Current medicinal chemistry. Anti-cancer agents最新文献

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.

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.

Fluorescence microscopy of trypanosomes from drug treated mice shows that biologically active heterocyclic diamidines that target the DNA minor groove bind rapidly and specifically to parasite kinetoplast DNA (k-DNA). The observation that the kinetoplast is destroyed, generally within 24 hours, after drug treatment is very important for understanding the biological mechanism, and suggests that the diamidines may be inhibiting some critical opening/closing step of circular k-DNA. Given the uncertainties in the biological mechanism, we have taken an empirical approach to generating a variety of synthetic compounds and DNA minor groove interactions for development of improved and new biological activities. Furamidine, DB75, is a diphenyl-diamidine that has the curvature to match the DNA minor groove as expected in the classical groove interaction model. Surprisingly, a linear diamidine with a nitrogen rich linker has significantly stronger binding than furamidine due to favorable linker and water-mediated DNA interactions. The water interaction is very dependant on compound structure since other linear compounds do not have similar interactions. Change of one phenyl of furamidine to a benzimidazole does not significantly enhance DNA binding but additional conversion of the furan to a thiophene (DB818) yields a compound with ten times stronger binding. Structural analysis shows that DB818 has a very favorable curvature for optimizing minor groove interactions. It is clear that there are many ways for compounds to bind to k-DNA and exert specific effects on kinetoplast replication and/or transcription that are required to obtain an active compound.

This paper describes extensive research on the activity of more of 100 cytotoxic compounds containing an oxygenated ring in their structure and isolated from natural plants or prepared by semisynthesis or synthesis from available intermediates. Anticancer drugs have been classified according to the chemical structure of the natural products that are considered to lead the series. The origin and mechanism of action involved in each case have been considered. This new family of natural, semisynthetic and synthetic products includes compounds with interesting antitumor activity such as podophyllotoxin derivatives, NK-611 (15), TOP-53 (16), NPF (24) and Tafluposide (28); camptothecin analogs such as 45 with a considerable cytotoxicity against beta-cell chronic lymphocytic leukemia (CLL), and 52 (new piperazinyl-CPT analog). New dioxygenated ellipticine analogs showed more activity and stability than the natural pattern when the structure incorporated a lactone function instead of the pyridine ring. In the acridine series the new tetracyclic derivatives 75 and 76 containing ethylenedioxy groups at the 2- and 3-positions of the acridine system exhibited the same activity as m-AMSA in vivo against murine P-388 leukemia. Other isolated compounds containing a dioxygenated ring in their structure such as 100 and 101 showed antitumor activities related to kinase inhibition, and are attractive candidates for development of new synthetic antitumor agents.

Aminopeptidase N (APN; CD13) is a member of zinc-containing ectoenzymes family involved in the degradation of neutral or basic amino acids (Ala>Phe>Leu>Gly) from N-terminal of bioactive peptides and amide or arylamide derivatives of amino acids. The expression of APN being up regulated has been implicated in the pathogenesis of a variety of diseases such as cancer, leukemia, diabetic nephropathy, and rheumatoid arthritis. Thus, APN inhibitors (APNIs) are expected to be useful for the treatment of these disorders. This article reviews briefly the structure characteristic and possible function of APN. The proposed biomolecular structures and mechanism of action used in the design of APNIs are thoroughly covered. Major emphasis is on recently published potent, small molecular weight APNIs and their essential structure activity relationship (SAR). Finally, available clinical results of compounds in development are summarized in this review.

There is great potential for the use of plant-derived agents in the fight to prevent onset or delay progression of the carcinogenic process. Epidemiological evidence for their chemopreventive action is compelling, but even though many of these compounds have an extensive history of use within the human populace, it is of increasing importance to determine more precisely the primary targets contributing to their efficacy, prior to embarking on large-scale clinical trials. This rapidly moving field now concentrates in particular, on the modulating effects these agents can have on cellular signalling pathways involved in the apoptotic, proliferative and angiogenic processes, perturbances to which, are common in many cancers. It is perhaps the ability of these agents to exhibit multi-site mechanisms of action that offers their key to success where conventional single-site agents have disappointed in the past. As well as being promising chemopreventive agents, there is also an exciting role for these compounds in combinatorial therapy with more traditional chemotherapeutics, potentially in lowering of toxicity and enhancing efficacy for treatment of more advanced cancers. This review will summarise known and proposed mechanisms of action for various chemopreventive agents of interest highlighting their potential in combination therapy, and will address benefits and problems of using such multi-site agents in long-term prevention/therapeutic regimes.

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.

Sesquiterpene lactones (SLs) are the active constituents of a variety of medicinal plants used in traditional medicine for the treatment of inflammatory diseases. In recent years, the anti-cancer property of various SLs has attracted a great deal of interest and extensive research work has been carried out to characterize the anti-cancer activity, the molecular mechanisms, and the potential chemopreventive and chemotherapeutic application of SLs. In this review, we attempt to summarize the current knowledge of the anti-cancer properties of SLs by focusing on the following important issues. First, we discuss the structure-activity relationship of SLs. All SLs contain a common functional structure, an alpha-methylene-gamma-lactone group, and this important chemical characteristic means that the thiol-reactivity of SLs is an underlying mechanism responsible for their bioactivities. Second, we assess the experimental evidence for the anti-cancer function of SLs obtained from both in vitro cell culture and in vivo animal models. Various SLs have been demonstrated to execute their anti-cancer capability via inhibition of inflammatory responses, prevention of metastasis and induction of apoptosis. Thirdly, we outline the molecular mechanisms involved in the anti-cancer activity of SLs, in particular, the SL-thiols reaction, the effect of SLs on cell signaling pathways such as nuclear transcription factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (MAPK). Finally, we recapitulate some important SLs with regards to their anti-cancer activities and their potential in anti-cancer drug development. Taken together, many SLs are emerging as promising anti-cancer agents with potential applications in both cancer chemotherapy and chemoprevention.

cis-diamminedichloroplatinum(II) (cisplatin) is among the most active antitumour agent used in human chemotherapy. The purpose of this review is to give an insight in several molecular mechanisms that mediate the sensitivity of cancer cells to this drug and to show how recent progress in our knowledge on some critical molecular events should lay the foundations of a more rational approach to anticancer drug design. Cisplatin is primarily considered as a DNA-damaging anticancer drug, mainly forming different types of bifunctional adducts in its reaction with cellular DNA. We will address the question of cellular activity disruption that cisplatin could cause through binding to more sensitive region of the genome such as telomeres. Cellular mechanisms of resistance to cisplatin are multifactorial and contribute to severe limitation in the use of this drug in clinics. They include molecular events modulating the amount of drug-DNA interaction, such as a reduction in cisplatin accumulation inside cancer cells or inactivation of cisplatin by thiol-containing species. Other important mechanisms acting downstream to the initial reaction of cisplatin with DNA, include an increase in adducts repair and a decrease in induction of apoptosis. Recently accumulating evidence suggest a role of the long patch DNA mismatch repair system in sensing cisplatin-damaged DNA and in triggering cell death through a c-Abl- and p73-dependent cascade; two other important pathways have been unravelled that are the mitogen-activated protein kinase cascade and the tumor suppressor p53. Several of these mechanisms underlying cisplatin resistance have been exploited to design new platinum derivatives. This issue will be covered in the present review.