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Microwave irradiation of 2-alkynyl-5-(phenyl or alkyl)tetrazoles affords 2-(phenyl or alkyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles via intramolecular [3+2] cyclization of nitrile-imine intermediates. In the present method, the use of 5-alkyltetrazoles as the starting materials is more advantageous because of the difficulties associated with conventional photoreactions. From 2-phenylalkynyl-5-methylthio-1H-tetrazoles, the reaction efficiently produces 2-methylthio-3-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. The procedure using the methylthio group is applied to the total synthesis of three naturally occurring withasomnines. The method is also extended to the construction of molecules in which bicyclic pyrazoles are fused to six- to eight-membered rings.

Chiral high-performance liquid chromatography (HPLC) analysis of natural pericosine A, which appeared in literature first in 1977, from Periconia byssoides was conducted using a column CHIRALPAK® AD-H to determine the enantiomeric composition of the original mixture which was found to be 68: 32 mixtures of (+)- and (-)-enantiomer, respectively. Furthermore, two independently isolated samples of pericosine A from the same fungus were also analyzed to show the two peaks in the HPLC charts at approximate 1:1 ratio. These results concluded that pericosine A derived from Periconia byssoides was indeed an enantiomeric mixture. Synthesized enantiomers were subjected to evaluation of antitumor activity against three kinds of tumor cells (p388, L1210, HL-60), indicating moderate cytotoxicity against all three kinds of tumor cell lines, but significant difference in potency between the enantiomers was not observed. In contrast, when both the enantiomers of pericosine A were evaluated against five kinds of glycosidases-inhibitory activities (α- and β-glucosidases, α- and β-galactosidases, and α-mannosidase), an apparent difference on anti-glycosidase assay was found between the enantiomers: (-)-pericosine A inhibited α-glucosidase at IC

Novel reactions using hetero-heavy atoms (P, S, Si, Se, and Sn) were developed and applied to the synthesis of biofunctional molecules and some medicine-candidates, in which the following items are covered. 1) Development of introduction of C1-unit using cyanophosphates (CPs). 2) Carbene-generation under neutral condition from CPs and its application to organic synthesis. 3) [3,3]Sigmatropic rearrangement-ring expansion reactions of medium-sized cyclic thionocarbonates containing a sulfur atom and their application to natural product synthesis. 4) Stereoselective synthesis of novel β-imidazole C-nucleosides via diazafulvene intermediates and their application to investigating ribozyme reaction mechanism. 5) Developments of novel histamine H3- and H4-receptor ligands using new synthetic methods involving Se or Sn atoms.

In this data file, the synthetic procedures for the preparation of a series of anticancer tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)]n+ (n = 1 or 2, tetrazolato-bridged complexes)) and of the bridging ligands of 5-substituted 1H-tetrazoles (5-R-1H-tetrazoles) are described. These compounds were characterized by 1H-, 13C-, 19F- and 195Pt-NMR spectroscopy and mass spectrometry.

We describe the use of allylic rearrangements of cyanophosphates for the efficient and practical synthesis of 3-(tetrazol-5-yl)-3,5-pregnadien-20-one, which is a potent 5α-reductase inhibitor (IC50: 15.6 nM), from pregnene-3,20-dione in 92% overall yield in four steps.

Alkylamino coupling reactions at the C4 positions of 4-halo-1H-1-tritylpyrazoles were investigated using palladium or copper catalysts. The Pd(dba)2 catalyzed C-N coupling reaction of aryl- or alkylamines, lacking a &beta, hydrogen atom, proceeded smoothly using tBuDavePhos as a ligand. As a substrate, 4-Bromo-1-tritylpyrazole was more effective than 4-iodo or chloro-1-tritylpyrazoles. Meanwhile, the CuI mediated C-N coupling reactions of 4-iodo-1H-1-tritylpyrazole were effective for alkylamines possessing a &beta, hydrogen atom.

Abstact We recently reported a novel synthetic method for five-membered unsaturated cyclic compounds from ketones involving cyanophosphates (CPs) under neutral conditions, in which alkylidene carbenes generated through tetrazole-fragmentation undergo [1,5]-C H insertions to produce the target compounds. The present paper describes the use of the tetrazole-fragmentation from CPs for the efficient and practical syntheses of (−)-neplanocin A and a protected tetrol, the latter of which is an important synthetic precursor of both (−)-neplanocin A and its analogues. Furthermore, formation of an unusual dihydropyran derivative was observed during the synthetic study of the tetrol.

