ArticleDOI
TL;DR: In this paper, the authors examine the concept that production of reactive intermediates increases during exercise and examine adaptations to exercise that may decrease oxidative stress, including increased antioxidant defenses, reduced basal production of oxidants, and reduction of radical leak during oxidative phosphorylation.
Abstract: Increased aerobic metabolism during exercise is a potential source of oxidative stress. In muscle, mitochondria are one important source of reactive intermediates that include superoxide (O2*-), hydrogen peroxide (H2O2), and possibly hydroxyl radical (HO*). The recent discovery that mitochondria may generate nitric oxide (NO*) also has implications for oxidant production and mitochondrial function. In this review, we critically examine the concept that production of reactive intermediates increases during exercise. Because the health benefits of regular exercise are well-documented, we also examine adaptations to exercise that may decrease oxidative stress. These include increased antioxidant defenses, reduced basal production of oxidants, and reduction of radical leak during oxidative phosphorylation.

412 citations


Journal ArticleDOI
TL;DR: This review presents a wide array of evidence that implicates oxidative stress (OS) in many aspects of oncology, including formation of reactive oxygen species (ROS) by the major classes of carcinogens, cancer stages, oncogene activation, aging, genetic and infectious illnesses, nutrition, and the role of antioxidants (AOs).
Abstract: For more than half a century, numerous proposals have been advanced for the mode of action of carcinogens. This review presents a wide array of evidence that implicates oxidative stress (OS) in many aspects of oncology, including: formation of reactive oxygen species (ROS) by the major classes of carcinogens (as well as minor ones), cancer stages, oncogene activation, aging, genetic and infectious illnesses, nutrition, and the role of antioxidants (AOs). Although diverse origins pertain, including both endogenous and exogenous agents, ROS are frequently generated by redox cycling via electron transfer (ET) groups, e.g., quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced products), and conjugated imines (or iminium species). We believe it is not coincidental that these functionalities are often found in carcinogens or their metabolites. The pervasive aspects of DNA binding by ultimate carcinogens, and mutations caused by ROS are treated. Often, ROS are implicated in more conventional rationales, such as oncogenes. A multi-faceted approach to mechanisms appears to be the most logical. The OS unifying theme represents an approach which is able to rationalize the diverse data associated with carcinogenesis. Because this theoretical framework aids in the understanding of cancer initiation, it can serve as a useful tool in combating cancer, particularly in relation to prevention. Significantly, the electron transfer--oxidative stress (ET-OS) scenario can also be applied to many drug categories, toxins, enzymes, and hormones.

385 citations


Journal ArticleDOI
TL;DR: Clearly established as one of the successful computational tools in rational drug design, a brief history of the evolution of this technology and detailed algorithms of Catalyst, the latest 3D searching software to be released are presented.
Abstract: Perceiving a pharmacophore is the first essential step towards understanding the interaction between a receptor and a ligand. Once a pharmacophore is established, a beneficial use of it is 3D database searching to retrieve novel compounds that would match the pharmacophore, without necessarily duplicating the topological features of known active compounds (hence remain independent of existing patents). As the 3D searching technology has evolved over the years, it has been effectively used for lead optimization, combinatorial library focusing, as well as virtual high-throughput screening. Clearly established as one of the successful computational tools in rational drug design, we present in this review article a brief history of the evolution of this technology and detailed algorithms of Catalyst, the latest 3D searching software to be released. We also provide brief summary of published successes with this technology, including two recent patent applications.

