当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers.

A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers.

Abstract：

:Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal cells. Therefore, selectively targeting nitrogen mustards to cancer cell mitochondria based on Δψmt could overcome those limitations. Herein, we describe the design, synthesis, and evaluation of Mito-Chlor, a triphenylphosphonium derivative of the nitrogen mustard chlorambucil. We show that Mito-Chlor localizes to cancer cell mitochondria where it acts on mtDNA to arrest cell cycle and induce cell death, resulting in a 80-fold enhancement of cell kill in a panel of breast and pancreatic cancer cell lines that are insensitive to the parent drug. Significantly, Mito-Chlor delayed tumor progression in a mouse xenograft model of human pancreatic cancer. This is a first example of repurposing chlorambucil, a drug not used in breast and pancreatic cancer treatment, as a novel drug candidate for these diseases.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Millard M,Gallagher JD,Olenyuk BZ,Neamati N

doi

10.1021/jm4012438

subject

Has Abstract

pub_date

2013-11-27 00:00:00

pages

9170-9

issue

22

eissn

0022-2623

issn

1520-4804

journal_volume

56

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Synthesis, in vitro pharmacology, and molecular modeling of syn-huprines as acetylcholinesterase inhibitors.

    abstract：:Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioiso...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm010949b

    authors： Camps P,Gómez E,Muñoz-Torrero D,Badia A,Vivas NM,Barril X,Orozco M,Luque FJ

    更新日期：2001-12-20 00:00:00

  • Novel multidrug resistance reversal agents.

    abstract：:A series of 59 alpha-aryl-alpha-thioether-alkyl, -alkanenitrile, and -alkanecarboxylic acid methyl ester tetrahydroisoquinoline and isoindoline derivatives (15a-48) were synthesized and evaluated as multidrug resistance (MDR) reversal agents. The compounds were tested on S1-B1-20 human colon carcinoma cells selected f...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9804477

    authors： Berger D,Citarella R,Dutia M,Greenberger L,Hallett W,Paul R,Powell D

    更新日期：1999-06-17 00:00:00

  • Structure-activity relationships of an antimicrobial peptide plantaricin s from two-peptide class IIb bacteriocins.

    abstract：:Class IIb bacteriocins are ribosomally synthesized antimicrobial peptides comprising two different peptides synergistically acting in equal amounts for optimal potency. In this study, we demonstrate for the first time potent (nanomolar) antimicrobial activity of a representative class IIb bacteriocin, plantaricin S (P...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm101540e

    authors： Soliman W,Wang L,Bhattacharjee S,Kaur K

    更新日期：2011-04-14 00:00:00

  • Resorcinol congeners of dopamine derived from benzocycloheptene and indan.

    abstract：:Series of N-alkylated derivatives of 2-amino-4,6-dihydroxyindan 3 and 6-amino-1,3-dihydroxybenzocycloheptene 2 were prepared for pharmacological testing as congeners of 2-amino-5,7-dihydroxytetralin, which elicits dopaminergic effects in a variety of assays. All of the subject compounds demonstrated a lower order of d...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00368a014

    authors： Cannon JG,Pease JP,Hamer RL,Ilhan M,Bhatnagar RK,Long JP

    更新日期：1984-02-01 00:00:00

  • Iodine-containing organic carbonates as investigative radiopaque compounds.

    abstract：:Carbonates containing an iodinated aromatic ring on one side of the carbonate linkage and an alkyl group on the other were prepared. The aromatic side consisted of p-iodophenyl, p-iodobenzyl, m-iodobenzyl, 3,5-diiodobenzyl, m-amino-2,4,6-triiodobenzyl, m-acetamido-2,4,6-triiodobenzyl, p-iodophenethyl, p-iodo-sec-phene...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00234a002

    authors： Newton BN

    更新日期：1976-12-01 00:00:00

  • Cardiotonic agents. 5. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitriles and related compounds. Synthesis and inotropic activity.

    abstract：:Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Alth...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00389a011

    authors： Sircar I,Duell BL,Bristol JA,Weishaar RE,Evans DB

    更新日期：1987-06-01 00:00:00

  • Efficient preparations of the beta-glucuronides of dihydroartemisinin and structural confirmation of the human glucuronide metabolite.

