ABSTRACT
Synthesis of 2' -beta-hydroxymethyl nucleosides 3-6 was accomplished, using stereoselective hydroxymethylation as a key step. Adenine nucleoside 3 showed potent anti-HCV activity, implying that 2' -beta-hydroxymethyl group has the appropriate electronic properties interfering with HCV polymerase.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Antiviral Agents/chemistry , Drug Design , Nucleosides/chemistry , Purines/chemistryABSTRACT
Novel apio carbocyclic nucleosides 18-21 were asymmetrically synthesized as potential antiviral and antitumor agent, starting from D-ribose employing aldol reaction, RCM reaction and Mitsunobu reaction as key reactions.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , 2-Aminopurine/analogs & derivatives , 2-Aminopurine/chemistry , Antineoplastic Agents/chemistry , Antiviral Agents/chemistry , Drug Design , Drug Screening Assays, Antitumor , Nucleosides/chemistryABSTRACT
Homo-apioneplanocin A (1) as a potential inhibitor of S-adenosylhomocysteine hydrolase was synthesized from D-ribose, employing stereoselective hydroxymethylation, regioselective oxidation, and regio- and chemoselective hydroboration as key steps.
Subject(s)
Adenosine/analogs & derivatives , Adenosylhomocysteinase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacology , Drug Design , Nucleosides/chemistry , StereoisomerismABSTRACT
Novel 2'-C-methyl-cyclopropyl-fused carbocyclic nucleosides as potential anti-HCV agents were stereoselectively synthesized, utilizing regioselective cleavage of the isopropylidene group and cyclic sulfate chemistry as key steps.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Antiviral Agents/chemistry , Drug Design , Humans , Indicators and Reagents , Nucleosides/chemistryABSTRACT
Four 5'-substituted fluoro-neplanocin A analogues la-d were designed and synthesized, and the inhibitory activity against SAH was in the following order: NH2 > SH > F, N3, indicating a hydrogen bonding donor is essential for inhibitory activity.
Subject(s)
Adenosine/analogs & derivatives , Adenosylhomocysteinase/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/pharmacology , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosylhomocysteinase/chemistry , Antiviral Agents/pharmacology , Catalysis , Drug Design , Hydrogen/chemistry , Hydrogen Bonding , Inhibitory Concentration 50 , Models, Chemical , Structure-Activity Relationship , TemperatureABSTRACT
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 , StereoisomerismABSTRACT
Fluoroneplanocin A (12) was designed as a novel mechanism-based inhibitor of S-adenosylhomocysteine hydrolase (SAH) and efficiently synthesized via an electrophilic vinyl fluorination reaction (n-BuLi, N-fluorobenzenesulfonimide at -78 degrees C). Fluoroneplanocin A exhibited 2-fold more potent SAH inhibitory activity than the parent neplanocin A. A new mechanism of irreversible inhibition discovered in this work might provide new alternatives in the design of a different class of antiviral agents operating via SAH inhibition.
Subject(s)
Adenosine/chemical synthesis , Antiviral Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Hydrolases/antagonists & inhibitors , Adenosine/analogs & derivatives , Adenosine/chemistry , Adenosine/pharmacology , Adenosylhomocysteinase , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , HIV-1/drug effects , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Humans , Vesicular stomatitis Indiana virus/drug effectsABSTRACT
A total synthesis of apio-neplanocin A, which combines properties of apio nucleoside and neplanocin A and is a potential inhibitor of S-adenosylhomocysteine hydrolase, was accomplished starting from D-ribose via stereoselective hydroxymethylation and RCM reaction. [reaction: see text]
Subject(s)
Adenosine/analogs & derivatives , Adenosine/chemistry , Adenosine/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Hydrolases/antagonists & inhibitors , Adenosylhomocysteinase , Molecular Structure , StereoisomerismABSTRACT
Two chitosanases produced by Aspergillus fumigatus KB-1 were purified by ion exchange and size exclusion chromatographies. Molecular weights of chitosanases were 111.23 kDa (chitosanase I) and 23.38 kDa (chitosanase II). The N-terminal amino acid sequence of chitosanase II was determined as follows: YNLPNNLKQIYDKHKGKXSXVLAKGFTN. The optimum pH of the chitosanase I and II was 6.5 and 5.5, respectively. The optimum temperatures were 60 degrees C for chitosanase land 70 degrees C for chitosanase II. Hydrolysis products of two chitosanases were analyzed by HPLC and GPC. Chitosanase I hydrolyzed substrate to glucosamine. Chitosanase II produced chitooligosaccharides.
