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1.
Cancer Lett ; 264(2): 309-15, 2008 Jun 18.
Article in English | MEDLINE | ID: mdl-18321638

ABSTRACT

Human A3 adenosine receptor (A3AR) agonists showed the anti-tumor activity in various in vitro and in vivo studies. The present study investigates the anti-proliferative effect of a novel adenosine analog 2-chloro-N6-(3-iodobenzyl)-4'-thioadenosine-5'-N-methyluronamide (thio-Cl-IB-MECA) in A549 human lung cancer cells. Thio-Cl-IB-MECA induced arrest of cell cycle progression in G0/G1 phase at lower concentrations (up to 20 microM) and apoptotic cell death at a higher concentration (80 microM), which were manifested by down-regulation of cyclin D1, c-myc, and CDK4, activation of caspase-3 and -9, and cleavage of poly(ADP-ribose) polymerase (PARP). The activation of Akt-mediated signaling was also inhibited by treatment with thio-Cl-IB-MECA. These data might suggest the potential therapeutic value of an adenosine analog in the treatment of human lung cancer.


Subject(s)
Adenosine/analogs & derivatives , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Lung Neoplasms/drug therapy , Adenosine/pharmacology , Adenosine A3 Receptor Agonists , Blotting, Western , Caspases/drug effects , Caspases/metabolism , Cell Line, Tumor , Enzyme Activation/drug effects , Gene Expression/drug effects , Humans , Proto-Oncogene Proteins c-akt/drug effects , Proto-Oncogene Proteins c-akt/metabolism
2.
Arch Pharm Res ; 29(11): 1061-5, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17146977

ABSTRACT

A new chiral derivatization agent with sugar moiety, 2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl isothiocyanate (GATC) was synthesized. Several beta-blockers were investigated for the possible separation of the enantiomers by reversed-phase HPLC after derivatization with this new chiral derivatization agent (GATC). GATC was reacted readily with beta-blockers at room temperature and the reaction mixture could directly be injected into the HPLC system. The corresponding diastereomers were well resolved on an ODS column with acetonitrile-ammonium acetate buffer as a mobile phase and monitored at UV 254 nm. The optimization of the derivatization procedure (concentration of GATC, reaction temperature and time) and HPLC conditions (pH and ionic strength of mobile phase) were investigated and compared with GITC.


Subject(s)
Adrenergic beta-Antagonists/isolation & purification , Isothiocyanates/chemistry , Monosaccharides/chemistry , Acetates , Acetonitriles , Adrenergic beta-Antagonists/chemistry , Amines/chemistry , Amino Alcohols/chemistry , Chromatography, High Pressure Liquid , Hydrogen-Ion Concentration , Indicators and Reagents , Stereoisomerism
3.
J Med Chem ; 49(18): 5532-43, 2006 Sep 07.
Article in English | MEDLINE | ID: mdl-16942026

ABSTRACT

The structure-activity relationships and molecular modeling of the uracil nucleotide activated P2Y6 receptor have been studied. Uridine 5'-diphosphate (UDP) analogues bearing substitutions of the ribose moiety, the uracil ring, and the diphosphate group were synthesized and assayed for activity at the human P2Y6 receptor. The uracil ring was modified at the 4 position, with the synthesis of 4-substituted-thiouridine 5'-diphosphate analogues, as well as at positions 2, 3, and 5. The effect of modifications at the level of the phosphate chain was studied by preparing a cyclic 3',5'-diphosphate analogue, a 3'-diphosphate analogue, and several dinucleotide diphosphates. 5-Iodo-UDP 32 (EC50 = 0.15 microM) was equipotent to UDP, while substitutions of the 2'-hydroxyl (amino, azido) greatly reduce potency. The 2- and 4-thio analogues, 20 and 21, respectively, were also relatively potent in comparison to UDP. However, most other modifications greatly reduced potency. Molecular modeling indicates that the beta-phosphate of 5'-UDP and analogues is essential for the establishment of electrostatic interactions with two of the three conserved cationic residues of the receptor. Among 4-thioether derivatives, a 4-ethylthio analogue 23 displayed an EC50 of 0.28 microM, indicative of favorable interactions predicted for a small 4-alkylthio moiety with the aromatic ring of Y33 in TM1. The activity of analogue 19 in which the ribose was substituted with a 2-oxabicyclohexane ring in a rigid (S)-conformation (P = 126 degrees , 1'-exo) was consistent with molecular modeling. These results provide a better understanding of molecular recognition at the P2Y6 receptor and will be helpful in designing selective and potent P2Y6 receptor ligands.