324 citations


Journal ArticleDOI
TL;DR: The role of topological indices in drug development research is updated and the use of these descriptors in lead optimization process is critically analyzed, with emphasis on combined use of connectivity and charge indices and TOSS-MODE approach.
Abstract: The role of topological indices in drug development research is updated. A series of definitions in the fields of topological indices and drug discovery technologies are introduced. In all cases where it is possible the IUPAC recommendations for terms used in medicinal chemistry and in computational drug design are used. Recent advances on the use of topological indices in the lead discovery process are reviewed making emphasis on two approaches: combined use of connectivity and charge indices and TOSS-MODE approach. Studies of similarity/dissimilarity and rational combinatorial library design are also updated. The use of these descriptors in lead optimization process is critically analyzed. Topological indices QSAR, the problem of 2D QSAR versus 3D QSAR, strategies of orthogonalization and the use of linear combination and semiempirical connectivity indices are also described. The main directions of progress for these indices in QSAR and drug research are analyzed with examples of application of novel statistical techniques, such as artificial neural networks, genetic algorithms and partial least squares. Future outlooks of development in this area of research are also given.

250 citations


Journal ArticleDOI
TL;DR: A number of cellular processes in which ROS and RNS have been implicated in redox signalling mechanisms are discussed, with particular attention paid to thiols and thiol-containing molecules in these processes.
Abstract: Reactive oxygen (ROS) and reactive nitrogen species (RNS) produced in vivo at levels that cannot be dealt with adequately by endogenous antioxidant systems can lead to the damage of lipids, proteins, carbohydrates and nucleic acids. Oxidative modification of these molecules by toxic levels of ROS and RNS represents an extreme event that can lead to deleterious consequences such as loss of function. More recently, however, interest has focused on the formation of these species at sub-toxic levels and their potential to act as biological signal molecules. Subtoxic ROS and RNS production can lead to alterations in cellular and extracellular redox state, and it is such alterations that have been shown to signal changes in cell functions. By the use of a variety of cell types it has been shown that numerous cellular processes including gene expression can be regulated by subtle changes in redox balance Examples of this include the activation of certain nuclear transcription factors, and the determination of cellular fate by apoptosis or necrosis. Cellular redox balance is, under normal circumstances, probably under genetic control and maintained by an array of enzymatic systems that ensure that overall reducing conditions prevail. Thiols, by virtue of their ability to be reversibly oxidised, are recognised as key components involved in the maintenance of redox balance. Additionally, increasing evidence suggests that thiol groups located on various molecules act as redox sensitive switches thereby providing a common trigger for a variety of ROS and RNS mediated signalling events. In this review we discuss a number of cellular processes in which ROS and RNS have been implicated in redox signalling mechanisms. Particular attention has been paid to the importance of thiols and thiol-containing molecules in these processes.

249 citations


Journal ArticleDOI
TL;DR: First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer is possible and inhibitors of HDAC are one of the most promising class of new anticancer agents.
Abstract: Inhibitors of histone deacetylase (HDAC) are an emerging class of anticancer agents. They induce hyperacetylation in chromatin usually resulting in activation of certain genes. They induce terminal cell differentiation and/or apoptosis in cancer cells. Histone deacetylase activity is recruited by co-repressor proteins to certain regions of the chromatin and aberrant histone acetylation caused by that recruitment is responsible for the pathogenesis of certain cancers on a molecular level. Inhibitors of HDAC have been identified in natural sources and also synthetic inhibitors are available. The best studied inhibitor is trichostatin A, a hydroxamic acid that exerts its activity by complexation of a zinc ion that is supposed to mediate the acetamide cleavage at the catalytic site. There are several synthetic hydroxamic acids that bear resemblance to trichostatin. Another class of potent inhibitors are naturally occurring and synthetic cyclotetrapeptides that all contain an unusual amino acid with an epoxyketone, ketone or hydroxamic acid function in the side chain. Phenylacetate, phenylbutyrate, butyrate and similar short chain fatty acids are also weak inhibitors. Further inhibitors from natural sources are the epoxide depudecin and depsipeptide FR 901228. The benzamide MS-275 belongs to a new class of synthetic HDAC inhibitors and displays oral activity in animal models. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer is possible. Thus, inhibitors of HDAC are one of the most promising class of new anticancer agents. New screening assays are useful tools that will facilitate identification of further inhibitors.

