It was found that a class of sulfolipids known as sulfo-quinovosyl-acyl-glycerols (SQAGs) from ferns and algae are potent inhibitors of eukaryotic DNA polymerase alpha and beta and effective anti-neoplastic agents. In developing a procedure for the chemical synthesis of sulfolipids, many derivatives and stereoisomers of SQAGs have been obtained including sulfo-quinovosyl-monoacyl-glycerols (SQMGs) and sulfo-quinovosyl-diacyl-glycerols (SQDGs). This review describes studies on the structure-function relationship between synthetic SQAGs and DNA polymerase alpha and beta, and the relationship to cytotoxic activity. The major action was probably dependent on the fatty acid effect, which was reported previously, although each of the SQAGs was a much stronger inhibitor than just the fatty acid present in the SQAGs. The inhibitory effect could be influenced by the chain size of fatty acids in the SQAGs. The sulfonyl group in quinovose was also needed to inhibit the enzymes. Lineweaver-Burk plots of SQAGs indicated that DNA polymerase alpha was non-competitively inhibited, but the SQAGs were effective as antagonists of both the template-primer DNA-binding and the nucleotide substrate-binding of DNA polymerase beta. Based on these results, the molecular actions of SQAGs and drug design strategies for developing new anti-neoplastic agents were discussed.
Cisplatin is one of the most potent and widely used anti-cancer agents in the treatment of various solid tumors. However, the development of resistance to cisplatin is a major obstacle in clinical treatment. Several mechanisms are thought to be involved in cisplatin resistance, including decreased intracellular drug accumulation, increased levels of cellular thiols, increased nucleotide excision-repair activity and decreased mismatch-repair activity. In general, the molecules responsible for each mechanism are upregulated in cisplatin-resistant cells; this indicates that the transcription factors activated in response to cisplatin might play crucial roles in drug resistance. It is known that the tumor-suppressor proteins p53 and p73, and the oncoprotein c-Myc, which function as transcription factors, influence cellular sensitivity to cisplatin. So far, we have identified several transcription factors involved in cisplatin resistance, including Y-box binding protein-1 (YB-1), CCAAT-binding transcription factor 2 (CTF2), activating transcription factor 4 (ATF4), zinc-finger factor 143 (ZNF143) and mitochondrial transcription factor A (mtTFA). Two of these-YB-1 and ZNF143-lack the high-mobility group (HMG) domain and can bind preferentially to cisplatin-modified DNA in addition to HMG domain proteins or DNA repair proteins, indicating that these transcription factors may also participate in DNA repair. In this review, we summarize the mechanisms of cisplatin resistance and focus on transcription factors involved in the genomic response to cisplatin.
Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their cytotoxic effects were most extensively examined. In this review, their broad range of effects on the tumors as shown by various in vitro and in vivo experiments and clinical studies are discussed. Hence, these cytotoxic coumarins represent an exploitable source of new anticancer agents, which might also help addressing side-toxicity and resistance phenomena. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. In this review, plant derived coumarins and their synthetic analogues were systematically evaluated based on their plant origin, structure-activity relationship and anticancer efficacy. Owing the their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action is not yet fully understood and correlation of effects with chemical structures is not conclusive at the moment. It is the objective of this review to summarize experimental data for different coumarins, used as cytotoxic agents, because promising data have been reported for a series of these agents. Yet, the results from different coumarins with various tumor lines are contradictory in part. We therefore conclude that there is still a long way to go until we know which cytotoxic agent will clinically be suitable for what tumor entity for treatment. Their ability to bind metal ions represents an additional means of modulating their pharmacological responses.
