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1.
The utility of the two docking programs DOCK and AutoDock in studying the binding of small molecules to the minor groove of B-DNA is examined. The AutoDock program is found to be more effective in both pose prediction and ranking of known binders over random compounds, and this superior performance is shown to be because of the scoring functions rather than the sampling algorithms. 相似文献
2.
Bartulewicz D Anchim T Dabrowska M Midura-Nowaczek K 《Il Farmaco; edizione pratica》2004,59(3):211-214
New carbocyclic potential minor groove binders were synthesised, using 3-nitrobenzoyl chloride and aliphatic alpha,omega-diamines with three, four and five methylene fragments. The half structures, compounds IV-VI can be compared to bis-amidines, compounds X-XII to bis-netropsin. All of the compounds were investigated antiproliferative and cytotoxic effects in the standard cell line of mammalian tumour MCF-7. 相似文献
3.
多靶点是抗肿瘤药物引起不良反应的主要原因之一,开发单一靶点药物是提高药物专属性的一种有效方法.以DNA小沟区为靶点的抗肿瘤药物是近年来研究的热点,它们主要是一些小分子化合物.目前已有多种小沟区结合剂处于基础和临床研究阶段,对近年来DNA小沟区结合剂的研究情况进行简要阐述. 相似文献
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6.
J. William Lown 《Drug development research》1995,34(2):145-183
The concept of lexitropsins, or information-reading molecules, is introduced within the antigene strategy as an alternative to, and complementary with, the antisense approach for cellular intervention and gene control. Consideration is given to alternative approaches to the development of DNA sequence selective binding agents because of their potential applications in diagnosis and treatment of cancer as well as in molecular biology. The chemical, physical, and pharmacological factors involved in the design of effective lexitropsins are discussed and illustrated with experimental results. Among the factors contributing to the molecular recognition processes are: the presence and disposition of hydrogen bond accepting and donating groups, ligand shape, chirality, stereochemistry, flexibility, and charge. For longer ligands, such as are required to target unique sequences in biological systems (14–16 base pairs), the critical feature is the phasing or spatial correspondence between repeat units in the ligand and the receptor. The recently discovered 2:1 lexitropsin-DNA binding motif provides a further refinement in molecular recognition in permitting discrimination between GC and CG base pairs. The application of these factors in the design and synthesis of novel agents which exhibit anticancer, antiviral, and antiretroviral properties, and in the inhibition of critical cellular enzymes including topoisomerases, is discussed. The emerging evidence of a relationship between sequence selectivity of the new agents and the biological response they invoke is also described. © 1995 Wiley-Liss, Inc. 相似文献
7.
Lauria A Montalbano A Barraja P Dattolo G Almerico AM 《Current medicinal chemistry》2007,14(20):2136-2160
Molecular recognition of DNA by small molecules and proteins is a fundamental problem in structural biology and drug design. Understanding of recognition in both sequence-selective and sequence neutral ways at the level of successful prediction of binding modes and site selectivity will be instrumental for improvements in the design and synthesis of new molecules as potent and selective gene-regulatory drugs. Minor groove is the target of a large number of non-covalent binding agents. DNA binding with specific sequences, mostly AT, takes place by means of a combination of directed hydrogen bonding to base pair edges, van der Waals interactions with the minor groove walls and generalized electrostatic interactions. These factors are also responsible for protein-DNA recognition, and a number of unifying rules governing the interactions have been elucidated although it has been realized that the earlier goal of a simple recognition code between amino acids and bases is not attainable. At present relatively little is understood about the mode of action at the molecular level of the majority of minor groove-interacting drugs, although there is increasing evidence that they may act by directly blocking or inhibiting protein-DNA recognition. The present review has the aim to focus on interactions between minor groove binders and DNA through a variety of techniques that are commonly used to analyze the DNA binding properties of small molecules. In fact in the last years several articles dealing with in silico techniques on DNA minor groove binders (molecular modeling, molecular dynamics, QSAR) have been published. All these studies can be considered a support in defining valid predictive models. For this reason a compendium of all matter could be an useful support for future developments. 相似文献
8.
Brostallicin is a bromoacryloyl derivative of distamycin A, which has shown very promising preclinical activity against a variety of human tumors both in vitro and in vivo. The drug has a limited toxicity towards bone marrow precursor cells in vitro resulting in a therapeutic index much higher than those achieved with other distamycin A derivatives. It retains activity against cancer cells resistant to alkylating agents, topoisomerase I inhibitors and cells with mismatch repair deficiency. Brostallicin has a peculiar mechanism of action involving activation upon binding to glutathione (GSH) catalyzed by glutathione-S-transferase (GST). As a consequence, cells expressing relatively high GST/GSH levels are more susceptible to treatment with brostallicin. Considering that increased levels of GST/GSH are often found in human tumors, this could represent an advantage for the drug in the clinic. Initial clinical studies indicate the tolerability of the drug and allow the determination of the optimal dose for subsequent studies. Some partial response were obtained in these initial phase I studies. Altogether, the results suggest brostallicin to be a new promising anticancer agent with a new mechanism of action. It also raises the possibility to use it in combination with other anticancer drugs currently used. 相似文献
9.