Journal ArticleDOI
TL;DR: The biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches are reviewed and major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties.
Abstract: Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.

Journal ArticleDOI
TL;DR: The latest advances in the synthesis and evaluation of the most promising backbone modified oligonucleotides will be discussed, with a view to their future as novel pharmaceuticals.
Abstract: Nucleic acids have been extensively modified by replacing the phosphodiester group or the whole sugar phosphodiester with alternative anionic, neutral and cationic structures. Several of these modified oligonucleotides exhibit improved properties including enhanced recognition and binding to RNA, duplex DNA and proteins. This has resulted in the development of new and more potent antisense and antigene agents, as well as aptamers. Furthermore, backbone modified oligonucleotides have also been used in the development of several alternative strategies, which rely on altogether different mechanisms of action and show significant promise for therapeutic intervention. In this review the latest advances in the synthesis and evaluation of the most promising backbone modified oligos will be discussed, with a view to their future as novel pharmaceuticals.

Journal ArticleDOI
TL;DR: Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cell-free enzymatic assays to the mode of action of these agents in intact cells.
Abstract: Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e., zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir (PMPA) disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine (MKC-442); and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease step, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polyoxometalates, zintevir, negatively charged albumins, cosalane analogues); (ii) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5 [bicyclams (i.e. AMD3100), polyphemusins (T22), TAK-779, MIP-1 alpha LD78 beta isoform]; (iii) virus-cell fusion, through binding to the viral glycoprotein gp41 [T-20 (DP-178), T-1249 (DP-107), siamycins, betulinic acid derivatives]; (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA) and NCp7 peptide mimics]; (v) proviral DNA integration, through integrase inhibitors such as L-chicoric acid and diketo acids (i.e. L-731,988); (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (fluoroquinolone K-12, Streptomyces product EM2487, temacrazine, CGP64222). Also, in recent years new NRTIs, NNRTIs and PIs have been developed that possess respectively improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides of d4T), or increased activity against NNRTI-resistant HIV strains [second generation NNRTIs, such as capravirine and the novel quinoxaline, quinazolinone, phenylethylthiazolylthiourea (PETT) and emivirine (MKC-442) analogues], or, as in the case of PIs, a different, non-peptidic scaffold [i.e. cyclic urea (DMP 450), 4-hydroxy-2-pyrone (tipranavir)]. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cell-free enzymatic assays to the mode of action of these agents in intact cells. A number of compounds (i.e. zintevir and L-chicoric acid, on the one hand; and CGP64222 on the other hand) have recently been found to interact with virus-cell binding and viral entry in contrast to their proposed modes of action targeted at the integrase and transactivation process, respectively.

Journal ArticleDOI
TL;DR: This article provides information about the different mechanisms responsible of quinolones interaction with NSAIDs, methylxanthines, warfarin and antiacids.
Abstract: This review focuses on the most recent research findings on adverse reactions caused by quinolone antibiotics. Reactions of the gastrointestinal tract, the central nervous system (CNS) and the skin are the most often observed adverse effects. Occasionally major events such as phototoxicity, cardiotoxicity, arthropathy and tendinitis occurr, leading to significant tolerability problems. Over the years, several structure-activity and side-effect relationships have been developed, in an effort to improve overall antimicrobial efficacy while reducing undesiderable side-effects. In this article we review the toxicity of fluoroquinolones, including the newer derivatives such levofloxacin, sparfloxacin, graepafloxacin and the 7-azabicyclo derivatives, trovafloxacin and moxifloxacin. A special attention is given to new data on mechanistic aspects, particularly those regarding CNS effects. In recent years extensive in vivo and in vitro experiments have been performed in an attempt to explain the neurotoxic effects of quinolones sometimes observed under therapeutic conditions. However, the molecular target or receptor for such effects is still not exactly known. Several mechanisms are thought to be responsible. The involvement of γ-aminobutyric acid (GABA) and excitatory aminoacid (EAA) neurotransmission and the kinetics of quinolones distribution in brain tissue are discussed. In addition, quinolones may interact with other drugs - theophylline and nonsteroidal antinflammatory drugs (NSAIDs) - in producing CNS effects This article provides information about the different mechanisms responsible of quinolones interaction with NSAIDs, methylxanthines, warfarin and antiacids.

