Publications by authors named "Mónica Cacho"

18 Publications

  • Page 1 of 1

Optimization of Hydantoins as Potent Antimycobacterial Decaprenylphosphoryl-β-d-Ribose Oxidase (DprE1) Inhibitors.

J Med Chem 2020 05 13;63(10):5367-5386. Epub 2020 May 13.

Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universitieitsplein 1, 2610 Wilrijk, Belgium.

In search of novel drugs against tuberculosis, we previously discovered and profiled a novel hydantoin-based family that demonstrated highly promising in vitro potency against . The compounds were found to be noncovalent inhibitors of DprE1, a subunit of decaprenylphosphoryl-β-d-ribose-2'-epimerase. This protein, localized in the periplasmic space of the mycobacterial cell wall, was shown to be an essential and vulnerable antimycobacterial drug target. Here, we report the further SAR exploration of this chemical family through more than 80 new analogues. Among these, the most active representatives combined submicromolar cellular potency and nanomolar target affinity with balanced physicochemical properties and low human cytotoxicity. Moreover, we demonstrate in vivo activity in an acute infection model and provide further proof of DprE1 being the target of the hydantoins. Overall, the hydantoin family of DprE1 inhibitors represents a promising noncovalent lead series for the discovery of novel antituberculosis agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00107DOI Listing
May 2020

Identification of 2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-N-phenylpropanamides as a novel class of potent DprE1 inhibitors.

Bioorg Med Chem Lett 2020 06 13;30(12):127192. Epub 2020 Apr 13.

Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.

The identification of a novel series of DprE1 inhibitors based on a 2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-N-phenylpropanamide scaffold is described herein. SAR exploration around the HTS hit 1 led to the identification of multiple analogues with potent DprE1 inhibition and good whole-cell antimycobacterial activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127192DOI Listing
June 2020

Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite.

ACS Infect Dis 2020 05 20;6(5):1098-1109. Epub 2020 Mar 20.

Global Health R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.

In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of , a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsinfecdis.9b00493DOI Listing
May 2020

Decaprenylphosphoryl-β-d-ribose Oxidase Inhibitors: Expeditious Reconstruction of Suboptimal Hits into a Series with Potent in Vivo Activity.

J Med Chem 2020 03 22;63(5):2557-2576. Epub 2020 Jan 22.

Medicinal Science and Technology, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, U.K.

Decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) is an essential enzyme in and has recently been studied as a potential drug target, with inhibitors progressing to clinical studies. Here we describe the identification of a novel series of morpholino-pyrimidine DprE1 inhibitors. These were derived from a phenotypic high-throughput screening (HTS) hit with suboptimal physicochemical properties. Optimization strategies included scaffold-hopping, synthesis, and evaluation of fragments of the lead compounds and property-focused optimization. The resulting optimized compounds had much improved physicochemical properties and maintained enzyme and cellular potency. These molecules demonstrated potent efficacy in an in vivo tuberculosis murine infection model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b01561DOI Listing
March 2020

Bimodal Actions of a Naphthyridone/Aminopiperidine-Based Antibacterial That Targets Gyrase and Topoisomerase IV.

Biochemistry 2019 11 28;58(44):4447-4455. Epub 2019 Oct 28.

VA Tennessee Valley Healthcare System , Nashville , Tennessee 37212 , United States.

Gyrase and topoisomerase IV are the targets of fluoroquinolone antibacterials. However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV but interact differently with the enzymes. This has led to the development of the "novel bacterial topoisomerase inhibitor" (NBTI) class of antibacterials. Despite the clinical potential of NBTIs, there is a relative paucity of data describing their mechanism of action against bacterial type II topoisomerases. Consequently, we characterized the activity of GSK126, a naphthyridone/aminopiperidine-based NBTI, against a variety of Gram-positive and Gram-negative bacterial type II topoisomerases, including gyrase from and gyrase and topoisomerase IV from and . GSK126 enhanced single-stranded DNA cleavage and suppressed double-stranded cleavage mediated by these enzymes. It was also a potent inhibitor of gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed decatenation. Thus, GSK126 displays a similar bimodal mechanism of action across a variety of species. In contrast, GSK126 displayed a variable ability to overcome fluoroquinolone resistance mutations across these same species. Our results suggest that NBTIs elicit their antibacterial effects by two different mechanisms: inhibition of gyrase/topoisomerase IV catalytic activity or enhancement of enzyme-mediated DNA cleavage. Furthermore, the relative importance of these two mechanisms appears to differ from species to species. Therefore, we propose that the mechanistic basis for the antibacterial properties of NBTIs is bimodal in nature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biochem.9b00805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450530PMC
November 2019

Identification and Profiling of Hydantoins-A Novel Class of Potent Antimycobacterial DprE1 Inhibitors.