Cozzi P 《Il Farmaco; edizione pratica》2000,55(3):168-173
DNA minor groove binders represent a class of cytotoxic antitumor agents whose DNA sequence specificity may lead to a high selectivity of action. Tallimustine, benzoyl nitrogen mustard derivative of distamycin A, showed excellent antitumor activity in the preclinical tests, but as other minor groove binders, showed severe myelotoxicity. Novel nitrogen mustard derivatives of distamycin showing improved activity profile, have been identified recently. Moreover, a series of alpha-halogenoacrylamido derivatives of distamycin-like frames, in which the typical amidino moiety has been replaced with other moieties, was found to show cytotoxic and antitumor activity and cytotoxicity/myelotoxicity ratio improved significantly in comparison to tallimustine. The structural features of the alkylating moieties and binding frames, of distamycin and distamycin-like derivatives disclosed recently are discussed. 相似文献
10.
Beria I Baraldi PG Cozzi P Caldarelli M Geroni C Marchini S Mongelli N Romagnoli R 《Journal of medicinal chemistry》2004,47(10):2611-2623
The mechanism of action of many antitumor agents involves DNA damage, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interacting agents have only a limited degree of sequence specificity, which implies that they may hit all the cellular genes. DNA minor groove binders, among which the derivatives of distamycin A play an important role, could provide significant improvement in cancer management, increasing gene specificity, due to high selectivity of interaction with thymine-adenine (TA) rich sequences. We now report and discuss the synthesis, the in vitro and in vivo activities, and some mechanistic features of alpha-halogenoacrylamido derivatives of distamycin A. The final result of this work was the selection of brostallicin 17 (PNU-166196). Brostallicin, presently in phase II clinical trials, shows a broad spectrum of antitumor activity and an apoptotic effect higher than distamycin derivative tallimustine. An important in vitro toxicological feature of brostallicin is the very good ratio between myelotoxicity on human haematopoietic progenitor cells and cytotoxicity on tumor cells, in comparison with clinically tested DNA minor groove binders. A peculiarity of brostallicin is its in vitro reactivity in the DNA alkylation assays only in the presence of glutathione. Moreover brostallicin's antitumor activity, both in in vitro and in vivo tumor models, is higher in the presence of increased levels of glutathione/glutathione-S-tranferases. These findings contribute to the definition of brostallicin as a novel anticancer agent that differs from other minor groove binders and alkylating agents for both the profile of activity and the mechanism of action and to classify the alpha-bromoacrylamido derivatives of distamycin as a new class of cytotoxics. Moreover, due to its interaction with glutathione, brostallicin may have a role for the tailored treatment of tumors characterized by constitutive or therapy-induced overexpression of glutathione/glutathione-S-tranferase levels. 相似文献
11.
Baraldi PG Nûnez Mdel C Espinosa A Romagnoli R 《Current topics in medicinal chemistry》2004,4(2):231-239
Analogues of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently under investigation. Distamycin A has driven researcher's attention not only for their biological activity, but also for its non intercalative binding to the minor groove of double-stranded B-DNA, where it forms strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent AT base pairs. The pyrrole-amide skeleton of distamycin A has been also used as DNA sequence selective vehicles for the delivery of alkylating functions to DNA targets, leading to a sharp increase of its cytotoxicity, in comparison to that, very weak, of distamycin itself. In the last few years, several hybrid compounds, in which known antitumor derivatives or simple active moieties of known antitumor agents have been tethered to distamycin frames, have been designed, synthesized and tested. Several efforts have been made to modify DNA sequence selectivity and stability of the distamycin and the structural modifications have been based on replacement of pyrrole by other heterocycles and/or benzoheterocycles obtaining a novel class of minor groove binding molecules called lexitropsins. The role of the amidino moiety, by means of the substitution with various groups, which includes ionizable, acid or basic, and non-ionizable groups, has been also studied. The synthesis of a hybrid deriving among the combination of the distamycin A and naturally occurring alkylating agent has been also reported. Several classes of distamycin derivatives that have been reported in the published literature have been described in this review article. 相似文献
12.
