Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 25
Filter
Add more filters










Publication year range
1.
J Asian Nat Prod Res ; 26(7): 812-823, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38477295

ABSTRACT

Nineteen isosteviol derivatives were designed and synthesized by C-16, C-19 and D-ring modifications of isosteviol. These compounds were screened for their cytotoxic activities against Hela and A549 cells in vitro. Among them, the inhibitory effect of compounds 3b and 16 on Hela cells was comparable to that of the positive control gefitinib, and the compounds 3b (IC50=7.84 ± 0.84 µM) and 7a (IC50=6.89 ± 0.33 µM) exhibited significant cytotoxicity superior to gefitinib (IC50=11.02 ± 3.27 µM) against A549 cells.


Subject(s)
Diterpenes, Kaurane , Drug Screening Assays, Antitumor , Humans , Diterpenes, Kaurane/pharmacology , Diterpenes, Kaurane/chemical synthesis , Diterpenes, Kaurane/chemistry , Molecular Structure , HeLa Cells , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , A549 Cells , Gefitinib/pharmacology , Structure-Activity Relationship , Cell Proliferation/drug effects , Quinazolines/pharmacology , Quinazolines/chemistry , Quinazolines/chemical synthesis
2.
J Asian Nat Prod Res ; 24(9): 849-859, 2022 Sep.
Article in English | MEDLINE | ID: mdl-34657548

ABSTRACT

Twelve novel cordycepin derivatives were designed and synthesized with modification at positions of 2', 5'-hydroxyl and N6 amino groups of cordycepin. The results showed that the inhibitory activities of 3, 4b, 6c and 6d on A549 were comparable to the positive control gefitinib, and the inhibitory activity of 6a on A549 was better than that of gefitinib. Also, the inhibitory activities of twelve cordycepin derivatives against E. coli 1924, S. aureus 4220 and S. mutans 3289 were studied. Among them, 4b showed certain inhibitory on S. mutans 3289, while 6b showed certain inhibition on S. aureus 4220.


Subject(s)
Escherichia coli , Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Deoxyadenosines , Gefitinib , Molecular Structure , Structure-Activity Relationship
3.
Eur J Med Chem ; 155: 406-417, 2018 Jul 15.
Article in English | MEDLINE | ID: mdl-29906687

ABSTRACT

Based on the potent anticancer activity of 6'-fluorocyclopentenyl-cytosine 2b in phase IIa clinical trials for the treatment of gemcitabine-resistant pancreatic cancer, we carried out a systematic structure-activity relationship study of 6'-fluorocyclopentenyl-pyrimidines 3a-i and -purines 3j-o to discover novel anticancer agents. We also synthesized the phosphoramidate prodrug 3p of adenine derivative 1b to determine if the anticancer activity depended on the inhibition of DNA and/or RNA polymerase in cancer cells and/or on the inhibition of S-adenosylhomocysteine (SAH) hydrolase. All of the synthesized pyrimidine nucleosides exhibited much less potent anticancer activity in vitro than the cytosine derivative 2b, acting as RNA and/or DNA polymerase inhibitor, indicating that they could not be efficiently converted to their triphosphates for anticancer activity. Among all the synthesized purine nucleosides, adenine derivative 1b and N6-methyladenine derivative 3k showed potent anticancer activity, showing equipotent inhibitory activity as the positive control, neplanocin A (1a) or Ara-C. However, the phosphoramidate prodrug 3p showed less anticancer activity than 1b, indicating that it did not act as a RNA and/or DNA polymerase inhibitor like 2b. This result also demonstrates that the anticancer activity of 1b largely depends on the inhibition of histone methyltransferase, resulting from strong inhibition of SAH hydrolase. The deamination of the N6-amino group, the addition of the bulky alkyl group at the N6-amino group, or the introduction of the amino group at the C2 position almost abolished the anticancer activity.


Subject(s)
Antineoplastic Agents/pharmacology , Cyclopentanes/pharmacology , Drug Design , Hydrocarbons, Fluorinated/pharmacology , Prodrugs/pharmacology , Purines/pharmacology , Pyrimidines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistry , Purines/chemical synthesis , Purines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
4.
J Med Chem ; 60(8): 3422-3437, 2017 04 27.
Article in English | MEDLINE | ID: mdl-28380296

ABSTRACT

Potent and selective A3 adenosine receptor (AR) agonists were identified by the replacement of 4'-oxo- or 4'-thionucleosides with bioisosteric selenium. Unlike previous agonists, 4'-seleno analogues preferred a glycosidic syn conformation and South sugar puckering, as shown in the X-ray crystal structure of 5'-N-methylcarbamoyl derivative 3p. Among the compounds tested, N6-3-iodobenzyl analogue 3d was found to be the most potent A3AR full agonist (Ki = 0.57 nM), which was ≥800- and 1900-fold selective for A1AR and A2AAR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA3AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N9 isomers, but compound 3t lacked A3AR activation, appearing to be a weak antagonist. 2-Cl-N6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 µM. This suggests the potential for the development of 4'-selenonucleoside A3AR agonists as novel antistroke agents.