Journal ArticleDOI
TL;DR: An overview of the sugar-modified nucleosides synthesized since the late 1990 according to their structural types along with the synthetic routes of some selected nucleoside analogs are given.
Abstract: In the search for effective, selective, and nontoxic antiviral and antitumour agents, a variety of strategies have been devised to design nucleoside analogs. These strategies have involved several formal modifications of the naturally occurring nucleosides, especially, alteration of the carbohydrate moiety. Since the naturally occurring purine nucleoside analog oxetanocin A and its derivatives have been found to be effective as anti-HIV-1 and anti-herpes virus agents in 1986, the syntheses of different types of sugar-modified nucleoside analogs have been reported. In this review we will give an overview of the sugar-modified nucleosides synthesized since the late 1990 according to their structural types along with the synthetic routes of some selected nucleosides.

Journal ArticleDOI
TL;DR: Sensitive detection methods such as the use of light-scattering techniques, molecular beacons, surface plasmon resonance, attenuated total internal reflection-FTIR, and the evanescent field excitation of fluorescence from surface-bound fluorophores have been developed to study the kinetics and specificity of hybridization events.
Abstract: This report emphasizes the interfacial chemistry that is required to ensure proper attachment of oligonucleotides onto the surface of microarrays. For example, strategies for the covalent attachment of pre-synthesized oligonucleotides to glass slides, gold films, polyacrylamide gel pads, polypyrrole films, and optical fibers are surveyed in an attempt to better define the parameters for optimal formation and detection of DNA hybrids. These parameters include among others, the nature and length of the linkers attaching oligonucleotides to the arrays, and the surface density of oligonucleotides required for unhindered hybridization with DNA targets. Sensitive detection methods such as the use of light-scattering techniques, molecular beacons, surface plasmon resonance, attenuated total internal reflection-FTIR, and the evanescent field excitation of fluorescence from surface-bound fluorophores have been developed to study the kinetics and specificity of hybridization events. Finally, the synthesis of oligonucleotides directly on glass surfaces and polypropylene sheets has been investigated to enable DNA sequencing by hybridization and achieve oligonucleotide densities of ca. 10(6) sequences per cm(2) on DNA chips.

Journal ArticleDOI
TL;DR: The current status of extensive efforts directed towards the discovery and development of new chemotherapeutic anticancer agents targeting cell cycle regulation in the G1 phase is reviewed, with particular focus on the compounds undergoing clinical investigations.
Abstract: As a result of substantial advances in recent cancer biology, cell cycle regulation in the G1 phase has attracted a great deal of attention as a promising target for the research and treatment of cancer. Many of the important genes associated with G1 regulation have been shown to play a key role in proliferation, differentiation and oncogenic transformation and programmed cell death (apoptosis). Currently, a variety of "cytostatic" agents that affects G1 progression and/or G1/S transition are being evaluated in clinical trials. Flavopiridol is a potent inhibitor of cyclin-dependent kinases (CDKs). UCN-01 was originally found to be a PKC-selective protein kinase antagonist. More recent studies have revealed that this agent can also inhibit several CDKs and the checkpoint kinase CHK1. FR901228, MS-27-275 and SAHA are histone deacetylase inhibitors that induce changes in the transcription of specific genes via the hyperacetylation of histones. The proteasome inhibitor PS-341 disrupts the degradation process of intracellular proteins, including cell cycle regulatory proteins such as cyclins. R115777, SCH66336 and BMS-214662 are non-peptidic farnesyl transferase inhibitors that prevent p21 ras oncogene activation. Rapamycin derivative CCI-779 downregulates signals through S6 kinase and FRAP (FKBP-rapamycin associating protein), affecting the expression levels of mRNAs important for progression from G1 to S phase. 17-Allylaminogeldanamycin targets the Hsp-90 (heat shock protein-90) family of cellular chaperones regulating the function of signaling proteins. TNP-470 (AGM-1470), a fumagillin derivative shows antiangiogenic action through binding to MetAP-2 (methionine aminopeptidase-2). The antitumor sulfonamide E7070, causing a cellular accumulation in the G1 phase, has been shown to suppress the activation of CDK2 and cyclin E expression in HCT116 colorectal cancer cell line highly sensitive to the drug. With respect to several growth factor receptors such as EGFR, PDGFR, bFGFR and VEGFR, potent and specific inhibitors of receptor tyrosine kinases have been also examined as hopeful drug candidates. In this report, we review the current status of extensive efforts directed towards the discovery and development of new chemotherapeutic anticancer agents targeting cell cycle regulation in the G1 phase, with particular focus on the compounds undergoing clinical investigations.