《Expert opinion on therapeutic patents》2013,23(6):891-904
Analogues of naturally occurring antitumour agents, such us distamycin A, which bind in the minor groove of DNA, represent a new class of antineoplastic compounds currently under investigation. Distamycin Ahas attracted researchers’ attention not only for its biological activity, but also for its non-intercalative binding to the minor groove of double-stranded B-DNA, where it forms a strong reversible complex preferentially at the nucleotide sequences consisting of 4 - 5 adjacent AT base pairs. Distamycin has also been used as a DNA sequence-selective vehicle for the delivery of alkylating functions to DNA targets, leading to a sharp increase in cytotoxicity, in comparison to that of distamycin alone. In the last few years, several hybrid compounds, in which known antitumour derivatives or simple active moieties of known antitumour agents have been tethered to distamycin frames, have been designed, synthesised and tested. Several efforts have been made to modify the DNA sequence selectivity and stability of distamycin; structural modifications have been based on replacement of pyrrole by other heterocycles and/or benzoheterocycles resulting in a novel class of minor groove binding molecules called lexitropsins. The role of the amidino moiety has also been studied by substitution with various groups, including ionisable, acid or basic and non-ionisable groups. The synthesis of a hybrid derived from combining distamycin A and a naturally occurring alkylating agent structurally related to pyrrolo [2,1-c][1,4] benzodiazepine group, such as anthramycin and DC-81, has been also reported. Several classes of distamycin derivatives that have been reported in the published literature and in recent patent fillings have been described in this review article. 相似文献
13.
Baraldi PG Cacciari B Guiotto A Romagnoli R Zaid AN Spalluto G 《Current pharmaceutical design》1998,4(3):249-276
It is generally accepted that neoplastic transformation is related to genes alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA bases moieties. Pyrrolo[2,1-c],[1,4].benzodiazepines (PBDs), CC-1065 and distamycins are three classes of minor groove binders which showed interesting cytotoxicity profiles, refined through already reviewed processes of SAR studies. Among the modifications to the three families of antitumor compounds, heterocyclic substitutions have been extensively applied by many groups in order to either modify the reactivity profile or introduce extra interactions within the minor groove, thus changing the binding site or modulating the binding sequence. The updated material related to these modifications has been rationalised and ordered to offer an overview of the argument. 相似文献
14.
Mann J Baron A Opoku-Boahen Y Johansson E Parkinson G Kelland LR Neidle S 《Journal of medicinal chemistry》2001,44(2):138-144
The synthesis and evaluation of the novel head-to-head bisbenzimidazole compound 2,2-bis[4'-(3' '-dimethylamino-1' '-propyloxy)phenyl]-5,5-bi-1H-benzimidazole is described. An X-ray crystallographic study of a complex with the DNA dodecanucleotide sequence d(CGCGAATTCGCG) shows the compound bound in the A/T minor groove region of a B-DNA duplex and that the head-to-head bisbenzimidazole motif hydrogen-bonds to the edges of all four consecutive A:T base pairs. The compound showed potent growth inhibition with a mean IC(50) across an ovarian carcinoma cell line panel of 0.31 microM, with no significant cross-resistance in two acquired cisplatin-resistant cell lines and a low level of cross-resistance in the P-glycoprotein overexpressing acquired doxorubicin-resistant cell line. Studies with the hollow fiber assay and in vivo tumor xenografts showed some evidence of antitumor activity. 相似文献
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The ecteinascidins (Ets), which are natural products derived from marine tunicates, exhibit potent antitumor activity. Of the numerous Ets isolated, Et 743 is presently being evaluated in phase II clinical trials. Et 743 binds in the minor groove of DNA and alkylates N2 of guanine. Although structurally similar to saframycin, which exhibits poor activity in cellular assays, Et 743 has shown good efficacy as an antitumor agent. In this study, DNA structural distortions induced by Et 743 were examined to provide insight into the molecular basis for the antitumor activity of Et 743. Electrophoretic mobility shifts of ligated oligomers containing site-directed adducts were used to examine the extent and direction of the Et 743-induced bend. Surprisingly, we find that Et 743 bends DNA toward the major groove, which is a unique feature among DNA-interactive agents that occupy the minor groove. 相似文献
16.
Rodríguez F Rozas I Kaiser M Brun R Nguyen B Wilson WD García RN Dardonville C 《Journal of medicinal chemistry》2008,51(4):909-923
A series of 75 guanidine and 2-aminoimidazoline analogue molecules were assayed in vitro against Trypanosoma brucei rhodesiense STIB900 and Plasmodium falciparum K1. The dicationic diphenyl compounds exhibited the best activities with IC 50 values against T. b. rhodesiense and P. falciparum in the nanomolar range. Five compounds (7b, 9a, 9b, 10b, and 14b) cured 100% of treated mice upon ip administration at 20 mg/kg in the difficult to cure T. b. rhodesiense STIB900 mouse model. Overall, the compounds that bear the 2-aminoimidazoline cations benefit from better safety profiles than the guanidine counterparts. The observation of a correlation between DNA binding affinity at AT sites and trypanocidal activity for three series of compounds supported the view of a mechanism of antitrypanosomal action due in part to the formation of a DNA complex. No correlation between antiplasmodial activity and in vitro inhibition of ferriprotoporphyrin IX biomineralisation was observed, suggesting that additional mechanism of action is likely to be involved. 相似文献
17.