Cyanophosphates (CPs) can easily be prepared via the reactions of carbonyl compounds with diethyl phosphorocyanidate (DEPC) in the presence of LiCN (cat.) under non-aqueous conditions. Treatment of ketone-derived CPs with TMSN 3 /Bu 2 SnO (cat.) in toluene at reflux produces cyclopentenes or heterocyclic products in good yields under neutral conditions. In this two-step transformation, CPs may form tetrazolylphosphates, which subsequently undergo successive fragmentation to generate alkylidene carbenes, which undergo [1,5]-C–H insertions to yield five membered compounds.

Derivatives of the highly antitumor-active compound [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)]2+ (5-H-Y), which is a tetrazolato-bridged dinuclear platinum(II) complex, were prepared by substituting a linear alkyl chain moiety at C5 of the tetrazolate ring. The general formula for the derivatives is [{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)]2+, where R is (CH2)nCH3 and n = 0 to 8 (complexes 1–9). The cytotoxicity of complexes 1–4 in NCI-H460 human non-small-cell lung cancer cells decreased with increasing alkyl chain length, and those of complexes 5–9 increased with increasing alkyl chain length. That is, the in vitro cytotoxicity of complexes 1–9 was found to have a U-shaped association with alkyl chain length. This U-shaped association is attributable to the degree of intracellular accumulation. Although circular dichroism spectroscopic measurement indicated that complexes 1–9 induced comparable conformational changes in the secondary structure of DNA, the tetrazolato-bridged complexes induced d...

Tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH3)2}2(&mu, OH)(&mu, 5-R-tetrazolato-N2,N3)]2+, tetrazolato-bridged complexes) are a promising source of next-generation platinum-based drugs. &beta, Cyclodextrin (&beta, CD) forms inclusion complexes with bulky organic compounds or substituents, changing their polarity and molecular dimensions. Here, we determined by 1H-NMR spectroscopy, the stability constants for inclusion complexes formed between &beta, CD and tetrazolato-bridged complexes with a bulky, lipophilic substituent at tetrazole C5 (complexes 1&ndash, 3, phenyl, n-nonyl, and adamantyl substitution, respectively). We then determined the in vitro cytotoxicity and in vivo antitumor efficacy of complexes 1&ndash, 3 against the Colon-26 colorectal cancer cell line in the absence or presence of equimolar &beta, CD. Compared with the platinum-based anticancer drug oxaliplatin (1R,2R-diaminocyclohexane)oxalatoplatinum(II)), complex 2 had similar cytotoxicity, complex 3 was moderately cytotoxic, and complex 1 was the least cytotoxic. The cytotoxicity of the complexes decreased in the presence of &beta, CD. When we examined the in vivo antitumor efficacy of complexes 1&ndash, 3 (10 mg/kg) against homografted Colon-26 colorectal tumors in male BALB/c mice, they showed a relatively low tumor growth inhibition compared with oxaliplatin. However, in the presence of &beta, CD, complex 3 had higher in vivo antitumor efficacy than oxaliplatin, suggesting a new direction for future research into tetrazolato-bridged complexes with high in vivo antitumor activity.

Three types of pyrazole-fused heterobicycles, i.e., 1,5-, 1,7-, and 2,5-dihydropyrano[3,2-c]pyrazoles, were synthesized from 4-allyloxy-1H-pyrazoles. A sequence of the Claisen rearrangement of 4-allyloxy-1H-pyrazoles, ruthenium-hydride-catalyzed double bond migration, O-allylation, and ring-closing metathesis was employed in this study.

The reaction of cyanophosphates, which are readily derived from γ-ketoaldehyde acetals, with TMSN3 (3 eq)/Bu2SnO (0.3 eq) in refluxing toluene directly furnished 3-substituted-2-cyclopentenones in modest to good yield under mild conditions. The present method was further applied toward the synthesis of dechlorotrichodenone C isolated from Trichoderma asperellum.

S-Alkyl-N-alkylisothiourea compounds, which contain various cyclic amines, were synthesized using 3-phenylpropionyl isothiocyanate (PPI) to discover novel non-imidazole histamine H3 receptor (H3R) antagonists. The synthetic route was improved remarkably by using 2-nitrophenylacetyl isothiocyanate (NPAI). Among the synthesized compounds, N-[4-(4-chlorophenyl)butyl]-S-[3-piperidin-1-yl)propyl]isothiourea (1k, OUP-186) exhibited potent and selective antagonism against human H3R but not human H4R, in vitro. Of particular interest, they did not show antagonism for the histamine release in rat brain microdialysis in vivo, suggesting species-selective differences in antagonist affinities. Furthermore, in silico docking studies of OUP-186 and its C2-homolog (OUP-181) in human/rat H3Rs suggested that the structural difference of antagonist-docking sites between human and rat H3Rs was attributable to the Ala122/Val122 mutation.