Subject(s)
Aspergillus fumigatus/enzymology , Chitin/analogs & derivatives , Glycoside Hydrolases/isolation & purification , Glycoside Hydrolases/metabolism , Amino Acid Sequence , Aspergillus fumigatus/isolation & purification , Chitin/isolation & purification , Chitin/metabolism , Chitosan , Molecular Sequence Data , Peptide Fragments/isolation & purification , Peptide Fragments/metabolismABSTRACT
Halogenated analogues of neplanocin A were synthesized from the key intermediate 1, among which fluoro-neplanocin A was found to be novel mechanism-based irreversible inhibitor of S-Adenosylhomocysteine hydrolase.
Subject(s)
Adenosine/chemical synthesis , Adenosylhomocysteinase/adverse effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Adenosine/analogs & derivatives , Adenosine/chemistry , Adenosine/pharmacology , Indicators and Reagents , Kinetics , Models, Molecular , Molecular ConformationABSTRACT
Novel halovinyl analogues of neplanocin A without 4'-hydroxymethyl group were easily synthesized starting from D-ribose via cyclopentenone 5 as a key intermediate and their inhibitory activity against SAH hydrolase was assayed.
Subject(s)
Adenine/analogs & derivatives , Adenine/chemical synthesis , Adenosylhomocysteinase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Adenine/chemistry , Adenine/pharmacology , Adenosine/analogs & derivatives , Adenosine/chemistry , Adenosine/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
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 BombardmentABSTRACT
On the basis of inhibitory activity of truncated cyclopentenyl cytosine against S-adenosylhomocysteine hydrolase (SAH), its fluorocyclopentenyl pyrimidine derivatives were efficiently synthesized from D-ribose via electrophilic fluorination as a key step. The final nucleosides were evaluated for SAH inhibitory activity, among which the uracil derivative 9 showed significant inhibitory activity (IC(50) = 8.53 microM). They were also evaluated for cytotoxic effects in several human cancer cell lines such as fibro sarcoma, stomach cancer, leukemia, and colon cancer, but they did not show any cytotoxic effects up to 100 microM, indicating that 4'-hydroxymethyl groups are essential for the anticancer activity.
Subject(s)
Adenosylhomocysteinase/antagonists & inhibitors , Adenosylhomocysteinase/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Fluorine Compounds/chemical synthesis , Fluorine Compounds/chemistry , Fluorine Compounds/pharmacology , Humans , Pyrimidines/chemical synthesisABSTRACT
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 RelationshipABSTRACT
On the basis of potent anti-HCV activity of 2'-C-methyladenosine, novel 2'-C-hydroxymethyladenosine analogues 2a-c were synthesized from d-ribose in order to lead to favorable interaction with HCV polymerase. Among compounds tested, adenosine derivative 2a exhibited potent anti-HCV activity, indicating that the hydroxyl group of 2'-C-hydroxymethyl substituent led to favorable interaction with HCV polymerase.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/metabolism , Hepatitis C/drug therapy , Purine Nucleosides/chemical synthesis , Chemistry, Pharmaceutical/methods , DNA-Directed RNA Polymerases/chemistry , Drug Design , Models, Chemical , Purine Nucleosides/therapeutic use , RNA, Viral/chemistry , Ribonucleosides/chemistryABSTRACT
For the purpose of developing optimal neoceptor-neoagonist pair, 3'-ureidoadenosine derivatives were synthesized. Among compounds tested, 2-chloro-3'-ureido-N6-(3-iodobenzyl)adenosine (10b) showed the best binding affinity (Ki = 0.20 microM) at the H272E mutant A3 AR, but was inactive at the natural A3 AR.
Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/analogs & derivatives , Urea/analogs & derivatives , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine/metabolism , Mutation , Receptor, Adenosine A3/genetics , Urea/chemical synthesis , Urea/chemistry , Urea/metabolismABSTRACT
On the basis of the biological activity of neplanocin A and apio-dideoxyadenosine (apio-ddA), novel apio-neplanocin A analogues 5a-d, combining the properties of two nucleosides, were stereoselectively synthesized. The apio moiety of the target nucleosides 5a-d was stereoselectively introduced by treating lactol 10 with 37% formaldehyde in the presence of potassium carbonate. The carbasugar moiety of neplanocin A was successively built by exposing diene 12 on a Grubbs catalyst in methylene chloride. The final nucleosides 5a-d were synthesized from the condensation of the glycosyl donor 14 with nucleic bases under the standard Mitsunobu conditions. Similarly, apio-aristeromycin 6 and (N)-apio-methanocarbaadenosine 7 were derived from the common intermediate 13 using catalytic hydrogenation and Simmons-Smith cyclopropanation as key steps. All of the final nucleosides 5a-d, 6, and 7 did not show significant inhibitory activity against S-adenosylhomocysteine hydrolase (SAH) up to 100 muM, maybe due to the absence of the secondary hydroxyl group at the C3'-position, which should be oxidized by cofactor-bound NAD(+). However, apio-neplanocin A (5a) showed potent and highly selective binding affinity (K(i) = 628 +/- 69 nM) at the A(3) adenosine receptor without any binding affinity at the A(1) and A(2A) adenosine receptors. In conclusion, we have first developed novel carbocyclic nucleosides with unnatural apio-carbasugars using stereoselective hydroxymethylation and RCM reaction and also discovered a new template of human A(3) adenosine receptor agonist, which play a great role in developing new A(3) adenosine receptor agonist as well as in identifying the binding site of the receptor.
Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/analogs & derivatives , Adenosine/chemical synthesis , Adenosine/pharmacology , Adenosylhomocysteinase/antagonists & inhibitors , Combinatorial Chemistry Techniques , Enzyme Inhibitors/chemical synthesis , Adenosine/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Molecular Structure , Receptors, Purinergic P1ABSTRACT
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/chemistryABSTRACT
Fluoro-DHCeA (4) was efficiently synthesized from d-cyclopentenone derivative 5 using electrophilic fluorination as a key step. Fluoro-DHCeA (4) was found to be as potent as DHCeA (3), but exhibited irreversible inhibition of enzyme unlike DHCeA (3) showing reversible inhibition. From this study, 4(')-hydroxymethyl groups of neplanocin A and fluoro-neplanocin A played an important role in binding to the active site of the enzyme.
Subject(s)
Adenine/analogs & derivatives , Adenine/chemical synthesis , Adenine/pharmacology , Adenosylhomocysteinase/antagonists & inhibitors , Cyclopentanes/chemical synthesis , Cyclopentanes/pharmacology , Enzyme Inhibitors/pharmacology , Fluorine/chemistry , Adenine/chemistry , Cyclopentanes/chemistry , Magnetic Resonance SpectroscopyABSTRACT
Four 5'-substituted fluoro-neplanocin A analogues 1a-d were designed and synthesized, using cyclopentenone derivative 2 as a key intermediate. The inhibitory activity against SAH was in the following order: NH(2)>SH>F, N(3), indicating a hydrogen bonding donor such as OH or NH(2) was essential for inhibitory activity. All the final compounds showed much less decreased cytotoxicity in two cancer cell lines (Col2 and A549), implying that phosphorylation of the 5'-hydroxyl group of fluoro-neplanocin A is closely related to its high cytotoxicity.