《Expert opinion on investigational drugs》2013,22(12):1939-1946
Brostallicin (PNU-166196), a-bromo-acrylamido tetra-pyrrole derivative, showed high cytotoxic potency and myelotoxicity dramatically reduced compared with other minor groove DNA-binding agents. In the presence of high intracellular glutathione concentrations, which are associated with resistance to chemotherapy, brostallicin performs a DNA minor groove attack leading to alkylation of DNA nucleophilic functions. In preclinical models, the antitumor activity of brostallicin has been tested in ovarian cancer xenografts, L1210 murine leukemia models, renal, colon and prostatic cancer cells and glutathione-S-transferase (GST) transfected human breast carcinoma cells. In clinical setting, the antitumor activity of brostallicin has been tested in ovarian cancer and in soft tissue sarcoma patients. A clear therapeutic advantage is also observed in preclinical models when brostallicin is combined with anticancer agents such as cisplatin (CDDP), doxorubicin, irinotecan and docetaxel. Brostallicin was also tested in combination with gefitinib, imatinib and bevacizumab in in vitro and in vivo studies, documenting a synergistic effect and with cetuximab showing an additive effect. Preliminary results of activity and toxicities of brostallicin in Phase I and II studies will be provided. 相似文献
18.
Baraldi PG Del Carmen Nunez M Tabrizi MA De Clercq E Balzarini J Bermejo J Estévez F Romagnoli R 《Journal of medicinal chemistry》2004,47(11):2877-2886
We have synthesized and evaluated a series of hybrids of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A, and alpha-methylene-gamma-butyrolactones with methyl, phenyl, and 4-substituted phenyl groups at the lactone C(gamma) position, denoted 5-17, for in vitro cytotoxic activity against a variety of cancer cell lines. The apoptotic and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methylpyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. It may be noted that in general, and especially for 11, 12, and 17, the cytotoxicity of the hybrids was much greater than that of the alpha-methylene-gamma-butyrolactone units 24a-g alone. Using the human leukemia cell line HL-60, we have tested the effects of a selected series of compounds on programmed cell death (apoptosis). The results clearly indicate that 11, 12, and 17, but not 9, are able to induce apoptosis as demonstrated from (i) identification of nuclear changes associated with apoptosis using fluorescence microscopy and (ii) by DNA laddering on agarose gel electrophoresis. Compound 12 was the most potent, especially after a short incubation period. It induced extensive hydrolysis of poly ADP-ribose polymerase (PARP), considered to be a hallmark of apoptosis, which plays a critical role in chromatin architecture and DNA metabolism. 相似文献
19.
随着近年来基因工程基础研究的迅速发展以及小分子配体与DNA相互作用的机制研究的逐步深入,DNA已成为抗肿瘤药物研究的一个重要的药理学作用靶点,DNA小沟区结合剂成为抗肿瘤药物研究的重要方向。目前已开发了大量结构新颖、靶点单一、高效低毒的有效药物,多种已处于临床研究阶段。该文对近5年来DNA小沟区结合剂的研究新进展进行简要综述。 相似文献
20.
Achim Bell Leonhard Kittler Günter Löber Christoph Zimmer 《Investigational new drugs》1995,13(4):271-284
Summary This report deals with the cleavage reaction of calf thymus (CT) topoisomerase II with oligonucleotides containing one main cleavage site and adjacent binding sites for minor groove binders. The sequences of the oligonucleotides were derived from a pBR 322 sequence, which contains one main topoisomerase II cleavage site. The cleavage reaction was performed under increasing concentrations of minor groove binders and it showed characteristic inhibition dependences of topoisomerase II to the binding sites and to the binding length of the minor groove binders. The extension of the minor groove binder length on DNA from 4 to 10 base pairs (bp) by netropsin and bis-netropsin, respectively, causes a strong increase of the topoisomerase II cleavage inhibition. The same is observed by the introduction of a second minor groove binder sequence symmetrically positioned around the topoisomerase II main cleavage site. The combination of two different minor groove binders can lead to an increased topoisomerase II inhibition but also to a prevention of total inhibition as shown with chromomycin A3 and distamycin A at concentrations of 0.1 and 0.25 M, respectively. 相似文献