J Med Chem 2018 12 13;61(24):11221-11249. Epub 2018 Dec 13.

Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences , University of Antwerp , Universiteitsplein 1 , 2610 Wilrijk , Belgium.

Tuberculosis is the leading cause of death worldwide from infectious diseases. With the development of drug-resistant strains of Mycobacterium tuberculosis, there is an acute need for new medicines with novel modes of action. Herein, we report the discovery and profiling of a novel hydantoin-based family of antimycobacterial inhibitors of the decaprenylphospho-β-d-ribofuranose 2-oxidase (DprE1). In this study, we have prepared a library of more than a 100 compounds and evaluated them for their biological and physicochemical properties. The series is characterized by high enzymatic and whole-cell activity, low cytotoxicity, and a good overall physicochemical profile. In addition, we show that the series acts via reversible inhibition of the DprE1 enzyme. Overall, the novel compound family forms an attractive base for progression to further stages of optimization and may provide a promising drug candidate in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b01356DOI Listing
December 2018

Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis.

J Med Chem 2018 12 12;61(24):11327-11340. Epub 2018 Dec 12.

GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa 2 , 28760 Tres Cantos , Madrid , Spain.

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b01533DOI Listing
December 2018

Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons.

ACS Infect Dis 2018 08 17;4(8):1211-1222. Epub 2018 May 17.

VA Tennessee Valley Healthcare System , Nashville , Tennessee 37212 , United States.

Tuberculosis is one of the leading causes of morbidity worldwide, and the incidences of drug resistance and intolerance are prevalent. Thus, there is a desperate need for the development of new antitubercular drugs. Mycobacterium tuberculosis gyrase inhibitors (MGIs) are napthyridone/aminopiperidine-based drugs that display activity against M. tuberculosis cells and tuberculosis in mouse models [Blanco, D., et al. (2015) Antimicrob. Agents Chemother. 59, 1868-1875]. Genetic and mutagenesis studies suggest that gyrase, which is the target for fluoroquinolone antibacterials, is also the target for MGIs. However, little is known regarding the interaction of these drugs with the bacterial type II enzyme. Therefore, we examined the effects of two MGIs, GSK000 and GSK325, on M. tuberculosis gyrase. MGIs greatly enhanced DNA cleavage mediated by the bacterial enzyme. In contrast to fluoroquinolones (which induce primarily double-stranded breaks), MGIs induced only single-stranded DNA breaks under a variety of conditions. MGIs work by stabilizing covalent gyrase-cleaved DNA complexes and appear to suppress the ability of the enzyme to induce double-stranded breaks. The drugs displayed little activity against type II topoisomerases from several other bacterial species, suggesting that these drugs display specificity for M. tuberculosis gyrase. Furthermore, MGIs maintained activity against M. tuberuclosis gyrase enzymes that contained the three most common fluoroquinolone resistance mutations seen in the clinic and displayed no activity against human topoisomerase IIα. These findings suggest that MGIs have potential as antitubercular drugs, especially in the case of fluoroquinolone-resistant disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsinfecdis.8b00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309371PMC
August 2018

Mycobacterium tuberculosis gyrase inhibitors as a new class of antitubercular drugs.

Antimicrob Agents Chemother 2015 Apr 12;59(4):1868-75. Epub 2015 Jan 12.

Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.03913-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356839PMC
April 2015

Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3.

PLoS One 2013 17;8(4):e60933. Epub 2013 Apr 17.

Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This 'genetic phenotype' was further confirmed by a 'chemical phenotype', whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060933PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629081PMC
November 2013

Pyrazolo[3,4-c]pyridazines as novel and selective inhibitors of cyclin-dependent kinases.

J Med Chem 2005 Nov;48(22):6843-54

Facultad de Farmacia, Universidad San Pablo CEU, Urbanización Montepríncipe, 28668-Boadilla del Monte, Madrid, Spain.

Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm058013gDOI Listing
November 2005

Synthesis, biological evaluation, and three-dimensional quantitative structure-activity relationship study of small-molecule positive modulators of adrenomedullin.

J Med Chem 2005 Jun;48(12):4068-75

Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, Urbanización Montepríncipe, Madrid, Spain.

