J. Appl. Cryst.の発刊に際して

This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions and have added a new designation, “natural product botanical” or “NB”, to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74...

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Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010

The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

New polymer synthesis by nitroxide mediated living radical polymerizations.

Bone is a hierarchically structured material with remarkable mechanical performance which may serve as a model for the development of biomimetic materials. Understanding its properties is essential for the assessment of diseases such as osteoporosis. This will lead to a critical evaluation of current therapies and aid in their more targeted development. While the full hierarchical structure of bone is extremely complex and variable, its basic building block, the mineralized collagen fibril, is rather universal. Due to the progress in experimental methods to characterize materials at the nanoscale, new insights have been gained into the structure/mechanical function relation in this nanocomposite. The amount of mineral is usually thought to determine the stiffness of the material, but recent results suggest that the properties of the organic matrix as well as the geometrical arrangement of the two components might have a much larger influence on the properties than traditionally assumed. Some recent results from experiment and numerical modeling leading to these ideas are reviewed.

Structure and mechanical quality of the collagen–mineral nano-composite in bone

The addition of iodine fluoride to N6,N6-dibenzoyl-9-(5-deoxy-2,3-O-isopropy~idene-~-D-er~f~ro-pent-4-enofuranosyl)adenine (9) leads to the formation of the corresponding 5’-deoxy-4’-fluoro-5’-iodo nucleosides with the P-D-ribofuranosyl (10) and a-L-lyxofuranosyl (11) configurations. Nucleophilic displacement of the 5’-iodo functions was very difficult but could be accomplished with azide ion giving the 5’-azido-4’-fluoro nucleosides (18, Ma). Photolysis of the azides followed by mild hydrolysis and borohydride reduction gave the corresponding 4’-flUOrO nucleosides (20, 2Oa) which were converted to their sulfamoyl esters (22, 22a) by way of intermediate 5’-O-tributyltin (21, 21a, R = SnBuj ) derivatives. Following removal of protecting groups the nucleoside antibiotic nucleocidin (1) and its cu-L-lyxofuranosyl epimer la were isolated. Several alternative methods for conversion of the 5’-iodo function in 10 and 11 to the hydroxy counterparts (20,ZOa) were investigated and this could be accomplished by oxidation with silver(I1) oxide followed by borohydride reduction. A number of consistent rules were established for assignment of configuration to 4’-fluoro-2’,3’-O-isopropylidene nucleosides from their N M R spectra. A number of other reactions of the 4’-fluoro-5’-iodo nucleosides are also described and some comments concerning the facile cleavage of the pyrimidine ring in N6-acetyl-N3,5’-cycloadenosine derivatives are presented. The microorganism Streptomyces calvus, isolated from an Indian soil sample, was shown in 1957 to elaborate an antibiotic substance related to adenosine and referred to as nu~ l e o c i d i n . ~ This substance was shown to exhibit a rather broad antibacterial spectrum and to be particularly active against trypanosome^.^ Its practical use as either an antibiotic or antitrypanosomal agent is, however, seriously limited by its toxicity, the LD50 of nucleocidin in mice being 0.2 mg/kg via intramuscular or intraperitoneal admini~t ra t ion .~ Nucleocidin has been shown to be a highly potent inhibitor of protein biosynthesis, but its precise mechanism of action has not been clearly defined.5 Several partial and complete structures were proposed for nucleocidin,6 but not until 1969 was it realized that the empirical formula properly contained fluorine.’ With this realization it was possible, by use of N M R and mass spectrometry, to conclude that nucleocidin was correctly represented as 4’fluoro-5’-O-sulfamoyladenosine (1) or an isomer thereof.

4'-Substituted nucleosides. 2. Synthesis of the nucleoside antibiotic nucleocidin.