The normalization of plasma alanine aminotransferase (ALT) has been proved to be a strategy for preventing the development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infection. Glycyrrhizin, a plant medicine, normalizes plasma ALT and prevents HCC. However, glycyrrhizin is administered intravenously and thereby chemical which is effective on oral administration is required. Coumarin compounds are active components of herbs used for the treatment of various diseases. The ability of coumarin compounds to lower plasma ALT were examined using mice concanavalin A-induced hepatitis and mice anti-Fas antibody-induced hepatitis. Furanocoumarins pd-Ia, pd-II and pd-III lower plasma ALT, but they are large molecules that are hardly absorbed on oral administration. Furocoumarin effectively lowers plasma ALT, but the safety range between the effective and toxic dosages is narrow. In contrast, osthole, a simple coumarin, causes strong reduction of plasma ALT and also inhibits caspase-3 activation. Furthermore, this chemical is quite safe upon large dose administration. In the structure of osthole, the methoxy group at position-7 and the 3-methyl-2-butenyl group at position-8 were elucidated to be essential for the beneficial effect of this chemical. We conclude that osthole will become a leading chemical for synthesizing a compound which prevents HCC on oral administration.
This essay develops the paradigm of "Interfacial Inhibitors" (Pommier and Cherfils, TiPS, 2005, 28: 136) for inhibitory drugs beside orthosteric (competitive or non-competitive) and allosteric inhibitors. Interfacial inhibitors bind with high selectivity to a binding site involving two or more macromolecules within macromolecular complexes undergoing conformational changes. Interfacial binding traps (generally reversibly) a transition state of the complex, resulting in kinetic inactivation. The exemplary case of interfacial inhibitor of protein-DNA interface is camptothecin and its clinical derivatives. We will also provide examples generalizing the interfacial inhibitor concept to inhibitors of topoisomerase II (anthracyclines, ellipticines, epipodophyllotoxins), gyrase (quinolones, ciprofloxacin, norfloxacin), RNA polymerases (alpha-amanitin and actinomycin D), and ribosomes (antibiotics such as streptomycin, hygromycin B, tetracycline, kirromycin, fusidic acid, thiostrepton, and possibly cycloheximide). We discuss the implications of the interfacial inhibitor concept for drug discovery.
The inhibition of angiogenesis is an emerging therapeutic strategy for cancer treatment. In contrast to conventional therapies, anti-angiogenic therapies primarily target tumor-associated endothelial cells which serve as a lifeline for tumor growth, progression and metastasis. By blocking the supply of essential nutrients and the removal of metabolites, anti-angiogenic therapies aim to delay both primary and metastastic tumor growth while overcoming the inherent cytotoxicities of classical chemotherapies. Indeed, tumor-related angiogenesis is a multi-step process initiated by a cascade of proangiogenic factors secreted from both the tumor and host tissues. These intricate processes involve a close interaction of tumor and associated endothelial cells as well as an intimate communication between proliferating endothelial cells, stromal cells and extracellular matrix components. Inhibition of these proangiogenic mechanisms has become a major challenge for the development of anti-cancer treatment modalities. In this regard, anti-angiogenic therapies embody a potentially powerful adjunct to traditional cancer therapies. In this review, we provide an overview of traditional anti-cancer drugs and discuss the fundamentals of anti-angiogenic therapies. While presenting the salient features of the anti-angiogenic agents targeting the individual phases of angiogenesis, we highlight the potential for specific agent development as novel anti-angiogenic therapeutics. Finally, we present and summarize emerging angiogenesis inhibitors.
Much progress has been made in recent years in developing small molecules that target the minor groove of DNA. Striking advances have led to the design of synthetic molecules that recognize specific DNA sequences with affinities comparable to those of eukaryotic transcription factors. This makes it feasible to modulate or inhibit DNA/protein interactions in vivo, a major step towards the development of general strategies of anti-gene therapy. Examples from anti-parasitic drugs also suggest that synthetic molecules can affect a variety of cellular functions crucial to cell viability by more generally targeting vast portions of genomes based on their biased base composition. This provides a rationale for developing approaches based on selective interactions with broad genomic targets such as satellite repeats that are associated with structural or architectural components of chromatin essential for cellular proliferation. Using examples drawn from the Drosophila melanogaster model system, we review here the use of synthetic polyamides or diamidines that bind the DNA minor groove and can be used as highly selective agents capable of interfering with specific protein/DNA interactions that occur in A+T-rich repeated sequences that constitute a significant portion of eukaryotic genomes. The satellite localization of cellular proteins that bind the minor groove of DNA via domains such as the AT hook motif is highly sensitive to these molecules. A major consequence of the competition between these proteins and their synthetic mimics is an alteration of the nuclear localization and function of proteins such as topoisomerase II, a major target of anti-cancer drugs.