3,5-Disubstituted 4-fluoroisoxazole, 4,4,5-trifluoroisoxazoline and 4,4-difluoro-5-hydroxyisoxazoline products were obtained from reaction of the corresponding isoxazoles with Selectfluor™ depending upon the reaction conditions. Although the fluorinations proceeded using conventional heating, microwave (μW) irradiation considerably shortened reaction times and enabled a high yielding one-pot cascade fluorination-cyclization from simple diketone substrates. In addition, a related 4-fluoroisoxazole-3-carboxyamide derivative was synthesized.

A novel synthetic method for the preparation of 2,4-disubstituted oxazoles was developed, entailing the reaction of dibutyltin diacylates Bu2Sn[OC(O)R]2 with 1-substituted acetylenes and TMSN3 to afford a range of 2,4-disubstituted oxazoles in good yields.

Inspired by the significant -glucosidase inhibitory activities of (+)- and (&minus, )-pericosine E, we herein designed and synthesized 16 analogs of these marine natural products bearing a methoxy group instead of a chlorine atom at C6. Four of these compounds exhibited moderate -glucosidase inhibitory activities, which were weaker than those of the corresponding chlorine-containing species. The four compounds could be prepared by coupling reactions utilizing the (&minus, )-pericosine B moiety. An additional in silico docking simulation suggested that the reason of reduced activity of the C6-methoxylated analogs might be an absence of hydrogen bonding between a methoxy group with the surrounding amino acid residues in the active site in -glucosidase.

Treatments of various nitriles with TMSN3 and Bu2Sn(OAc)2 at 30 °C in benzene for 60 h yielded the corresponding 5-substituted 1H-tetrazoles in good to excellent yields. This method is a mild and efficient alternative reagent system for Wittenberger tetrazole-synthesis that uses TMSN3 and Bu2SnO in toluene at high temperature (93–110 °C) for 24–72 h.

Three types of pyrazole-fused heterobicycles, i.e., 1,5-, 1,7-, and 2,5-dihydropyrano[3,2-c]pyrazoles, were synthesized from 4-allyloxy-1H-pyrazoles. A sequence of the Claisen rearrangement of 4-allyloxy-1H-pyrazoles, ruthenium-hydride-catalyzed double bond migration, O-allylation, and ring-closing metathesis was employed in this study.

We synthesized and characterized 15 new derivatives of the highly anticancer-active platinum(II) complex [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)]2+ (5-H-Y) by making substitutions at tetrazole C5. We then evaluated the comprehensive structure-cytotoxicity relationships of a total of 23 derivatives in two murine lymphocytic leukaemia cell lines, sensitive and resistant to cisplatin. We also report the in vivo antitumor efficacy of three ester derivatives, two of which exhibited much higher efficacy than oxaliplatin against mouse homografted Colon-26 colorectal tumor.

Synthesis of novel pyrazole-fused heterocycles, i.e., dihydro-1H- or 2H-oxepino[3,2-c]pyrazoles (6 or 7) from 4-allyloxy-1H-pyrazoles (1) via combination of Claisen rearrangement and ring-closing metathesis (RCM) has been achieved. A suitable catalyst for the RCM of 5-allyl-4-allyloxy-1H-pyrazoles (4) was proved to be the Grubbs second generation catalyst (Grubbs2nd) to give the predicted RCM product at room temperature in three hours. The same reactions of the regioisomer, 3-allyl-4-allyloxy-1H-pyrazoles (5), also proceeded to give the corresponding RCM products. On the other hand, microwave aided RCM at 140 °C on both of 4 and 5 afforded mixtures of isomeric products with double bond rearrangement from normal RCM products in spite of remarkable reduction of the reaction time to 10 min.

A potent histamine H3 receptor antagonist OUP-186 with an S-alkyl-N-alkylisothiourea structure was synthesized using 3-phenylpropanoyl isothiocyanate (PPI) as an SCN source. The synthetic route was significantly improved by replacing 3-phenylpropanoyl isothiocyanate with 2-nitrophenylacetyl isothiocyanate (NPAI), giving a 74% overall yield in three steps from 4-(4-chlorophenyl)butylamine. In addition, the 2-nitrophenylacetyl isothiocyanate method successfully yielded two fluorine-containing analogues, and a shorter, C2 homologue of OUP-186.