Subject(s)
Receptors, Purinergic P2/drug effects , Uridine Diphosphate/analogs & derivatives , Uridine Diphosphate/chemical synthesis , Cell Line, Tumor , Humans , Models, Molecular , Purinergic P2 Receptor Agonists , Stereoisomerism , Structure-Activity Relationship , Uridine Diphosphate/pharmacology
4.
Novartis Found Symp ; 276: 58-68; discussion 68-72, 107-12, 275-81, 2006.
Article in English | MEDLINE | ID: mdl-16805423

ABSTRACT

Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X(2/3)/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X(2/3)/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformationally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4nM at the P2Y1 receptor, with >10000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed.


Subject(s)
Nucleotides/chemistry , Purinergic P2 Receptor Agonists , Purinergic P2 Receptor Antagonists , Animals , Humans , Ligands , Models, Molecular , Molecular Structure , Nucleotides/metabolism , Protein Conformation , Receptors, Purinergic P2/metabolism
5.
Bioorg Med Chem ; 14(14): 4718-30, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16603368

ABSTRACT

A large series of N6-substituted-4'-thioadenosines were synthesized starting from D-gulonic-gamma-lactone, and structure-activity relationships were studied at the human A3 and other subtypes of adenosine receptors (ARs). 2-Chloro-substituted and 2-H analogues were compared. 2-Chloro-N6-methyl-4'-thioadenosine 19b was a highly potent and selective agonist (Ki=0.8+/-0.1 nM in binding) at the A3AR, and displayed the same relative efficacy in receptor activation as a known full agonist, Cl-IB-MECA. Most of N6-substituted-4'-thioadenosines were less potent in binding than the corresponding N6-substituted-adenosines or N6-substituted-4'-thioadenosine-5'-uronamides. N6-(3-Iodobenzyl) derivative 19g was demonstrated to be an A3AR-selective partial agonist displaying a Ki value of 3.2 nM.


Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/analogs & derivatives , Thionucleosides/chemical synthesis , Thionucleosides/pharmacology , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/metabolism , Adenosine/pharmacology , Animals , CHO Cells , Cricetinae , Cyclic AMP/metabolism , Drug Design , Humans , In Vitro Techniques , Kinetics , Ligands , Magnetic Resonance Spectroscopy , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A2A/metabolism , Recombinant Proteins/agonists , Structure-Activity Relationship , Thionucleosides/chemistry , Thionucleosides/metabolism
6.
Mol Cancer Ther ; 5(3): 685-92, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16546983

ABSTRACT

Agonists to A3 adenosine receptor (A3AR) have been reported to inhibit cell growth and/or induce apoptosis in various tumors. We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells. Anchorage-dependent cell growth and in vivo tumor growth were attenuated by LJ-529, independently of its estrogen receptor (ER) alpha status. In addition, apoptosis was induced as evidenced by the activation of caspase-3 and c-poly(ADP)ribose polymerase. Furthermore, the Wnt signaling pathway was down-regulated and p27(kip) was induced by LJ-529. In ER-positive cells, the expression of ER was down-regulated by LJ-529, which might have additionally contributed to attenuated cell proliferation. In ER-negative, c-ErbB2-overexpressing SK-BR-3 cells, the expression of c-ErbB2 and its downstream extracellular signal-regulated kinase pathway were down-regulated by LJ-529. However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested. In conclusion, our novel findings open the possibility of LJ-529 as an effective therapeutic agent against both ER-positive and ER-negative breast cancers, particularly against the more aggressive ER-negative, c-ErbB2-overexpressing types.


Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/analogs & derivatives , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Estrogen Receptor alpha/metabolism , Thionucleosides/therapeutic use , Adenosine/therapeutic use , Animals , Apoptosis , Breast Neoplasms/chemistry , Breast Neoplasms/genetics , Caspase 3 , Caspases/drug effects , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Down-Regulation , Estrogen Receptor alpha/analysis , Estrogen Receptor alpha/genetics , Humans , Mice , Poly(ADP-ribose) Polymerases/drug effects , Receptor, ErbB-2/metabolism , Signal Transduction/drug effects , Wnt Proteins/metabolism , Xenograft Model Antitumor Assays
7.
J Med Chem ; 49(1): 273-81, 2006 Jan 12.
Article in English | MEDLINE | ID: mdl-16392812

ABSTRACT

We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N(6)-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that, similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronamide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR.


Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/analogs & derivatives , Adenosine/pharmacology , Amides/pharmacology , Uronic Acids/pharmacology , Adenosine/chemistry , Adenosine A1 Receptor Agonists , Adenosine A2 Receptor Agonists , Amides/chemical synthesis , Amides/chemistry , Animals , CHO Cells , Cricetinae , Drug Evaluation, Preclinical , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Uronic Acids/chemical synthesis , Uronic Acids/chemistry
8.
Article in English | MEDLINE | ID: mdl-16247997

ABSTRACT

4'-Thionucleoside derivatives as potent and selective A3 adenosaine receptor agonists were synthesized, starting from D-gulono-gamma-lactone via D-thioribosyl acetate as a key intermediate, among which the 2-chloro-N6-methyladenosine-5-methyluronamide showed the most potent and selective binding affinity (Ki = 0.28 +/- 0.09 nM) at the human A3 adenosine receptor.


Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/analogs & derivatives , Receptor, Adenosine A3/chemistry , Thionucleosides/chemistry , Acetates/chemistry , Adenosine/chemistry , Animals , Furans/chemistry , Gluconates/chemistry , Humans , Kinetics , Lactones/chemistry , Ligands , Models, Chemical , Nucleosides/chemistry , Oxygen/chemistry , Protein Binding , Rats
9.
Article in English | MEDLINE | ID: mdl-16247998

ABSTRACT

The preparative and stereoselective synthesis (45- 50% overall yields, >50 g scale) of the key carbasugars 7a-d was achieved from D-ribose via stereoselective Grignard reaction and oxidative rearrangement as key reactions.


Subject(s)
Cyclopentanes/chemistry , Cyclopentanes/chemical synthesis , Molecular Biology/methods , Nucleosides/chemistry , Alcohols/chemistry , Catalysis , Models, Chemical , Oxygen/chemistry , Ribose/chemistry , Stereoisomerism
10.
Biochem Pharmacol ; 70(6): 918-24, 2005 Sep 15.
Article in English | MEDLINE | ID: mdl-16051194

ABSTRACT

Human A3 adenosine receptor (A3AR) agonists have been shown to play important roles in several physiological and pathological processes, including growth inhibition of human cancer cells. On this line, we recently found that a novel adenosine analog, 2-chloro-N6-(3-iodobenzyl)-4'-thioadenosine-5'-N-methyluronamide (thio-Cl-IB-MECA) was a potent human A3AR agonist, and is superior to a known agonist Cl-IB-MECA [Jeong LS, Jin DZ, Kim HO, Shin DH, Moon HR, Gunaga P, et al. J Med Chem 2003;46:3775]. Here, we report that a novel A3AR agonist, thio-Cl-IB-MECA inhibited the growth of human promyelocytic leukemia HL-60 cells by arresting cell cycle and induction of apoptosis. Thio-Cl-IB-MECA induced the cell cycle arrest of G0/G1 in the early time and at lower concentration (up to 25 microM). At higher concentration (50 microM), the apoptotic cell deaths were manifested by observation of the increase of sub-G0 phase of cell cycle distribution, DNA fragmentation and poly(ADP-ribose) polymerase (PARP) cleavage. In addition, the down-regulation of checkpoint protein cyclin D1 and c-myc by thio-Cl-IB-MECA was well correlated with the arrest of cell cycle transition of G1 to S phase. Further study revealed that the growth inhibitory activity of thio-Cl-IB-MECA is also related with the modulation of Wnt signaling pathway. The levels of beta-catenin, phosphorylated forms of GSK-beta and Akt were down-regulated by the treatment of thio-Cl-IB-MECA (10 nM) in a time-dependent manner, providing one of plausible mechanistic evidence for the involvement of the Wnt signaling pathway in the HL-60 cell growth inhibitory effects by thio-Cl-IB-MECA. These results suggest that a novel A3AR agonist, thio-Cl-IB-MECA can down-regulate Wnt signaling, inhibit proliferation and induce apoptosis in HL-60 leukemia cells, and thus provide the possibility of this compound in the potential therapeutic value of the treatment of leukemia.


Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/analogs & derivatives , Apoptosis/drug effects , G1 Phase/drug effects , Leukemia, Promyelocytic, Acute/pathology , Resting Phase, Cell Cycle/drug effects , Adenosine/pharmacology , Blotting, Western , HL-60 Cells , Humans
11.
Curr Med Chem ; 11(19): 2585-637, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15544465

ABSTRACT

The classical 4'-oxonucleoside analogs exhibit interesting biological activities such as antibiotic, antiviral and antitumor, which are believed to be the result of inhibition of the viral or cellular DNA or RNA polymerase after being converted to their corresponding 5'-triphosphates. However, the activity of 4'-oxonucleosides were limited by their susceptibility to degradation by nucleoside phosphorylases or acid hydrolysis. This aspect called for the chemical modification of the carbohydrate portion. This compulsion led to two kinds of strategies; (1) replacement of the 4'-oxygen by the methylene group - carbocyclic nucleosides; (2) replacement of the 4' oxygen by sulphur-4'-thionucleosides. This group has also conferred the resistance to the nucleoside cleavage. Although, there were some pioneering work on 4'-thionucleosides in 1960s and 1970s, the interest in this group of compounds was rekindled by the antiviral activities of 2'-deoxy-4'-thionucleosides reported independently by Secrist et al. and Walker et al. Subsequent contributions by the other authors, enhanced its standing as an important class of antiviral agents. Following is a reasonably exhaustive account of this class of compounds reported after 1990.