Exploiting C–H bond activation is difficult, although some success has been achieved using precious metal catalysts. Recently, it was reported that C–H bonds in aromatic heterocycles were converted to C–Si bonds by reaction with hydrosilanes under the catalytic action of potassium tert-butoxide alone. The use of Earth-abundant potassium cation as a catalyst for C–H bond functionalization seems to be without precedent, and no mechanism for the process was established. Using ambient ionization mass spectrometry, we are able to identify crucial ionic intermediates present during the C–H silylation reaction. We propose a plausible catalytic cycle, which involves a pentacoordinate silicon intermediate consisting of silane reagent, substrate, and the tert-butoxide catalyst. Heterolysis of the Si–H bond, deprotonation of the heteroarene, addition of the heteroarene carbanion to the silyl ether, and dissociation of tert-butoxide from silicon lead to the silylated heteroarene product. The steps of the silylation m...

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Ionic and Neutral Mechanisms for C–H Bond Silylation of Aromatic Heterocycles Catalyzed by Potassium tert-Butoxide

Collagenous peptides containing the Ehrlich chromogen (EC) were selectively isolated from a tryptic digest of bovine tendon by coupling to a diazotized polyacrylamide support. The isolated p-phenol-azo-EC peptides were purified and characterized by amino acid and sequence analyses. EC occurred in stoichiometric amounts in trimeric cross-linked chains originating from the known cross-link regions of type-I collagen. The major locus of the EC was alpha 2(I)Hyl-933 x alpha 1(I)Lys(Hyl)-9N x alpha 2(I)Lys(Hyl)-5N but it was also shown to occur at the loci alpha 1(I)Hyl-87 x alpha 1(I)Lys(Hyl)-16C x alpha 1(I)Lys(Hyl)-16C and alpha 1(I)Hyl-930 x alpha 1(I)Lys(Hyl)-9N x alpha 2(I)Lys(Hyl)-5N. After sequence analyses of the C-terminal helical cross-link region alpha 2(I)928-963, corrections are presented for residues 927, 930, 932 and 933 of the bovine alpha 2(I) chain. The collagen-associated EC is postulated to be a trisubstituted pyrrole formed by the reaction of the aldehyde form of a telopeptidyl lysine residue with a bifunctional keto amino cross-link. It is also proposed that when the telopeptidyl lysine residue is hydroxylated the above reaction will result in pyridinoline formation.

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Identification of the loci of the collagen-associated Ehrlich chromogen in type I collagen confirms its role as a trivalent cross-link

The mechanism of the Mitsunobu esterification reaction. Part I. The involvement of phosphoranes and oxyphosphonium salts

The aminoglycoside antibiotic neomycin B has been converted into several novel building blocks that can be used for the specific modification of three of the four ring systems. Under carefully controlled conditions, the Mitsunobu reaction can be used to selectively dehydrate the ido ring to give the talo epoxide. Subsequently however, under more forcing conditions, the 2-deoxy streptamine ring undergoes Mitsunobu dehydration to give an aziridine. An unusual remote neighboring group effect was observed. When the primary hydroxyl of the ribose ring was blocked, aziridine formation on the deoxystreptamine ring did not occur. Both the epoxide and epoxide-aziridine neomycin building blocks can be ring-opened with azide and subjected to "click" type chemistry with terminal alkynes to generate a series of new neomycin analogues. These reactions can all be carried out without recourse to O-protecting groups. A detailed conformational analysis by NMR revealed some unexpected conformer preferences in these systems.

Ian D. Jenkins

Papers

4'-Substituted nucleosides. 2. Synthesis of the nucleoside antibiotic nucleocidin.

Ionic and Neutral Mechanisms for C–H Bond Silylation of Aromatic Heterocycles Catalyzed by Potassium tert-Butoxide

Identification of the loci of the collagen-associated Ehrlich chromogen in type I collagen confirms its role as a trivalent cross-link

The mechanism of the Mitsunobu esterification reaction. Part I. The involvement of phosphoranes and oxyphosphonium salts

Multisite modification of neomycin B: combined Mitsunobu and click chemistry approach.