The role of selenium in the prevention of cancer has been recently established by laboratory experiments, clinical trials, and epidemiological data. Most of the effects are related to the function of selenium in antioxidant enzyme systems. Animal data, epidemiological data, and intervention trials have shown a clear role for selenium derivatives in both prevention of specific cancers and antitumorigenic effects in postinitiation phases of cancer. Consequently, selenium supplementation has moved from the realm of correcting nutritional deficiencies to one of pharmacological intervention, especially in the clinical domain of cancer chemoprevention. Accordingly, there has been substantial interest directed toward the synthesis of selenium-containing derivatives in recent years that could be used as cancer chemopreventive agents. The current review aims to outline recent developments in the application of selenium derivatives as cancer preventive agents.
DNA helicases have essential roles in nucleic acid metabolism by facilitating cellular processes including replication, recombination, DNA repair, and transcription. The vital roles of helicases in these pathways are reflected by their emerging importance in the maintenance of genomic stability. Recently, a number of human diseases with cancer predisposition have been shown to be genetically linked to a specific helicase defect. This has led researchers to further investigate the roles of helicases in cancer biology, and to study the efficacy of targeting human DNA helicases for anti-cancer drug treatment. Helicase-specific inhibition in malignant cells may compromise the high proliferation rates of cancerous tissues. The role of RecQ helicases in response to replicational stress suggests a molecular target for selectively eliminating malignant tumor cells by a cancer chemotherapeutic agent. Alternate DNA secondary structures such as G-quadruplexes that may form in regulatory regions of oncogenes or G-rich telomere sequences are potential targets for cancer therapy since these sequence-specific structures are proposed to affect gene expression and telomerase activation, respectively. Small molecule inhibitors of G-quadruplex helicases may be used to regulate cell cycle progression by modulating promotor activation or disrupting telomere maintenance, important processes of cellular transformation. The design of small molecules which deter helicase function at telomeres may provide a molecular target since telomerase activity is necessary for the proliferation of numerous immortal cells. Although evidence suggests that helicases are specifically inhibited by certain DNA binding compounds, another area of promise in anti-cancer therapy is siRNA technology. Specific knockdown of helicase expression can be utilized as a means to sensitize oncogenic proliferating cell lines. This review will address these topics in detail and summarize the current avenues of research in anti-cancer therapy targeting helicases through small molecule inhibitors of DNA-protein complexes, DNA binding drugs, or down-regulation of helicase gene expression.
Aporphinoids form an important group of plant secondary metabolites. Some of these compounds are used for a long time in traditional medicine for the treatment of various diseases, from benign syndromes to more severe illnesses. More than 500 aporphine alkaloids have been isolated from various plant families and many of these compounds display potent cytotoxic activities which may be exploited for the design of anticancer agents. Here we review the origin, biosynthesis, structure and cytotoxic properties of the prominent members of this class of compounds. Simple aporphinoids (boldine, dicentrine) as well as oxo-, pro- and dehydro-aporphines, and dimeric forms such as thalicarpine, are discussed here. Their mechanisms of action are not well known but DNA-manipulating enzymes such as polymerases and topoisomerases are among the most frequently cited targets for these benzylisoquinoline compounds. This review presents an updated view of the cytotoxic properties of the aporphinoids and their potential contribution to the development of anticancer agents.
CDK2 is an attractive target for the design of new therapeutic antitumor agent. Numerous CDK2 inhibitors have been discovered and their crystallographic structures either in complex with CDK2 or CDK2/Cyclin A have been published. This review aims to summarize the publicly available structural characterization of CDK2/(Cyclin A) -- ligand complexes and to highlight the similarities among the binding modes of structurally diverse inhibitors.