Journal ArticleDOI
TL;DR: The question whether metabolites produced for the self-protection of fungi can be used for pharmaceutical applications for humans will be addressed and discussed.
Abstract: Higher fungi are characterised by the production of macroscopic fruiting bodies to generate and to distribute their spores. These fruiting bodies are under constant threat of other organisms feeding on them. As a consequence these organisms developed a number of strategies for protection, one of them is the production of toxins. The fungal subdivision Basidiomycotina produce toxic sesquiterpenes many of them are derived from the protoilludane skeleton. This skeleton is transformed and rearranged to a large number of compounds. Some of these sesquiterpenes show interesting biological properties which may be attractive for medicinal chemistry. The overview describes the different types of bioactive fungal sesquiterpenes derived from humulene known to date in Basidiomycotina and their formation. The metabolites are discussed according to their sesquiterpene skeleton and the different metabolites are compared. Where available biological activities concerning antifungal, antibacterial, cytotoxic and enzyme inhibition data are given. Special attention was paid for the different activities of these metabolites and the attempts made to use them in medicinal chemistry. The question whether metabolites produced for the self-protection of fungi can be used for pharmaceutical applications for humans will be addressed and discussed.

Journal ArticleDOI
TL;DR: Significant results can be expected from mass selection for the breeding of lines of Artemisia annua rich in artemisinin, but dominance variance is also present in the total genetic variability, indicating that crosses between selected genotypes should generate progenies with particularly high art Artemisinin content.
Abstract: Artemisinin, the endoperoxide sesquiterpene lactone produced by the Chinese medicinal herb Artemisia annua, is very difficult to synthesise. Moreover, its production by mean of cell, tissue or organ cultures is very low. Presently, only its extraction from cultivated plants is viable. A large variation in artemisinin content has been observed in the leaves of plants from different origins. The genetic basis of this variation has been assessed and evidence for a quantitative inheritance of the artemisinin concentration presented. Additive genetic components were predominant, resulting in a high narrow-sense heritability estimate. Thus, goods results can be expected from mass selection for the breeding of lines of Artemisia annua rich in artemisinin. Yet, dominance variance is also present in the total genetic variability, indicating that crosses between selected genotypes should generate progenies with particularly high artemisinin content. As a matter of fact, selection and crossing, in wild populations, of genotypes with high artemisinin concentration resulted in hybrid lines containing up to 1.4 % artemisinin (on dry leaves basis).