Cyanophosphates (CPs) can be easily prepared from either ketones or aldehydes, and their reaction with NaN3–Et3N·HCl results in the formation of azidotetrazoles. Under microwave irradiation, successive fragmentation of the azidotetrazoles generates alkylidene carbenes that undergo [1,2]-rearrangement and are transformed into homologous alkynes. Treatment of ketone-derived CPs with TMSN3 and Bu2SnO as catalyst in toluene at reflux directly yields the corresponding internal alkynes, whereas the reaction of aldehyde-derived CPs with NaN3–Et3N·HCl in THF at reflux or TMSN3–Bu2SnO (cat.) in toluene at reflux provides homologous terminal alkynes in good yields. These reactions take place under neutral conditions and can be successfully extended to obtain alkynes that are not usually accessible from the corresponding carbonyl compounds by the Ohira–Bestmann or Shioiri procedures, which require basic conditions.

Pericosine E (6), a metabolite of Periconia byssoides OUPS-N133 was originally isolated from the sea hare Aplysia kurodai, which exists as an enantiomeric mixture in nature. The enantiospecific syntheses of both enantiomers of Periconia byssoides OUPS-N133 has been achieved, along with six stereoisomers, using a common simple synthetic strategy. For these efficient syntheses, highly regio- and steroselective processes for the preparation of bromohydrin and anti-epoxide intermediates were applied. In order to access the unique O-linked carbadisaccharide structure, coupling of chlorohydrin as a donor and anti-epoxide as an acceptor was achieved using catalytic BF3·Et2O. Most of the synthesized compounds exhibited selectively significant inhibitory activity against α-glycosidase derived from yeast. The strongest analog showed almost 50 times the activity of the positive control, deoxynojirimycin.

The synthesis of C4-linked imidazole C 0 - and C 2 -2′-deoxyribonucleoside phosphoramidites (dPAs), in which the final phosphitylations are greatly improved by 4,5-dicyanoimidazole-promoted conversion, is described. The respective dPAs are successfully incorporated into the sequence of a 15-nt DNA, and the abilities of one or two imidazoles to pair with different bases are investigated through thermal melting ( T m ) experiments on the resulting DNA duplexes. Furthermore, computational models of the imidazole-modified DNAs are found to be in good agreement with the results of the thermal melting experiments.

The first synthesis of (-)-pericosine E (6), a metabolite of the Periconia byssoides OUPS-N133 isolated originally from the sea hare Aplysia kurodai, has been achieved. Efficient and regioselective synthetic procedures for the synthesis of key intermediates, anti- and syn-epoxides 9 and 10, were developed using an anti-epoxidation of diene 12 with TFDO and a bromohydrination of 12 with NBS in CH(3)CN/H(2)O (2:3), respectively. In addition, comparison of the specific optical rotations between synthetic 6 and natural 6 elucidated that the naturally preferred enantiomer of pericosine E had the same absolute configuration as (-)-6 synthesized from chlorohydrin (-)-8 and anti-epoxide (+)-9.

Nucleoside phosphoramidites (PAs) are the most widely used building blocks in the contemporary solid-phase synthesis of oligonucleotides. Accurate molecular weight measurements of such acid-labile compounds may be easily determined in a matrix system comprising triethanolamine (TEOA)-NaCl by liquid secondary ionization mass spectrometry (LSIMS) or fast atom bombardment mass spectrometry (FABMS), using a double-focusing mass spectrometer. The present method rapidly and easily measures the accurate MWs of various PAs as adduct ions [M+Na]⁺, affording molecular formulas in place of elemental analysis. Further, the intensities by LSIMS of [M+Na]⁺ were found to be enhanced to the highest degree by adjustment of the mole ratio of PA and NaCl, fixing the amount of TEOA. In addition, the effects of the metal ion in the matrix were investigated. The present method is a powerful tool for the mass spectral identification of polyfunctionalized nucleoside PAs.

Efficient transformations of inactive nitriles into 5-substituted 1H-tetrazoles in DMF in a microwave reactor are described. The present method is applied to the synthesis of tetrazolato-bridged dinuclear platinum(II) complex and tetrazole C1-ribonucleoside phosphoramidite.

