Synthesis of alpha-L-threofuranosyl nucleoside triphosphates (tNTPs)

[structure: see text] The alpha-l-threofuranosyl nucleoside triphosphates of T, G, and D (tTTP, tGTP, and tDTP) were synthesized from the described 2'-O-DMT-protected derivatives using the Eckstein method, while the corresponding C derivative (tCTP) was prepared from the 2'-O-acetyl derivative. The prepared alpha-l-threofuranosyl nucleoside triphosphates, despite being one carbon shorter than the native 2'-deoxyfuranosyl nucleoside triphosphates, are effective substrates for selected DNA polymerases.     

Synthesis of dinucleoside (N3'-->MeP5') methanephosphonamidates

[structure: see text] Three different approaches were used for the synthesis of dinucleoside methanephosphonamidates [3'-NH-P(O)(CH3)O-5'], starting from dichloromethylphosphine or dichloromethanephosphonate as the phosphorus-containing moiety. 5'-DMT-3'-amino-3'-deoxythymidine and N(4)-benzoyl-5'-DMT-3'-amino-2',3'-dideoxycytidine were used as the aminonucleoside precursors and the respective 3'-protected nucleosides (thymidine or N(4)-benzoyl-2'-deoxycytidine) as the 5'-hydroxyl reagents.     

Synthesis and characterization of sulfur-voided cubanes. Structural analogues for the MoFe(3)S(3) subunit in the nitrogenase cofactor.

A new class of Mo/Fe/S clusters with the MoFe(3)S(3) core has been synthesized in attempts to model the FeMo-cofactor in nitrogenase. These clusters are obtained in reactions of the (Cl(4)-cat)(2)Mo(2)Fe(6)S(8)(PR(3))(6) [R = Et (I), (n)Pr (II)] clusters with CO. The new clusters include those preliminarily reported: (Cl(4)-cat)MoFe(3)S(3)(PEt(3))(2)(CO)(6) (III), (Cl(4)-cat)(O)MoFe(3)S(3)(PEt(3))(3)(CO)(5) (IV), (Cl(4)-cat)(Pyr)MoFe(3)S(3)(PEt(3))(2)(CO)(6) (VI), and (Cl(4)-cat)(Pyr)MoFe(3)S(3)(P(n)Pr(3))(3)(CO)(4) (VIII). In addition the new (Cl(4)-cat)(O)MoFe(3)S(3)(P(n)Pr(3))(3)(CO)(5) cluster (IVa), the (Cl(4)-cat)(O)MoFe(3)S(3)(PEt(3))(2)(CO)(6)cluster (V), the (Cl(4)-cat)(O)MoFe(3)S(3)(P(n)Pr(3))(2)(CO)(6) cluster (Va), the (Cl(4)-cat)(Pyr)MoFe(3)S(3)(P(n)Pr(3))(2)(CO)(6) cluster (VIa), and the (Cl(4)-cat)(P(n)Pr(3))MoFe(3)S(3)(P(n)Pr(3))(2)(CO)(6) cluster (VII) also are reported. Clusters III-VIII have been structurally and spectroscopically characterized. EPR, zero-field (57)Fe-M?ssbauer spectroscopic characterizations, and magnetic susceptibility measurements have been used for a tentative assignment of the electronic and oxidation states of the MoFe(3)S(3) sulfur-voided cuboidal clusters. A structural comparison of the clusters with the MoFe(3)S(3) subunit of the FeMo-cofactor has led to the suggestion that the storage of reducing equivalents into M-M bonds, and their use in the reduction of substrates, may occur with the FeMo-cofactor, which also appears to have M-M bonding. On the basis of this argument, a possible N(2)-binding and reduction mechanism on the FeMoco-cofactor is proposed.     

Synthesis of chemically stabilized phosmidosine analogues and the structure--activity relationship of phosmidosine

Phosmidosine is known to have potent antitumor activity and the unique property of stopping cell growth at the G(1) phase in the cell cycle. However, this natural product having N-prolylphosphoramidate and O-methyl ester linkages on the 5'-phosphoryl residue is unstable under basic conditions and even during the chemical synthesis due to its inherent methyl transfer activity. To find stable derivatives of phosmidosine, a variety of phosmidosine analogues 1a-d replaced by longer alkyl groups in place of the methyl group on the phosphoramidate linkage were synthesized by reaction of alkyl N-(N-tritylprolyl)phosphorodiamidite derivatives 7a-d with an 8-oxoadenosine derivative 4 protected with acid-labile protecting groups. Consequently, the O-ethyl ester derivative 1b was found to be sufficiently stable in aqueous solution. When the prolyl group was replaced by other aminoacyl moieties, the reaction of N-tritylaminoacylamide derivatives 25a-d with an appropriately protected 8-oxoadenosine 5'-(ethyl phosphoramidite) derivative 9 gave better results than the above coupling reaction. A phosphoramidothioate derivative 17 and several simple compounds such as 11, 13, and 15 lacking partial structures of phosmidosine were also synthesized. The antitumor activities of these modified analogues were extensively studied to clarify the structure-activity relationship of phosmidosine. As a result, the two diastereoisomers of longer alkyl-containing phosmidosine analogues both proved to have similar antitumor activities. Replacement of l-proline with other l-amino acids or d-proline resulted in considerable decrease of the antitumor activity. The non-nucleotidic materials 13 did not show any antitumor activity, but a simple core compound of 11 exhibited weak cytotoxicity. The phosphoramidothioate derivative 17 maintained essentially a similar antitumor activity, but the efficiency decreased slightly.     