Journal ArticleDOI
TL;DR: The well known biochemical target sites such as folate metabolism, pyrimidine metabolism and polyamines for the designing of antimalarial drugs, and the newly discovered biochemical target Sites, alpha-tublin and DNA topoisomerases have been highlighted.
Abstract: This review starts from a brief introduction followed by the list of commercial antimalarial drug. According to the nature of chemical entities, these drugs have been divided into the following categories--Quinolines, pyrimidines, amidinies, guanidines, sulfonamides, sulfones, acridines, antibiotics and sesquiterpene lactones. The site of action and status of the antimalarial drugs have been described against each category. A brief description of reasons behind the search of a new antimalarial drug have been discussed. Finally, the review deals the well known biochemical target sites such as folate metabolism, pyrimidine metabolism and polyamines for the designing of antimalarial drugs. The detail description of the newly discovered biochemical target sites, alpha-tublin and DNA topoisomerases, have been highlighted. In the conclusion section, we have discussed the future strategies for the chemotherapy of malaria.

Journal ArticleDOI
TL;DR: The advances from monoamine-based treatment strategies are discussed, the future developments in the treatment of depression are looked at and modulation of N-methyl-D-aspartate receptors, neuropeptide receptors and the intracellular messenger system may provide an entirely new set of potential therapeutic targets are suggested.
Abstract: Early antidepressant medications e.g. tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are effective because they enhance either noradrenergic or serotonergic mechanisms, or both. Unfortunately, these compounds block cholinergic, histaminergic and alpha-1-adrenergic receptor sites, interact with a number of other medications and bring about numerous undesirable side effects. Several chemically unrelated agents have been developed and introduced in the past decade to supplement the early antidepressants. These include selective inhibitors of the reuptake of serotonin (the selective serotonin reuptake inhibitors (SSRIs)) or noradrenaline (reboxetine) or both (SNRIs: milnacipran and venlafaxine), as well as drugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine. All these newer compounds are the results of rational developmental strategies to find drugs that were as effective as the TCAs but of higher safety and tolerability profile. In spite of the remarkable structural diversity, most currently introduced antidepressants are monoamin based and modulating monoamine activity as a therapeutic strategy continues to dominate antidepressant research. It must be emphasised, however, that these newer antidepressants are far from the ideal ones, also resulting in undesirable side effects and requiring 2-6 weeks of treatment to produce therapeutic effect. Furthermore, approximately 30% of the population do not respond to current therapies. An important new development has been the emergence of potential novel mechanisms of action beyond the monoaminergic synapse. The results of recent novel developmental approaches have suggested that modulation of N-methyl-D-aspartate (NMDA), neuropeptide (substance P and corticotrophin-releasing factor) receptors and the intracellular messenger system may provide an entirely new set of potential therapeutic targets. This paper discusses the advances from monoamine-based treatment strategies and looks at the future developments in the treatment of depression.

Journal ArticleDOI
TL;DR: From the discussed studies it can be concluded that the careful selection of relevant structural and biological data processed with appropriate QSAR and especially 3D-QSAR methods, is a promising approach to structure-activity studies of MDR reversers.
Abstract: Multidrug resistance, MDR, is a major obstacle in the chemotherapeutic treatment of cancer. MDR can be reversed by drugs that vary widely in their chemical structure and main biological action. Many efforts are directed to find out the relationships between the structure and MDR reversal effect of these drugs. In this review we try to summarize the results of a variety of studies on identification of structure-activity relationships, SARs, and quantitative SARs, QSARs, of different MDR reversing drugs. As any reasonable (Q)SAR study relies on a real or putative presentation about the mechanism of action of the studied compounds, the most significant MDR mechanisms revealed till now are shortly discussed. Special attention is paid to P-glycoprotein, P-gp, related MDR as the most experimentally and clinically tested form of drug resistance. The currently proposed models of P-gp functioning and mechanisms of MDR modulation are presented. Problems that can arise in (Q)SARs studies are discussed in advance to allow the reader to judge on possible pitfalls. The physicochemical and structural properties of MDR modulators as found by different research groups are commented and summarized. From the discussed studies it can be concluded that the careful selection of relevant structural and biological data processed with appropriate QSAR and especially 3D-QSAR methods, is a promising approach to structure-activity studies of MDR reversers.