Subject(s)
Antineoplastic Agents/chemistry , Antiviral Agents/chemistry , Thionucleosides/chemistry , Animals , Antineoplastic Agents/therapeutic use , Antiviral Agents/therapeutic use , Humans , Thionucleosides/therapeutic use
12.
Biochem Pharmacol ; 67(5): 893-901, 2004 Mar 01.
Article in English | MEDLINE | ID: mdl-15104242

ABSTRACT

We have found previously that structural features of adenosine derivatives, particularly at the N6- and 2-positions of adenine, determine the intrinsic efficacy as A3 adenosine receptor (AR) agonists. Here, we have probed this phenomenon with respect to the ribose moiety using a series of ribose-modified adenosine derivatives, examining binding affinity and activation of the human A3 AR expressed in CHO cells. Both 2'- and 3'-hydroxyl groups in the ribose moiety contribute to A3 AR binding and activation, with 2'-OH being more essential. Thus, the 2'-fluoro substitution eliminated both binding and activation, while a 3'-fluoro substitution led to only a partial reduction of potency and efficacy at the A3 AR. A 5'-uronamide group, known to restore full efficacy in other derivatives, failed to fully overcome the diminished efficacy of 3'-fluoro derivatives. The 4'-thio substitution, which generally enhanced A3 AR potency and selectivity, resulted in 5'-CH2OH analogues (10 and 12) which were partial agonists of the A3 AR. Interestingly, the shifting of the N6-(3-iodobenzyl)adenine moiety from the 1'- to 4'-position had a minor influence on A3 AR selectivity, but transformed 15 into a potent antagonist (16) (Ki = 4.3 nM). Compound 16 antagonized human A3 AR agonist-induced inhibition of cyclic AMP with a K(B) value of 3.0 nM. A novel apio analogue (20) of neplanocin A, was a full A3 AR agonist. The affinities of selected, novel analogues at rat ARs were examined, revealing species differences. In summary, critical structural determinants for human A3 AR activation have been identified, which should prove useful for further understanding the mechanism of receptor activation and development of more potent and selective full agonists, partial agonists and antagonists for A3 ARs.


Subject(s)
Adenosine/pharmacology , Receptor, Adenosine A3/metabolism , Ribose/chemistry , Adenosine/chemistry , Animals , Binding Sites , CHO Cells , Cricetinae , Humans , Kinetics , Molecular Conformation , Rats , Receptor, Adenosine A3/drug effects , Species Specificity , Structure-Activity Relationship
13.
J Org Chem ; 69(7): 2634-6, 2004 Apr 02.
Article in English | MEDLINE | ID: mdl-15049678

ABSTRACT

The preparative and stereoselective synthesis (45-50% overall yields) of the target compound 17 has been accomplished from D-ribose. The bulky protecting groups such as TBDPS and Trityl enforced the facial selectivity during Grignard reaction to give the tertiary beta-allylic alcohol 16 as the sole product, which was oxidatively rearranged to the key molecule 17 in excellent yield.


Subject(s)
Chemistry, Organic/methods , Nucleosides/chemical synthesis , Ribose/chemistry , Adenosine/analogs & derivatives , Adenosine/chemistry , Catalysis , Molecular Structure , Nucleosides/analysis , Oxidation-Reduction , Stereoisomerism , Structure-Activity Relationship
15.
J Med Chem ; 46(18): 3775-7, 2003 Aug 28.
Article in English | MEDLINE | ID: mdl-12930138

ABSTRACT

4'-Thio analogues 3-5 of Cl-IB-MECA (2) (K(i) = 1.0 +/- 0.2 nM at the human A(3) adenosine receptor) were synthesized from d-gulono-gamma-lactone via 4-thioribosyl acetate 14 as the key intermediate. All synthesized 4'-thionucleosides exhibited higher binding affinity to the human A(3) adenosine receptor than Cl-IB-MECA, among which 4 showed the most potent binding affinity (K(i) = 0.28 +/- 0.09 nM). 4 was also selective for A(3) vs human A(1) and human A(2A) receptors by 4800- and 36000-fold, respectively.


Subject(s)
Adenosine/analogs & derivatives , Adenosine/chemistry , Purinergic P1 Receptor Agonists , Thionucleosides/chemical synthesis , Animals , CHO Cells , Cerebral Cortex/metabolism , Corpus Striatum/metabolism , Cricetinae , Humans , Ligands , Radioligand Assay , Rats , Receptor, Adenosine A3 , Structure-Activity Relationship , Thionucleosides/chemistry , Thionucleosides/pharmacology
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