Synthesis and conformational analysis of novel N(OCH3)-linked disaccharide analogues

N(OMe)-linked disaccharide analogues, isosteric to the corresponding natural disaccharides, have been synthesized by chemoselective assembly of unprotected natural monosaccharides with methyl 6-deoxy-6-methoxyamino-alpha-D-glucopyranoside in an aqueous environment. The coupling reactions were found to be chemo- and stereoselective affording beta-(1-->6) disaccharide mimics when using Glc and GlcNAc; in the case of Gal, the beta-anomer was prevalent (beta:alpha=7:1). An iterative method for the synthesis of linear N(OMe) oligosaccharide analogues was demonstrated, based on the use of an unprotected monosaccharide building block in which an oxime functionality at C-6 is converted during the synthesis into the corresponding methoxyamino group. The conformational analysis of these compounds was carried out by using NMR spectroscopy, ab initio, molecular mechanics, and molecular dynamics methods. Optimized geometries and energies of fourteen conformers for each compound have been calculated at the B3LYP/6-31G* level. Predicted conformational equilibria were compared with the results based on NMR experiments and good agreement was found. It appears that N(OMe)-linked disaccharide analogues exhibit a slightly different conformational behavior to their parent natural disaccharides.     

Substrate specificity of an active dinuclear Zn(II) catalyst for cleavage of RNA analogues and a dinucleoside

The cleavage of the diribonucleoside UpU (uridylyl-3'-5'-uridine) to form uridine and uridine (2',3')-cyclic phosphate catalyzed by the dinuclear Zn(II) complex of 1,3-bis(1,4,7-triazacyclonon-1-yl)-2-hydroxypropane (Zn(2)(1)(H(2)O)) has been studied at pH 7-10 and 25 degrees C. The kinetic data are consistent with the accumulation of a complex between catalyst and substrate and were analyzed to give values of k(c) (s(-)(1)), K(d) (M), and k(c)/K(d) (M(-)(1) s(-)(1)) for the Zn(2)(1)(H(2)O)-catalyzed reaction. The pH rate profile of values for log k(c)/K(d) for Zn(2)(1)(H(2)O)-catalyzed cleavage of UpU shows the same downward break centered at pH 7.8 as was observed in studies of catalysis of cleavage of 2-hydroxypropyl-4-nitrophenyl phosphate (HpPNP) and uridine-3'-4-nitrophenyl phosphate (UpPNP). At low pH, where the rate acceleration for the catalyzed reaction is largest, the stabilizing interaction between Zn(2)(1)(H(2)O) and the bound transition states is 9.3, 7.2, and 9.6 kcal/mol for the catalyzed reactions of UpU, UpPNP, and HpPNP, respectively. The larger transition-state stabilization for Zn(2)(1)(H(2)O)-catalyzed cleavage of UpU (9.3 kcal/mol) compared with UpPNP (7.2 kcal/mol) provides evidence that the transition state for the former reaction is stabilized by interactions between the catalyst and the C-5'-oxyanion of the basic alkoxy leaving group.     

G3(MP2) ring strain in bicyclic phosphorus heterocycles and their hydrocarbon analogues

[Figure: see text] The ring strain present in 2-aza-1-phosphabicyclo[n.1.0]alka(e)nes (n = 1-5) is calculated at the G3(MP2) level using homodesmotic reactions. The influence of cyclopropa(e)nation and heteroatom substitution is analyzed by a comparison with the corresponding bicyclic hydrocarbons and separate ring systems. It is shown that the strain caused by fusion with a cyclopropane is the sum of the separate rings, whereas the strain resulting from fusion with cyclopropene leads to strain energies much larger than the sum of rings, as a result of the inverted nature of the bridgehead carbon. In all ring structures but one, cyclohexane, substitution by nitrogen and phosphorus is favorable and the effect is most pronounced for the most condensed structures. The calculated strain energies correlate very well with the experimental stability and reactivity of the bicyclic iron-amino phosphirane and phosphirene complexes.     