Adrenomedullin (AM) is a peptide hormone implicated in blood pressure regulation and in the pathophysiology of several diseases such as hypertension, cancer, diabetes, and renal disorders, becoming an interesting new target for the development of drugs. In a recent high-throughput screening study, a positive modulator with a bistriazole structure has been identified.(1) In this work, a new series of structurally related compounds has been synthesized by reaction of phenoxyacetic acid with the corresponding dihydrazide, followed by treatment of the formed bisoxadiazoles with benzylamine. The affinity toward AM of the lead compound, and a structurally related family obtained from the small-molecule NCI library together with the synthesized series, has been determined. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study and conformational and molecular dynamics simulations have shown that the presence of a free NH and a phenyl group is essential for the interaction of these compounds with AM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm050021+DOI Listing
June 2005

Adrenomedullin: a new target for the design of small molecule modulators with promising pharmacological activities.

Eur J Med Chem 2005 Aug;40(8):737-50

Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, Urbanización Montepríncipe, 28668 Boadilla del Monte, Madrid, Spain.

Adrenomedullin (AM) is a 52-amino acid peptide with a pluripotential activity. AM is expressed in many tissues throughout the body, and plays a critical role in several diseases such as cancer, diabetes, cardiovascular and renal disorders, among others. While AM is a protective agent against cardiovascular disorders, it behaves as a stimulating factor in other pathologies such as cancer and diabetes. Therefore, AM is a new and promising target for the development of molecules which, through their ability to regulate AM levels, could be used in the treatment of these pathologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2004.10.016DOI Listing
August 2005

New analogues of amonafide and elinafide, containing aromatic heterocycles: synthesis, antitumor activity, molecular modeling, and DNA binding properties.

J Med Chem 2004 Mar;47(6):1391-9

Departamentos de Ciencias Químicas, Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo CEU, Urbanización Montepríncipe, 28668-Boadilla del Monte, Madrid, Spain.

Amonafide- and elinafide-related mono and bisintercalators, modified by the introduction of a pi-excedent furan or thiophene ring fused to the naphthalimide moiety, have been synthesized. These compounds have shown an interesting antitumor profile. The best compound, 9, was 2.5-fold more potent than elinafide against human colon carcinoma cells (HT-29). Molecular dynamic simulations and physicochemical experiments have demonstrated that these compounds are capable of forming stable DNA complexes. These results, together with those previously reported by us for imidazo- and pyrazinonaphthalimide analogues, have prompted us to propose that the DNA binding process does not depend on the electronic nature of the fused heterocycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm0308850DOI Listing
March 2004

DNA sequence recognition by bispyrazinonaphthalimides antitumor agents.

Biochemistry 2003 Oct;42(40):11751-61

INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, 59045 Lille, France.

Bifunctional DNA intercalating agents have long attracted considerable attention as anticancer agents. One of the lead compounds in this category is the dimeric antitumor drug elinafide, composed of two tricyclic naphthalimide chromophores separated by an aminoalkyl linker chain optimally designed to permit bisintercalation of the drug into DNA. In an effort to optimize the DNA recognition capacity, different series of elinafide analogues have been prepared by extending the surface of the planar drug chromophore which is important for DNA sequence recognition. We report here a detailed investigation of the DNA sequence preference of three tetracyclic monomeric or dimeric pyrazinonaphthalimide derivatives. Melting temperature measurements and surface plasmon resonance (SPR) studies indicate that the dimerization of the tetracyclic planar chromophore considerably augments the affinity of the drug for DNA, polynucleotides, or hairpin oligonucleotides and promotes selective interaction with G.C sites. The (CH(2))(2)NH(CH(2))(3)NH(CH(2))(2) connector stabilizes the drug-DNA complexes. The methylation of the two nitrogen atoms of this linker chain reduces the binding affinity and increases the dissociation rates of the drug-DNA complexes by a factor of 10. DNase I footprinting experiments were used to investigate the sequence selectivity of the drugs, demonstrating highly preferential binding to G.C-rich sequences. It also served to select a high-affinity site encompassing the sequence 5'-GACGGCCAG which was then introduced into a biotin-labeled hairpin oligonucleotide to accurately measure the binding parameters by SPR. The affinity constant of the unmethylated dimer for this sequence is 500 times higher than that of the monomer compound and approximately 10 times higher than that of the methylated dimer. The DNA groove accessibility was also probed with three related oligonucleotides carrying G --> c(7)G, G --> I, and C --> M substitutions. The level of drug binding to the two hairpin oligonucleotides containing 7-deazaguanine (c(7)G) or 5-methylcytosine (M) residues is unchanged or only slightly reduced compared to that of the unmodified target. In contrast, incorporation of inosine (I) residues considerably decreases the extent of drug binding or even abolishes the interaction as is the case with the monomer. The pyrazinonaphthalimide derivatives are thus much more sensitive to the deletion of the exocyclic guanine 2-amino group exposed in the minor groove of the duplex than to the modification of the major groove elements. The complementary SPR footprinting methodology combining site selection and quantitative DNA affinity analysis constitutes a reliable method for dissecting the DNA sequence selectivity profile of reversible DNA binding small molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bi034637hDOI Listing
October 2003

Synthesis, biological evaluation and DNA binding properties of novel mono and bisnaphthalimides.