Aminoglycosides, traditional RNA binders, were found to be a new class of triple helical nucleic acid-stabilizing ligands. Neomycin, of all the aminoglycosides, has shown the most significant effects in stabilizing DNA, RNA, and hybrid triple helices. When compared with minor groove binders or intercalators, neomycin excels at triple helical stabilization in most cases. Molecular modeling studies suggest that neomycin reaches into the larger Watson-Hoogsteen groove. The charge and shape complementarity are the key factors in neomycin-triplex recognition. By conjugating neomycin with intercalators such as BQQ (a potent triple helix intercalating agent designed by Hélène), we have progressed in developing more potent triple helix stabilizing ligands. The design of such dual or even triple recognition ligands opens a new paradigm for recognition of triple helix nucleic acids. The article herein presents studies of neomycin as the first molecule that can selectively stabilize nucleic acid triplex structures. These studies are supported by our recent discovery that neomycin prefers to bind to A-like conformations, of which triple helix structures are known to display some characteristics. These findings will contribute to the development of a new series of triplex-specific ligands, and may contribute to either antisense or antigene therapies.
Cancer is a serious disease with a complex pathogenesis, which threats human life greatly. Currently, great efforts have been put to the identification of novel anticancer targets and the discovery of anticancer drugs following the progress of chemogenomics, which will be reviewed briefly in this article. Furthermore, during the past 5 years, the global effort of sequencing human genome has provided us with an enormous number of potential targets associated with cancer therapy. As a result, the New Drug Discovery (NDD) is undergoing a transition "from gene to drug". Accordingly, the targets for anticancer drugs studies now are focused on some biological macromolecular targets associated with cancer and several interactive mechanisms involved in the growth and metastasis of cancer cells as well as tumor angiogenesis, such as Matrix Metalloproteinases (MMPs), Aminopeptidase N (APN), Tyrosine Kinase (TK), Farnesyltransferase (FTase) and cell Signal Transduction Pathway and so forth. Among these targets the MMP-2, -9 and APN are the most extensively studied enzymes in our laboratory. The peptidomimetics Matrix Metalloproteinase Inhibitors (MMPIs) and APN inhibitors (APNIs) with the molecular scaffold of pyrrolidine, 3-amino-2-hydroxy-4-phenyl butyric acid (AHPA) and glutamylide, which have been designed and synthesized in our laboratory, will be described in the review, among which the pyrrolidine scaffold is patented with the IC(50) ranging from 1 nM to 300 nM against MMP-2, and MMP-9.
Chemical compounds that interfere with microtubules such as the vinca alkaloids and taxanes are important chemotherapeutic agents for the treatment of cancer. As our knowledge of microtubule-targeting drugs increases, we realize that the mechanism underlying the anti-cancer activity of these agents may mainly lie in their inhibitory effects on spindle microtubule dynamics, rather than in their effects on microtubule polymer mass. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell cycle progression at mitosis and eventually leading to apoptotic cell death. The effectiveness of microtubule-targeting drugs for cancer therapy has been impaired by various side effects, notably neurological and hematological toxicities. Drug resistance is another notorious factor that thwarts the effectiveness of these agents, as with many other cancer chemotherapeutics. Several new microtubule-targeting agents have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to the existing microtubule-targeting drugs. Continued investigation of the mechanisms of action of microtubule-targeting drugs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance may provide more effective therapeutic options for cancer patients.
Tumor suppressor genes can promote p53-mediated apoptosis. Apoptosis is an important protective mechanism for normal cell growth. Aberrant regulation of p53 expression is linked to cancer development. The loss of function of p53 often results in tumorigenicity. It is reported that the high incidence of tumors in p53-deficient animals is highly attributed to p53-induced apoptosis. Malignancies that retain the wild-type p53 gene are associated with the biologic activity of p53 function. Most cancer cells show defects in p53 or inhibition in the associated pathways. A lot of effort has been focused on reactivating mutant p53, or recombinant technique to incorporate p53 in cells. Regulation of p53 has been described at both transcription and translation level. Activation of the p53 pathway appears to be an effective approach in inhibiting tumor development. In the present study, we have reviewed the recent developments of specific compounds that can regulate p53 expression and its function in cell growth and development. Integral to this is the function of other proteins that affect p53 activity.