Subject(s)
Adenosine A3 Receptor Agonists/pharmacology , Adenosine/analogs & derivatives , Adenosine/pharmacology , Organoselenium Compounds/chemistry , Adenosine/chemistry , Adenosine A3 Receptor Agonists/chemistry , Carbon-13 Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Proton Magnetic Resonance Spectroscopy
5.
Bioorg Med Chem ; 24(16): 3418-28, 2016 08 15.
Article in English | MEDLINE | ID: mdl-27283788

ABSTRACT

A series of C8-substituted-4'-thioadenosine analogs 3a-3g, 15, and 17 and their truncated derivatives 4a-4j, 23-25, and 27 have been successfully synthesized from d-ribose and d-mannose, respectively, employing Pummerer type or Vorbrüggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100µM. However, the 8-iodo derivatives 15, 17, and 27 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity.


Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Thionucleosides/chemistry , Thionucleosides/pharmacology , Carbon-13 Magnetic Resonance Spectroscopy , Cell Line, Tumor , Drug Design , Humans , Proton Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom Bombardment , Thionucleosides/chemical synthesis
6.
Bioorg Med Chem Lett ; 25(20): 4500-4, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26343825

ABSTRACT

A series of pentacyclic triterpenoids derivatives bearing O-[4-(1-piperazinyl)-4-oxo-butyryl moiety has been synthesized and investigated for their potential antiproliferative activities. Pentacyclic triterpenoids derivative compounds were synthesized by a four or six step synthetic procedure. The activity studies were evaluated using Cell Counting Kit-8 method, and Western blotting analysis on A549 cells, MCF-7 cells and Hela cells. Compounds methyl 3-O-[4-(1-piperazinyl)-4-oxo-butyryl]olean-12-ene-28-oate (OA-4) and compound 2-O-[4-(1-piperazinyl)-4-oxo-butyryl]-3,23-dihydroxyurs-12-ene-28-oate (AA-5) were found to be promising antiproliferative agents. These compounds show potentiality for further optimization as antitumor drugs.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Pentacyclic Triterpenes/chemistry , Pentacyclic Triterpenes/pharmacology , Piperazines/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Pentacyclic Triterpenes/chemical synthesis , Piperazines/chemistry , Structure-Activity Relationship
7.
Chem Pharm Bull (Tokyo) ; 62(8): 764-71, 2014.
Article in English | MEDLINE | ID: mdl-25087628

ABSTRACT

A large number of bioactive pentacyclic triterpenoids have been shown to have multiple biological activities. This study was conducted to evaluate the inhibitory activities of 6 newly synthesized and novel pentacyclic triterpenoids against enterovirus 71 (EV71). The parent compound, ursolic acid (UA), showed the greatest inhibitory activity against EV71, while oleanolic acid (OA), asiatic acid (AA), and synthetic derivatives of 18-ß-glycyrrhetinic acid (GA) and OA also exhibited inhibitory effects, although to lesser extents. The results suggest these compounds show potential for further optimization as antiviral candidates for treatment of EV71 infections.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Enterovirus A, Human/drug effects , Enterovirus Infections/drug therapy , Triterpenes/chemistry , Triterpenes/pharmacology , Virus Replication/drug effects , Enterovirus A, Human/physiology , Enterovirus Infections/virology , Humans , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Pentacyclic Triterpenes/chemistry , Pentacyclic Triterpenes/pharmacology , Ursolic Acid
8.
J Med Chem ; 55(9): 4521-5, 2012 May 10.
Article in English | MEDLINE | ID: mdl-22524616

ABSTRACT

On the basis of the potent biological activity of cyclopentenyl-pyrimidines, fluorocyclopentenyl-pyrimidines were designed and synthesized from D-ribose. Among these, the cytosine derivative 5a showed highly potent antigrowth effects in a broad range of tumor cell lines and very potent antitumor activity in a nude mouse tumor xenograft model implanted with A549 human lung cancer cells. However, its 2'-deoxycytidine derivative 5b did not show any antigrowth effects, indicating that 2'-hydroxyl group is essential for the biological activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclopentanes/chemical synthesis , Cytosine/analogs & derivatives , Lung Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cyclopentanes/pharmacology , Cytosine/pharmacology , Humans , Lung Neoplasms/pathology , Male , Mice , Mice, Nude , Xenograft Model Antitumor Assays
9.
J Med Chem ; 54(4): 930-8, 2011 Feb 24.
Article in English | MEDLINE | ID: mdl-21226494

ABSTRACT

The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3'-oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4'-CH(2)OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4'-CH(2)OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.