Synthesis and biological evaluation of (-)-laulimalide analogues

[reaction: see text] The syntheses of five laulimalide analogues are described, incorporating modifications at the C(16)-C(17)-epoxide, the C(20)-alcohol, as well as the C(1)-C(3)-enoate of the parent natural product. The resultant analogues are active in drug-sensitive HeLa and MDA-MB-435 cell lines. Significantly, like laulimalide, these analogues are poor substrates for the drug transport protein P-glycoprotein (Pgp) and are thus effective against Taxol-resistant cell lines.     

Synthesis of xyloketal A, B, C, D, and G analogues

A series of demethyl analogues of the natural products xyloketal A, B, C, D, and G have been prepared in a notably direct manner from 3-hydroxymethyl-2-methyl-4,5-dihydrofuran and a series of corresponding phenols. These syntheses featured a boron trifluoride diethyl etherate-promoted electrophilic aromatic substitution reaction as a key step. In the case of the synthesis of analogues of xyloketal A, the process was found to be highly efficient (up to 93% yield). The optimized isolated yield of these reaction products is remarkable in view of the fact that this transformation involves, minimally, six individual reactions. Moreover, these synthetic studies provide significant insight into the possible biogenic origin of the xyloketal natural products.     

Synthesis of 1-(2-ethyl-3-indolyl)-1-(3-pyridyl)ethylene and related ellipticine analogues

Indole, 2-methylindole, and 3-etliylindole have been condensed with acetyl- and propionylpyridine, respectively. When propionylpyridine was used as the reactant, the product always was a 1-(pyridyl)-1-indoly[propylene. Condensation of 2-substituted indoles with 3-acetylpyridine gave similar products, whereas a similar condensation with 4-acetylpyridine gave 1,2-bis(3-indolyl)-1-(4-pyridyl)ethanes (e.g. 7a ). Condensation of unsubstituted indole with 3-or 4-acetylpyridine respectively, gave 1,1-bis(3-indolyl)-1-(pyridyl)ethanes (e.g. 6c ).     

Antitumor agents. V. Synthesis and antileukemic activity of E-ring-modified (RS)-camptothecin analogues.

Several E-ring-modified analogues of (RS)-camptothecin were synthesized by total synthesis via Friedl?nder condensation and evaluated for cytotoxicity and antitumor activity against P388 mouse leukemia cells. Among them, (RS)-20-deoxyamino-7-ethyl-10-methoxycamptothecin (25c) was found to be more active than (RS)-camptothecin (1) in the in vivo assay.     

Synthesis of enzymatically crosslinkable peptide-poly(L-lysine) conjugate and creation of bio-inspired hybrid fibers

Poly(L-lysine)s having an Nepsilon-substituted tetrapeptide, Lys-Gly-Tyr-Gly, were synthesized by the coupling of the protected tetrapeptide active ester, Boc-Lys(Z)-Gly-Tyr(Bzl)-Gly (4-hydroxyphenyl)dimethylsulfonium methylsulfate and Nepsilon-group of the poly(L-lysine) side chain. The Nepsilon-substituted tetrapeptide functions as the substrate of tyrosinase and is responsible for the enzyme-mediated interpolymer cross-linking. The degree of Nepsilon-substitution (DS) was mostly controlled by changing the stoichiometry between the Nepsilon-amino groups of the parent poly(L-lysine) and the protected tetrapeptide active ester. Two kinds of samples having DS values of 8.6 and 18 mol-% were prepared. The resulting cationic Nepsilon-(Lys-Gly-Tyr-Gly)-poly(L-lysine) (abbreviated as PLL(GYGK)) was spun into hybrid fibers with the anionic polysaccharide gellan via a polyionic complexation reaction at the interface between aqueous solutions of the two polymers. The mechanical strengths of the PLL(GYGK)-gellan hybrid fibers were superior to those of the original poly(L-lysine)-gellan fibers. The mechanical strength of the hybrid fibers further increased upon the tyrosinase-mediated cross-linking reaction of the PLL(GYGK). This result indicates that the covalent cross-bridge formation between the Nepsilon-substituted peptides significantly contributed to reinforcement of the hybrid fibers. The present study affords a new methodology for reinforcement inspired by a biological process.     

Synthesis of psoralens and analogues.

This review presents briefly the various classical syntheses of psoralens and angelicins which generally start from preformed suitably substituted coumarin or benzofuran derivatives. However, the discovery of the photocyclo-C-4 addition of psoralens to pyrimidine bases prompted new developments in this area. In particular, improved synthesis of psoralens and substituted angelicins, and synthesis of new analogues such as furochromenes, pyridopsoralens, pyrano benzopyrandiones, dioxinocoumarins and aza-psoralens were described recently. This review focuses on the chemical syntheses of these various compounds.