Org Biomol Chem 2003 Feb;1(4):648-54

Departamento de CC. Químicas, Facultad de CC. Experimentales y de la Salud, Universidad San Pablo CEU, Urb. Montepríncipe, Boadilla del Monte, 28668 Madrid, Spain.

A novel series of mono and bisnaphthalimides was synthesized and their antiproliferative activities were evaluated against three tumor cell lines. Bisnaphthalimides 3 and 4, bearing a pyrazine ring fused to the naphthalimide system, showed activities in the order of 10(-8) microM, similar to elinafide. DNA binding properties and the ability to induce DNA damage were studied for some of the most active compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/b209042bDOI Listing
February 2003

Chromophore-modified bisnaphthalimides: DNA recognition, topoisomerase inhibition, and cytotoxic properties of two mono- and bisfuronaphthalimides.

Biochemistry 2003 Apr;42(14):4136-50

INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France. [email protected] lille.inserm.fr

Bisnaphthalimides represent a promising group of DNA-targeted anticancer agents. In this series, the lead compounds elinafide and bisnafide have reached clinical trials, and the search for more potent analogues remains a priority. In the course of a medicinal chemistry program aimed at discovering novel antitumor drugs based on the naphthalimide skeleton, different dimeric molecules containing two tetracyclic neutral DNA intercalating chromophores were synthesized. The naphthalimide unit has been fused to a benzene ring (azonafide derivatives), an imidazole, a pyrazine, or, as reported here, a furan ring which increases the planar surface of the chromophore and enhances its stacking properties. We report a detailed investigation of the DNA binding capacity of the dimeric molecule MCI3335 composed of two furonaphthalimide units connected by a 12 A long amino alkyl linker [(CH(2))(2)-NH-(CH(2))(3)-NH-(CH(2))(2)] identical to that of elinafide. Qualitative and quantitative binding studies, in particular using surface plasmon resonance, establish that the dimer binds considerably more tightly to DNA (up to 1000 times) than the corresponding monomer and exhibits a higher sequence selectivity for GC-rich sequences. DNase I footprinting experiments attest that the dimer, and to a lesser extent the monomer, preferentially intercalate at GC sites. The strong binding interaction between the drugs and DNA perturbs the relaxation of supercoiled DNA by topoisomerases, but the test compounds do not promote DNA cleavage by topoisomerase I or II. Despite the lack of poisoning effect toward topoisomerase II, MCI3335 displays a very high cytotoxicity toward CEM human leukemia cells, with an IC(50) in the low nanomolar range, approximately 4 times inferior to that of the reference drug elinafide. Confocal microscopy observations indicate that the monomer shows a stronger tendency to accumulate in the cell nuclei than the dimer. The extremely high cytotoxic potential of MCI3335 is attributed to its enhanced capacity to bind to DNA and to inhibit DNA synthesis, as evidenced by flow cytometry experiments using the BrdU assay. The results provide novel mechanistic information that furthers the understanding of the structure-activity relationships in the bisnaphthalimide series and identify MCI3335 as a novel lead compound for further preclinical investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bi027415cDOI Listing
April 2003

Synthesis, antitumor activity, molecular modeling, and DNA binding properties of a new series of imidazonaphthalimides.

J Med Chem 2002 Dec;45(26):5813-6

Departamentos de Química Orgánica y Farmacéutica, Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo CEU, Urbanización Montepríncipe, 28668-Boadilla del Monte, Madrid, Spain.

A series of mono and bisintercalators based on the 5,8-dihydrobenz[de]imidazo[4,5-g]isoquinoline-4,6-dione system were synthesized and evaluated for growth inhibitory properties in several human cell lines. All target compounds showed activity in the micromolar range. Representative compounds were evaluated using UV--vis spectroscopy and viscosimetric determinations, showing that they behave as DNA intercalators. Molecular modeling techniques were used in order to rationalize the moderate activity observed for bisnaphthalimides.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm020950qDOI Listing
December 2002