Subject(s)
Adenosine/analogs & derivatives , Adenosylhomocysteinase/chemistry , Adenosylhomocysteinase/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacology , Adenosylhomocysteinase/antagonists & inhibitors , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Dynamics Simulation , Optical Rotation , Spectrometry, Mass, Fast Atom Bombardment
10.
Nucleic Acids Symp Ser (Oxf) ; (52): 555-6, 2008.
Article in English | MEDLINE | ID: mdl-18776500

ABSTRACT

The structure of 2',3'-didehydro-2',3'-dideoxynucleosides (d4Ns) was applied to design the novel bioisosteric 4'-seleno-d4Ns as potential inhibitors of human immunodeficiency virus reverse transcriptase (HIV RT). Conversion of 2',3'-dihydroxyl groups of 4'-selenoribofuranosyl pyrimidines into the olefin was accomplished by treatment of cyclic 2',3'-thiocarbonate with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine.


Subject(s)
Anti-HIV Agents/chemical synthesis , Dideoxynucleosides/chemical synthesis , Organoselenium Compounds/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Dideoxynucleosides/chemistry , Dideoxynucleosides/pharmacology , Nucleic Acid Conformation , Organoselenium Compounds/chemistry , Organoselenium Compounds/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology
11.
Arch Pharm Res ; 31(7): 843-9, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18704325

ABSTRACT

On the basis of potent anti-hepatitis C virus (HCV) activity of 2'-C-hydroxymethyladenosine, 3'-C-hydroxymethyl-substituted pyrimidine and purine nucleosides as potential anti-HCV agents were designed and synthesized from D-xylose via stereoselective Grignard reaction and conversion of the vinyl into hydroxymethyl group as key steps.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Purine Nucleosides/chemical synthesis , Purine Nucleosides/pharmacology , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Drug Design , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation
12.
Org Lett ; 10(2): 209-12, 2008 Jan 17.
Article in English | MEDLINE | ID: mdl-18088134

ABSTRACT

The first synthesis of 4'-selenonucleosides was achieved using a Pummerer-type condensation as a key step. All stereoelectronic effects shown in 4'-oxonucleosides were overwhelmed by the size of selenium and steric interactions, driving the conformation to the C2'-endo/ C3'-exo twist (Southern) conformation.


Subject(s)
Nucleosides/chemical synthesis , Organoselenium Compounds/chemical synthesis , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Nucleic Acid Conformation , Nucleosides/chemistry , Organoselenium Compounds/chemistry
13.
Eur J Med Chem ; 43(4): 675-82, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17673337

ABSTRACT

For the development of novel antitumor agents, we designed and synthesized 2,6-diaryl-substituted pyridine derivatives bearing three aryl groups, which are the bioisosteres of terpyridine, and evaluated their biological activities. Most of the 18 prepared compounds showed moderate cytotoxicity against several human cancer cell lines. From the structure-activity relationships we may conclude that the number of aryl groups employed would be critical for their biological activities.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacology , Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Pyridines/chemistry , Structure-Activity Relationship , Topoisomerase I Inhibitors , Tumor Cells, Cultured
14.
Article in English | MEDLINE | ID: mdl-18066886

ABSTRACT

Synthesis of fluorocyclopentenyl pyrimidine nucleosides 6-9 was enantiopurely accomplished employing oxidative rearrangement, RCM reaction and electrophilic fluorination starting from d-ribose. Cytosine analog 8 was found to exhibit significant anticancer activity in various human tumor cell lines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Humans , Pyrimidines/chemistry
15.
Arch Pharm Res ; 30(10): 1205-9, 2007 Oct.
Article in English | MEDLINE | ID: mdl-18038898

ABSTRACT

Improved syntheses of potent and selective A3 adenosine receptor agonists, Cl-IB-MECA and thio-Cl-IB-MECA were accomplished from cheap stating material, D-ribose. New synthetic methods were found to be superior to old methods from the viewpoint of use of cheap starting material, number of steps, and overall yields.


Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/analogs & derivatives , Ribose/chemistry , Thionucleosides/chemical synthesis , Adenosine/chemical synthesis , Adenosine/pharmacology , Molecular Structure , Thionucleosides/pharmacology
16.
Arch Pharm (Weinheim) ; 340(9): 491-5, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17763376

ABSTRACT

A series of 2-substituted-7-heptyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1(2H)-ones was synthesized. The anticonvulsant effect and neurotoxicity of the compounds were calculated with maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests with intraperitoneally injected mice. Among the synthesized compounds, 2-propionyl-7-heptyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one 4b was the most active one and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED(50)) of 8.2 mg/kg, median toxicity dose (TD(50)) of 318.3 mg/kg, and the protective index (PI) of 39.0 which is much greater than the PI of the reference drugs phenytoin and carbamazepine.


Subject(s)
Anticonvulsants/chemical synthesis , Quinolones/chemical synthesis , Animals , Anticonvulsants/chemistry , Anticonvulsants/toxicity , Mice , Quinolones/chemistry , Quinolones/toxicity , Structure-Activity Relationship
17.
Bioorg Med Chem Lett ; 17(16): 4456-9, 2007 Aug 15.
Article in English | MEDLINE | ID: mdl-17582766

ABSTRACT

5'-Deoxy-5'-ureidoadenosine was designed and synthesized as a potent inhibitor of S-adenosylhomocysteine hydrolase (SAH), in which 5'-ureido group acted as multiple hydrogen bonding donor in binding with active site residues of SAH in the molecular modeling study.


Subject(s)
Adenosylhomocysteinase/metabolism , Deoxyadenosines/chemistry , Adenosylhomocysteinase/chemistry , Binding Sites , Deoxyadenosines/chemical synthesis , Drug Design , Hydrogen Bonding , Models, Molecular , Molecular Structure , Structure-Activity Relationship
18.
Arch Pharm Res ; 29(12): 1091-5, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17225456

ABSTRACT

For the development of novel antitumor agents, we designed and synthesized terpyridines, and their biological activities were evaluated. Although most of the newly prepared terpyridines showed strong cytotoxicity against several human cancer cell lines, [2,2';6',2"]-terpyridine displayed the most significant cytotoxicity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Pyridines/chemical synthesis , Pyridines/toxicity , Cell Line, Tumor , Cell Survival/drug effects , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Structure-Activity Relationship , Topoisomerase I Inhibitors
19.
Nucleic Acids Symp Ser (Oxf) ; (49): 107-8, 2005.
Article in English | MEDLINE | ID: mdl-17150656

ABSTRACT

Novel pyrimidine nucleosides with fluorocyclopentene ring were synthesized from D-ribose via stereoselective Grignard reaction and electrophilic vinyl fluorination as key steps. Among compounds tested, cytosine derivative 15a was found to show high growth inhibition against a broad range of human tumor cell lines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cyclopentanes/chemistry , Humans , Pyrimidine Nucleosides/chemistry
20.
Arch Pharm Res ; 27(5): 512-7, 2004 May.
Article in English | MEDLINE | ID: mdl-15202556

ABSTRACT

The structural relationship of 16 asiatic acid (AA) derivatives, including AA and asiaticoside (AS) to cytotoxicity and anti-hepatofibrotic activity in HSC-T6 cells, were investigated. Cytotoxicities of AA derivatives varied from 5.5 microM to over 2000 microM of IC50 depending on AA functional group modifications. Substituting the hydroxyl group at the C(2) to N[triple bond]C and substituting bulky groups for dihydroxyl groups at (3), (23) of the A-ring increased the cytotoxicity, but keto group at C(11) and benzoyl ester at C(2) were greatly reduced it. Modification of the carboxylic acid group at C28 also reduced the cytotoxicity. The collagen synthesis determined by hydroxyproline content in the cells was inhibited from a maximum of 48% (Zlx-i-85 and 87) to 15% (AS) by AA derivatives. The anti-hepatofibrotic effect of these compounds might be due to the reduced expression of prolyl 4-hydroxylase alpha and beta subunits and TIMP2. However, the inhibition of collagen by asiaticoside derivatives did not show any structural-activity relationship.


Subject(s)
Hepatocytes/drug effects , Triterpenes/chemistry , Triterpenes/toxicity , Animals , Cell Line , Cell Line, Transformed , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Hepatocytes/physiology , Pentacyclic Triterpenes , Rats , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...