Steroid sulfatase (STS) is the only well characterized enzyme in human cells that is capable to desulfate estrone 3-sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS) as a first step in the conversion of these precursors to active hormones. STS has been found to be highly expressed in estrogen-dependent breast tumors in post-menopausal women and is regarded as a crucial component of the local estrogen production that is required for tumor growth and survival. Inhibitors of STS are expected to block the intra-tumoral estrogen synthesis and, therefore, are considered as potential new therapeutic agents for the treatment of estrogen-dependent cancers of the breast and the endometrium. In this review, we give an overview on the current status in the field of medicinal chemistry of STS inhibitors. Newer developments comprise potent aryl sulfamate-based irreversible inhibitors, and several types of reversible inhibitors. Other directions include compounds with dual mode of action, such as compounds that block both STS and aromatase, or act as STS inhibitors and antiproliferative or antiangiogenic agents at the same time. In particular, these agents featuring an extended mode of action hold promise to be included in the armamentarium to fight endocrine-dependent cancer.
Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that catalyze the deacetylation and acetylation of lysine residues located in the NH(2) terminal tails of histones and non-histone proteins. Perturbation of this balance is often observed in human cancers and inhibition of HDACs has emerged as a novel therapeutic strategy against cancer. To date, more that 30 groups, academic and industrial, are involved in research related to these target enzymes. Over the past year, dozens of research papers and patent applications describing new HDAC inhibitors belonging to different structural classes have been disclosed. The present review highlights the latest developments in design and synthesis of HDAC inhibitors -- potential anti-cancer drugs.
Azadirachta indica, commonly known as neem, has attracted worldwide prominence in recent years, owing to its wide range of medicinal properties. Neem has been extensively used in Ayurveda, Unani and Homoeopathic medicine and has become a cynosure of modern medicine. Neem elaborates a vast array of biologically active compounds that are chemically diverse and structurally complex. More than 140 compounds have been isolated from different parts of neem. All parts of the neem tree- leaves, flowers, seeds, fruits, roots and bark have been used traditionally for the treatment of inflammation, infections, fever, skin diseases and dental disorders. The medicinal utilities have been described especially for neem leaf. Neem leaf and its constituents have been demonstrated to exhibit immunomodulatory, anti-inflammatory, antihyperglycaemic, antiulcer, antimalarial, antifungal, antibacterial, antiviral, antioxidant, antimutagenic and anticarcinogenic properties. This review summarises the wide range of pharmacological activities of neem leaf.
Recent investigations on the G-quadruplex motif propose a new strategy for the making of antitumour drugs. Quadruplex-drug complexes have been suggested to inhibit telomerase activity; further, aptamers based on the quadruplex motif have been proved useful as tools aimed at binding and inhibiting particular proteins, thus serving as pharmaceutically active agents. However, the design of new aptamers is difficult because many factors affecting their activity and stability have not still been clarified. The knowledge of the energetics of quadruplex formation is a crucial point in view of their potential therapeutic utilization both as targets as well as therapeutic agents. In this review the energetic aspects of both quadruplex assembly and quadruplex-ligand interactions are discussed together with a summary of recent studies on physico-chemical properties in solution of quadruplex structures obtained from synthetic aptamers, including PNA-DNA chimeras.
Pyrylium-type salts derived from DMXAA and FAA are proposed to play an important mechanistic role in anticancer action. Electron transfer (ET) processes apparently initiate cell signaling cascades that lead to the observed effects, such as, antivascular influences, cytokine induction, and apoptosis. Possible participation of nitric oxide and serotonin is discussed. Structure-activity relationships involving DMXAA, FAA, acridines, and quinolines support the hypothetical framework, as well as electrochemistry and photochemistry. Similarity is pointed out to the action of plant hormones, e.g. ethylene. Involvement of ET pathways places the cationic salts within the general mechanistic framework for other anticancer agents. Other drug activities of xanthenones are in accord with the ET approach. Insight into fundamental mechanistic aspects should aid in development of improved drugs in this class through rational design.