Journal ArticleDOI
TL;DR: Future research should 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.
Abstract: 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 occurring 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.

Journal ArticleDOI
TL;DR: Drug design can be mechanism-led, with the wealth of literature quantifying redox properties of drug candidates a rich source of potential new leads and the potential for rapid expansion of these concepts to diverse diseases is considerable.
Abstract: Hypoxia is a feature of some regions of many tumours, ischaemic events, and arthritis. Drugs activated in hypoxia have wide potential application, particularly in overcoming the resistance of hypoxic tumour cells to radiotherapy. Key features of such drugs include redox properties appropriate for activation by reductase enzymes (typically flavoproteins), and oxygen-sensitive reduction chemistry such that normal levels of oxygen inhibit or reverse reduction. In many cases this selectivity is achieved by a fast, free-radical reaction in which the drug radical (often an obligate intermediate in drug reduction) reduces oxygen to form superoxide radicals and thus 'futile cycles' the drug in normoxic tissues. However, this enhances cellular oxidative stress, which may be linked to normal tissue toxicity. Appropriate redox properties are found with nitroarene, quinone, or aromatic N-oxide moieties. A particularly promising and versatile exploitation of bioreductive activation is for reduction of such 'triggers' to activate release of an 'effector', an agent that can obviously be active against diverse conditions associated with hypoxia. The same approach can also be used in diagnosis of hypoxia. Much information concerning the reactions of intermediates in drug action and the quantitative prediction of redox properties of analogues has been accrued. Drug design can be mechanism-led, with the wealth of literature quantifying redox properties of drug candidates a rich source of potential new leads. There is a clear appreciation of the kinetic factors that limit drug efficacy or selectivity. Thus the potential for rapid expansion of these concepts to diverse diseases is considerable.

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TL;DR: The redox mechanisms of oxygen radical formation by MPTP, tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase will be discussed and possible clinical applications of these mechanisms will be briefly presented.
Abstract: Parkinsons disease occurs in 1percent of people over the age of 65 when about 60percent of the dopaminergic neurons in the substantia nigra of the midbrain are lost. Dopaminergic neurons appear to die by a process of apoptosis that is induced by oxidative stress. Oxygen radicals abstract hydrogen from DNA forming DNA radicals that lead to DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and apoptosis. Oxygen radicals can be formed in dopaminergic neurons by redox cycling of MPP+ , the active metabolite of MPTP. This redox cycling mechanism involves the reduction of MPP+ by a number of enzymes, especially flavin containing enzymes, some of which are found in mitochondria. Tyrosine hydroxylase is present in all dopaminergic neurons and is responsible for the synthesis of dopamine. However, tyrosine hydroxylase can form oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin. Dopamine may be oxidized by monoamine oxidase to form oxygen radicals and 3,4-dihydroxyphenylacetaldehyde. This aldehyde may be oxidized by aldehyde dehydrogenase with the formation of oxygen radicals and 3,4-dihydroxyphenylacetic acid. The redox mechanisms of oxygen radical formation by MPTP, tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase will be discussed. Possible clinical applications of these mechanisms will be briefly presented.

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TL;DR: It is apparent that oxidative stress, the excess of free radicals over the means of scavenging these harmful agents, may play critical roles in the molecular basis of accelerated aging, Alzheimer's disease, and Huntington's disease.
Abstract: Oxidative stress in brain is emerging as a potential causal factor in aging and age-related neurodegenerative disorders. Brain tissue from living patients is difficult to acquire; hence, animal models of aging and age-related neurodegenerative disorders, though not perfect models, have provided tissue to study the role of oxidative stress in these disorders. In this review, the central role of oxidative damage in brain in models of accelerated aging (progeria and Werner's syndrome) and the age-related neurodegenerative disorders, Alzheimer's disease and Huntington's disease, will be presented and evaluated. To the extent that the animal models faithfully mirror their respective disorders, and based on the totality of the studies, it is apparent that oxidative stress, the excess of free radicals over the means of scavenging these harmful agents, may play critical roles in the molecular basis of accelerated aging, Alzheimer's disease, and Huntington's disease.

