Synthesis of the Cyclopentyl Nucleoside (−)‐Neplanocin A from D‐Glucose via Zirconocene‐Mediated Ring Contraction

Two approaches for the conversion of d‐ glucose to (?) ‐neplanocin A ( 2 ), both based on the zirconocene‐promoted ring contraction of a vinyl‐substituted pyranoside, are herein evaluated (Scheme 1). In the first pathway (Scheme 2), the substrate possesses the α‐d‐ allo configuration (see 6 ) such that ultimate introduction of the nucleobase would require only an inversion of configuration. However, this precursor proved unresponsive to Cp₂Zr (=[ZrCl₂(Cp)₂]), an end result believed to be a consequence of substantive nonbonded steric effects operating in a key intermediate (Scheme 5). In contrast, the C(2) epimer (see 7 ) experienced the desired metal‐promoted conversion to an enantiomerically pure polyfunctional cyclopentane (see 5 in Scheme 3). The substituents in this product are arrayed in a manner such that conversion to the target nucleoside can be conveniently achieved by a double‐inversion sequence (Scheme 4). Recourse to palladium(0)‐catalyzed allylic alkylation did not provide an alternate means of generating 2 .     

Pin1 and Par14 peptidyl prolyl isomerase inhibitors block cell proliferation

Disruption of the parvulin family peptidyl prolyl isomerase (PPIase) Pin1 gene delays reentry into the cell cycle when quiescent primary mouse embryo fibroblasts are stimulated with serum. Since Pin1 regulates cell cycle progression, a Pin1 inhibitor would be expected to block cell proliferation. To identify such inhibitors, we screened a chemical compound library for molecules that inhibited human Pin1 PPIase activity in vitro. We found a set of compounds that inhibited Pin1 PPIase activity in vitro with low microM IC50s and inhibited the growth of several cancer lines. Among the inhibitors, PiB, diethyl-1,3,6,8-tetrahydro-1,3,6,8-tetraoxobenzo[lmn] phenanthroline-2,7-diacetate ethyl 1,3,6,8-tetrahydro-1,3,6,8-tetraoxo-benzo[lmn] phenanthroline-(2H,7H)-diacetate, had the least nonspecific toxicity. These results suggest that Pin1 inhibitors could be used as a novel type of anticancer drug that acts by blocking cell cycle progression.     

Sulfobetaine zwitterionomers based on n‐butyl acrylate and 2‐ethoxyethyl acrylate: Monomer synthesis and copolymerization behavior

New materials with potential applications for adhesives and coatings, based on copolymers containing zwitterionic pendent groups, were investigated. n‐Butyl acrylate and 2‐ethoxyethyl acrylate were copolymerized with a series of five zwitterionic sulfobetaine monomers. The structure of the monomers was varied in terms of the zwitterion intercharge spacing and the bulkiness of the alkyl substituents at the quaternary ammonium unit. Four of the five zwitterionic sulfobetaine methacrylate (SBM) monomers used in the study were synthesized. An evaluation of the reactivity ratios for the copolymer systems was performed with programs based on statistically sound techniques such as the error‐in‐variables model and the nonlinear‐least‐squares method. Reactivity ratio estimates for all 10 comonomer pairs were obtained, and they showed clear variations in reactivity with the structure of the SBM. In general, the more hydrophobic the SBM was, the lower its reactivity was with respect to the acrylate monomers. © 2002 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 40: 511–523, 2002; DOI 10.1002/pola.10138     

Photoaffinity labeling of the N-methyltransferase domains of cyclosporin synthetase