    abstract：:New and greatly improved preparations of the 12alpha,1'beta- (5) and 12beta,1'beta- (6) glucuronides of dihydroartemisinin (DHA, 2) are reported using anomeric hydroxy and imidate glucuronate intermediates. Comparison of the synthetic and natural materials shows that the human metabolite of DHA is the 12alpha-epimer 5...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm001061a

    authors： O'Neill PM,Scheinmann F,Stachulski AV,Maggs JL,Park BK

    更新日期：2001-04-26 00:00:00

  • Novel β- and γ-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen.

    abstract：:Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b02022

    authors： Kim K,Kwon H,Barinka C,Motlova L,Nam S,Choi D,Ha H,Nam H,Son SH,Minn I,Pomper MG,Yang X,Kutil Z,Byun Y

    更新日期：2020-03-26 00:00:00

  • Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT2B/5HT2C Serotonin Receptor Antagonists.

    abstract：:Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT2B and 5HT2C receptors (5HTRs). We explored the structure-activity relationship at 5HT2Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b01183

    authors： Tosh DK,Ciancetta A,Warnick E,Crane S,Gao ZG,Jacobson KA

    更新日期：2016-12-22 00:00:00

  • Conformational effects on the activity of drugs. 7. Synthesis and pharmacological properties of 2-(p-nitrophenyl)-substituted morpholines.

    abstract：:A series of 1-(p-nitrophenyl)-2-aminoethanol derivatives and their morpholine analogues have been synthesized and pharmacologically investigated in order to confirm some pharmacological observations made with the N-isopropyl-substituted compounds. In agreement with the previously obtained results, the weak alpha-adren...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00192a023

    authors： Balsamo A,Crotti P,Lapucci A,Macchia B,Macchia F,Del Tacca M,Mazzanti L,Ceserani R

    更新日期：1979-06-01 00:00:00

  • 3-Quinolinecarboxamides. A series of novel orally-active antiherpetic agents.

    abstract：:A series of novel 3-quinolinecarboxamides that are structurally similar to the quinolone class of antibacterial agents possess excellent antiherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3-, and 7-positions, analogues were identified that have up to 5-fold increased HSV-2 plaque-reduction potency...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00063a008

    authors： Wentland MP,Perni RB,Dorff PH,Brundage RP,Castaldi MJ,Bailey TR,Carabateas PM,Bacon ER,Young DC,Woods MG

    更新日期：1993-05-28 00:00:00

  • Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1) inhibitors.

    abstract：:Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea h...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901472u

    authors： Wang YS,Strickland C,Voigt JH,Kennedy ME,Beyer BM,Senior MM,Smith EM,Nechuta TL,Madison VS,Czarniecki M,McKittrick BA,Stamford AW,Parker EM,Hunter JC,Greenlee WJ,Wyss DF

    更新日期：2010-02-11 00:00:00

  • X-ray snapshot of the mechanism of inactivation of human neutrophil elastase by 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives.

    abstract：:The mechanism of action of a general class of mechanism-based inhibitors of serine proteases, including human neutrophil elastase (HNE), has been elucidated by determining the X-ray crystal structure of an enzyme-inhibitor complex. The captured intermediate indicates that processing of inhibitor by the enzyme generate...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm700966p

    authors： Huang W,Yamamoto Y,Li Y,Dou D,Alliston KR,Hanzlik RP,Williams TD,Groutas WC

    更新日期：2008-04-10 00:00:00

  • Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation.

    abstract：:EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR i...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00403

    authors： Hao Y,Wang X,Zhang T,Sun D,Tong Y,Xu Y,Chen H,Tong L,Zhu L,Zhao Z,Chen Z,Ding J,Xie H,Xu Y,Li H

    更新日期：2016-08-11 00:00:00

  • 2-Methyl-1,3-dioxaazaspiro[4.5]decanes as novel muscarinic cholinergic agonists.

    abstract：:Many nonquaternary ammonium muscarinic agonists have been developed over the last few years, but most of the existing compounds (e.g., arecoline, RS-86, AF-30) behave as weak partial agonists at cholinergic receptors in tissues of limited receptor reserve. The current paper describes the synthesis and biochemical asse...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00397a039

    authors： Saunders J,Showell GA,Snow RJ,Baker R,Harley EA,Freedman SB

    更新日期：1988-02-01 00:00:00

  • Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase.