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TL;DR: LY335979 is among the most potent modulators of Pgp with a Ki of 59 nM, and is selective for Pgp, and does not modulate MRP-mediated resistance by MRP1 ( ABCC1) and MRP2 (ABCC2).
Abstract: Multidrug resistance may be conferred by P-glycoprotein (Pgp, ABCB1) or the multidrug resistance associated protein (MRP). These membrane proteins are members of the ATP binding cassette transporter superfamily and are responsible for the removal from the cell of several anticancer agents including doxorubicin. Modulators can inhibit these transporters. LY335979 is among the most potent modulators of Pgp with a Ki of 59 nM. LY335979 is selective for Pgp, and does not modulate MRP-mediated resistance by MRP1 (ABCC1) and MRP2 (ABCC2). LY335979 significantly enhanced the survival of mice implanted with Pgp-expressing murine leukemia (P388/ADR) when administered in combination with either daunorubicin, doxorubicin or etoposide. Coadministration of LY335979 with paclitaxel compared to paclitaxel alone significantly reduced the tumor mass of the Pgp-expressing UCLA-P3.003VLB lung carcinoma in a xenograph model and delayed the development of tumors in mice implanted with the parental drug-sensitive UCLA-P3 tumor. LY335979 was without significant effect on the pharmacokinetics of these anticancer agents. This may be due impart to its poor inhibition of four major cytochrome P450 isozymes important in metabolizing doxorubicin and other oncolytics. The selectivity and potency of this modulator allows the clinical evaluation of the role of Pgp in multidrug resistance. LY335979 is currently in clinical trials.

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TL;DR: A rapid method for the measurement of octanol/water partition coefficients (log P(oct) via fast gradient reversed phase retention and the calculation of the hydrogen bond acidity of the compounds is proposed.
Abstract: We propose a rapid method for the measurement of octanol/water partition coefficients (log P(oct)) via fast gradient reversed phase retention and the calculation of the hydrogen bond acidity of the compounds. The cycle time of the generic gradient HPLC method is 5 minutes. The general solvation equation obtained for the log Poct values and the fast gradient Chromatographic Hydrophobicity Indices with acetonitrile (CHI(ACN)) and methanol

Journal ArticleDOI
TL;DR: Experiments with ferrous reagents indicate that active peroxides including 14 and its congeners kill the parasite by alkylation with a sterically non-encumbered C-centered radical, however, another possibility is the involvement of a Fe(IV)=O species as the toxic agent.
Abstract: The discovery that the sesquiterpene peroxide yingzhaosu A (13) and 1,2,4-trioxane artemisinin (14) are active against chloroquine-resistant strains of Plasmodium falciparum, has opened a new era in the chemotherapy of malaria. In vitro and in vivo tests with synthetic structurally simpler trioxanes clearly demonstrate that much of the skeleton of 14 is redundant and that chirality is not required for activity. In addition, structure-activity relations and the search for the pharmacophore reveal that high antimalarial activity can be displayed by molecules which do not resemble the geometry of 13 and 14 at all. The possible mode of action of 13, 14, and synthetic peroxides is examined. They are believed to kill intraerythrocytic Plasmodium by interacting with the heme discarded by proteolysis of ingested hemoglobin. Complexation of heme with the peroxide bond followed by electron transfer generates an oxy radical that evolves to the ultimate parasiticidal agent. Experiments with ferrous reagents indicate that active peroxides including 14 and its congeners kill the parasite by alkylation with a sterically non-encumbered C-centered radical. However, another possibility is the involvement of a Fe(IV)=O species as the toxic agent. The review covers our own and other contributions to this timely topic and evaluates the different mechanisms proposed for the mode of action of peroxidic antimalarials.