Histamine is involved in various physiological functions, including its neurotransmitter actions in the central nervous system and its action as a causative agent of inflammation, allergic reactions, and gastric acid secretions. Histamine expression and biosynthesis have been detected in breast cancer cells. It was recently suggested that the histamine H

Novel C5-linked C0- and C2-tetrazole ribonucleoside phosphoramidites were designed and synthesized via tetrazole C-nucleosides. Pivaloyloxymethyl (POM) and methyl-substituted POM (MePOM) groups were introduced as N-protecting groups in the tetrazole ring that can be readily removed under mild basic conditions. The phosphoramidites were successfully incorporated into the VS ribozyme substrate and hence providing a chemogenetic approach to determine which nucleobases of ribozymes function as the acid or base, in the studies of ribozyme general acid and base catalysis.

The divergent synthesis of natural withasomnines and analogues was achieved from 4-hydroxypyrazoles, which was prepared via alkaline hydrolysis of the Baeyer-Villiger oxidation products from 4-formylpyrazoles. Key steps of this synthesis are regioselective Claisen rearrangement of 4-allyloxypyrazoles and the Suzuki-Miyaura coupling of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl trifluoromethanesulfonate and commercially available arylboronic acids. The Suzuki-Miyaura coupling at the final step of this strategy enabled facile access to natural withasomnines and their analogues. The biological activities of the twelve synthesized compounds against cyclooxygenases-1 and -2 (COX-1 and COX-2) were evaluated.

The synthesis of a novel C4-linked C2-imidazole ribonucleoside phosphoramidite (ICN-C2-PA 1) with a two-carbon linker between imidazole and ribose moieties is described. In the phosphoramidite, POM and 2-cyanoethyl groups were selected to protect the endocyclic amine function of imidazole and the 2'-hydroxyl function of D-ribose, respectively. The C2-imidazole nucleoside, a flexible structural mimic of a purine nucleobase, was successfully incorporated using ICN-C2-PA 1 into position 638 of the VS ribozyme through 2'-TBDMS chemistry to study the role of G638 in general acid-base catalysis. The modified VS ribozyme (G638C2Imz) exhibited significantly greater catalytic activity than observed with the C0-imidazole that has no carbon atoms linking the ribose and the C4-imidazole. Imidazole nucleoside analogues with variable spacer lengths could provide a valuable general methodology for exploring the catalytic mechanisms of ribozymes.

The (2R,5S)-trans- and (2S,5S)-cis-stereoisomers 1a and 1b of 4(5)-(5-aminotetrahydropyran-2-yl)imidazole, which have two chiral centers and adopt a stable chair conformation, were synthesized via cyclization of diol intermediates 7 using L-glutamine as the starting material. Their enantiomers, (2S,5R)-trans-1c and (2R,5R)-cis-1d, were synthesized by the same methodology from D-glutamine. Stereo isomers 1a-d were converted into cyanoguanidines 11a-d, and into N-isopropyl and N-3,3-dimethylbutyl derivatives 12a-d and 13a-d, respectively. The results of in vivo brain microdialysis of the derivatives apparently indicated that only (2S,5R)-isomers increased the release of neuronal histamine. Among the many (2S,5R)-N-alkyl derivatives, 13c (OUP-133) and 18 (OUP-153) increased histamine release to 180-190% and 180-200% of basal levels, respectively, and were found to be novel histamine H(3) antagonists.

The nucleolytic ribozymes catalyse site-specific phosphodiester cleavage and ligation transesterification reactions in RNA. The hairpin ribozyme folds to generate an intimate loop-loop interaction to create the local environment in which catalysis can proceed. We have studied the ion-induced folding using single-molecule FRET experiments, showing that the four-way helical junction accelerates the folding 500-fold by introducing a discrete intermediate that juxtaposes the loops. Using FRET we can observe individual hairpin ribozyme molecules as they undergo multiple cycles of cleavage and ligation, and measure the rates of the internal reactions, free of uncertainties in the contributions of docking and substrate dissociation processes. On average, the cleaved ribozyme undergoes several docking-undocking events before a ligation reaction occurs. On the basis of these experiments, we have explored the role of the nucleobases G8 and A38 in the catalysis. Both cleavage and ligation reactions are pH dependent, corresponding to the titration of a group with pKa=6.2. We have used a novel ribonucleoside in which these bases are replaced by imidazole to investigate the role of acid-base catalysis in this ribozyme. We observe significant rates of cleavage and ligation, and a bell-shaped pH dependence for both.

3(5)-(β-D-Ribofuranosyl)pyrazole 1 and 3(5)-(2-deoxyβ-D-ribofuranosyl)pyrazole (2) were stereoselectively synthesized by cyclization of 1,2-diazafulvene intermediates obtained from 2,3,5-tri-O-benzyl-D-ribose (5) and 3,5-di-O-benzyl-2-deoxy-D-ribose (10), respectively.