    abstract：:A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm800914n

    authors： Barrow JC,Stauffer SR,Rittle KE,Ngo PL,Yang Z,Selnick HG,Graham SL,Munshi S,McGaughey GB,Holloway MK,Simon AJ,Price EA,Sankaranarayanan S,Colussi D,Tugusheva K,Lai MT,Espeseth AS,Xu M,Huang Q,Wolfe A,Pietrak B,Z

    更新日期：2008-10-23 00:00:00

  • Improved structure-activity relationship analysis of HIV-1 protease inhibitors using interaction kinetic data.

    abstract：:Despite the availability of large amounts of data for HIV-protease inhibitors and their effectiveness with wild type and resistant enzyme, there is limited knowledge about how this and other information can be systematically applied to the development of new antiviral compounds. To identify in vitro parameters that co...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0499110

    authors： Shuman CF,Vrang L,Danielson UH

    更新日期：2004-11-18 00:00:00

  • Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

    abstract：:Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of E...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00421

    authors： Heightman TD,Berdini V,Braithwaite H,Buck IM,Cassidy M,Castro J,Courtin A,Day JEH,East C,Fazal L,Graham B,Griffiths-Jones CM,Lyons JF,Martins V,Muench S,Munck JM,Norton D,O'Reilly M,Palmer N,Pathuri P,Reader M,R

    更新日期：2018-06-14 00:00:00

  • Self-immolative anthracycline prodrugs for suicide gene therapy.

    abstract：:Four novel potential prodrugs derived from daunorubicin (8, 10) and doxorubicin (12, 14) were designed and synthesized. They are self-immolative prodrugs for suicide gene therapy activation by the enzyme carboxypeptidase G2 (CPG2) subsequently releasing the corresponding anthracyclines, by a 1,6-elimination mechanism....

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980696v

    authors： Niculescu-Duvaz I,Niculescu-Duvaz D,Friedlos F,Spooner R,Martin J,Marais R,Springer CJ

    更新日期：1999-07-01 00:00:00

  • 4-Benzyloxy-gamma-sultone derivatives: discovery of a novel family of non-nucleoside inhibitors of human cytomegalovirus and varicella zoster virus.

    abstract：:We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the 4-keto-1,2-oxathiole-2,2-dioxide (beta-keto-gamma-sultone) heterocyclic system. Several 4- and 5-substituted-5H-1,2-oxathiole-2,2-dioxide derivatives were found to have a selective inhibitory activity against ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm8014662

    authors： De Castro S,García-Aparicio C,Andrei G,Snoeck R,Balzarini J,Camarasa MJ,Velázquez S

    更新日期：2009-03-26 00:00:00

  • Orally absorbable cephalosporin antibiotics. 3. Preparation of biologically active R isomer of 7-(3-benzothienylglycylamido)deacetoxycephalosporanic acid.

    abstract：:The methyl and isopropyl esters of (RS)-3-benzothienylglycine were resolved with (+)- and (-)-tartaric acid in acetonitrile to give the corresponding R and S salts. The R-salt 4 was hydrolyzed to (R)-3-benzothienylglycine (5). The amino group in 5 was protected with the Boc function and the protected R amino acid 6 co...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00150a024

    authors： Kukolja S,Pfeil JL,Draheim SE,Ott JL

    更新日期：1985-12-01 00:00:00

  • Design and synthesis of pyrrolidine-5,5-trans-lactams (5-oxo-hexahydro-pyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 1. The alpha-methyl-trans-lactam template.

    abstract：:Mechanism-based inhibitors of human cytomegalovirus (HCMV) protease have been designed based on the pyrrolidine-5,5-trans-lactam ring system. New routes to the beta-methyl-, desmethyl-, and alpha-methyl-pyrrolidine-5,5-trans-lactam templates have been developed from 2,4-diaminobutyric acid. ESI/MS studies have shown t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm000078q

    authors： Borthwick AD,Angier SJ,Crame AJ,Exall AM,Haley TM,Hart GJ,Mason AM,Pennell AM,Weingarten GG

    更新日期：2000-11-16 00:00:00

  • Novel bioactive and stable neurotensin peptide analogues capable of delivering radiopharmaceuticals and molecular beacons to tumors.

    abstract：:The prevalence of neurotensin receptor (NTR) in several human tumors makes it an attractive target for the delivery of cytotoxic drugs and imaging agents. Native neurotensin (NT) is a tridecapeptide that binds to NTR and induces tumor growth. Unfortunately, NT has a short plasma half-life, which hinders its use for in...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm030081k

    authors： Achilefu S,Srinivasan A,Schmidt MA,Jimenez HN,Bugaj JE,Erion JL

    更新日期：2003-07-17 00:00:00

  • Ergot alkaloids. Synthesis of nitrosourea derivatives of ergolines as potential anticancer agents.

    abstract：:Nitrosourea derivatives of ergolines have been synthesized for the purpose of obtaining agents with both prolactin-and tumor-inhibitory activity. Two derivatives of 8-amino-6-methylergoline (3), 8-[3-(2-chloroethyl)-3-nitrosoureido]-1-nitroso-6-methylergoline (5c) and 8-[3-2-chloroethyl)-3-nitrosoureido]-6-methylergol...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00187a008

    authors： Crider AM,Lu CK,Floss HG,Cassady JM,Clemens JA

    更新日期：1979-01-01 00:00:00

  • Analgesics. 3. Selected 1-substituted and 1,3-disubstituted 5-propionoxy-5-(1-phenylethyl)barbituric acids.

    abstract：:Several 1,3-disubstituted and 1-substituted derivatives of 5-propionoxy-5-(1-phenylethyl)barbituric acid were synthesized and evaluated for analgesic activity. Three of these compounds, 1,3-bis(methoxymethyl)-5-propionoxy-5-(1-phenylethyl)barbituric acid (2), 1,3-dimethyl-5-propionoxy-5-(1-phenylethyl)barbituric acid...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00241a010

    authors： Vida JA,Samour CM,O'Dea MH,Reinhard JF

    更新日期：1975-07-01 00:00:00

  • Discovery of Potent, Selective, and Short-Acting Peptidic V2 Receptor Agonists.

    abstract：:The vasopressin analogue desmopressin (desamino-d-arginine8 vasopressin, dDAVP, 1) is a potent vasopressin 2 (V2) receptor (V2R) agonist approved in many countries for the treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders. Since 1 is primarily excreted via the kidneys, an...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b00132

    authors： Wiśniewski K,Qi S,Kraus J,Ly B,Srinivasan K,Tariga H,Croston G,La E,Wiśniewska H,Ortiz C,Laporte R,Rivière PJ,Neyer G,Hargrove DM,Schteingart CD

    更新日期：2019-05-23 00:00:00

  • Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen.

    abstract：:The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00108a030

    authors： Carroll FI,Abraham P,Mascarella SW,Singh P,Moreland CG,Sankar SS,Kwon YW,Triggle DJ

    更新日期：1991-04-01 00:00:00

  • Synthesis of some 1, 8- and 2, 8-disubstituted derivatives of adenosine cyclic 3', 5'-phosphate and their interaction with some enzymes of cAMP metabolism.

    abstract：:1, 8-Disubstituted derivatives of adenosine cyclic 3', 5'-phosphate (cAMP) were synthesized by N-oxidation or N-methylation of previously reported 8-substituted cAMP derivatives to yield 8-bromoadenosine cyclic 3', 5'-phosphate 1-oxide and 8-(benzylthio)-1-methyladenosine cyclic 3', 5'-phosphate. Substituents were int...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00225a017

    authors： Uno H,Meyer RB,Shuman DA,Robins RK,Simon LN,Miller JP

    更新日期：1976-03-01 00:00:00

  • Prospective identification of biologically active structures by topomer shape similarity searching.

    abstract：:The principle of bioisosterism-similarly shaped molecules are more likely to share biological properties than are other molecules-has long helped to guide drug discovery. An algorithmic implementation of this principle, based on shape comparisons of a single rule-generated "topomer" conformation per molecule, had been...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm990159q

    authors： Cramer RD,Poss MA,Hermsmeier MA,Caulfield TJ,Kowala MC,Valentine MT

    更新日期：1999-09-23 00:00:00

  • Impact of Binding Site Comparisons on Medicinal Chemistry and Rational Molecular Design.

    abstract：:Modern rational drug design not only deals with the search for ligands binding to interesting and promising validated targets but also aims to identify the function and ligands of yet uncharacterized proteins having impact on different diseases. Additionally, it contributes to the design of inhibitors with distinct se...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.6b00078

    authors： Ehrt C,Brinkjost T,Koch O

    更新日期：2016-05-12 00:00:00