The multifunctional polypeptide cyclosporin synthetase (CySyn) remains one of the most complex nonribosomal peptide synthetase described. In this study we used a highly specific photoaffinity labeling procedure with the natural cofactor S-adenosyl-L-methionine (AdoMet), 14C-isotopically labeled at the Sdelta methyl group to probe the concerted AdoMet-binding interaction of the N-methyltransferase (N-MTase) centers of CySyn. The binding stoichiometry for the enzyme-AdoMet complex was determined to be 1:7, which is in agreement with inferences made from analysis of the complementary DNA sequence of the simA gene encoding the CySyn polypeptide. The photolabeling of the AdoMet-binding sites displayed homotropic negative cooperativity, characterized by a curvilinear Scatchard plot with upward concavity. Although, the process of N-methyl transfer is not a critical event for peptide elongation, the destabilizing homotropic interactions between N-MTase centers that were observed may represent a mechanism whereby the enzyme preserves the proficiency of the substrate-channeling process of cyclosporin peptide assembly over a broad range of cofactor concentrations. Furthermore, we demonstrated the utility of the photolabeling procedure for tracking the enzyme during purification.     

Titanium(IV) and zirconium(IV) sulfato complexes containing the Kläui tripodal ligand: molecular models of sulfated metal oxide surfaces

Treatment of titanyl sulfate in about 60 mM sulfuric acid with NaL(OEt) (L(OEt) (-)=[(eta(5)-C(5)H(5))Co{P(O)(OEt)(2)}(3)](-)) afforded the mu-sulfato complex [(L(OEt)Ti)(2)(mu-O)(2)(mu-SO(4))] (2). In more concentrated sulfuric acid (>1 M), the same reaction yielded the di-mu-sulfato complex [(L(OEt)Ti)(2)(mu-O)(mu-SO(4))(2)] (3). Reaction of 2 with HOTf (OTf=triflate, CF(3)SO(3)) gave the tris(triflato) complex [L(OEt)Ti(OTf)(3)] (4), whereas treatment of 2 with Ag(OTf) in CH(2)Cl(2) afforded the sulfato-capped trinuclear complex [{(L(OEt))(3)Ti(3)(mu-O)(3)}(mu(3)-SO(4)){Ag(OTf)}][OTf] (5), in which the Ag(OTf) moiety binds to a mu-oxo group in the Ti(3)(mu-O)(3) core. Reaction of 2 in H(2)O with Ba(NO(3))(2) afforded the tetranuclear complex (L(OEt))(4)Ti(4)(mu-O)(6) (6). Treatment of 2 with [{Rh(cod)Cl}(2)] (cod=1,5-cyclooctadiene), [Re(CO)(5)Cl], and [Ru(tBu(2)bpy)(PPh(3))(2)Cl(2)] (tBu(2)bpy=4,4'-di-tert-butyl-2,2'-dipyridyl) in the presence of Ag(OTf) afforded the heterometallic complexes [(L(OEt))(2)Ti(2)(O)(2)(SO(4)){Rh(cod)}(2)][OTf](2) (7), [(L(OEt))(2)Ti(O)(2)(SO(4)){Re(CO)(3)}][OTf] (8), and [{(L(OEt))(2)Ti(2)(mu-O)}(mu(3)-SO(4))(mu-O)(2){Ru(PPh(3))(tBu(2)bpy)}][OTf](2) (9), respectively. Complex 9 is paramagnetic with a measured magnetic moment of about 2.4 mu(B). Treatment of zirconyl nitrate with NaL(OEt) in 3.5 M sulfuric acid afforded [(L(OEt))(2)Zr(NO(3))][L(OEt)Zr(SO(4))(NO(3))] (10). Reaction of ZrCl(4) in 1.8 M sulfuric acid with NaL(OEt) in the presence Na(2)SO(4) gave the mu-sulfato-bridged complex [L(OEt)Zr(SO(4))(H(2)O)](2)(mu-SO(4)) (11). Treatment of 11 with triflic acid afforded [(L(OEt))(2)Zr][OTf](2) (12), whereas reaction of 11 with Ag(OTf) afforded a mixture of 12 and trinuclear [{L(OEt)Zr(SO(4))(H(2)O)}(3)(mu(3)-SO(4))][OTf] (13). The Zr(IV) triflato complex [L(OEt)Zr(OTf)(3)] (14) was prepared by reaction of L(OEt)ZrF(3) with Me(3)SiOTf. Complexes 4 and 14 can catalyze the Diels-Alder reaction of 1,3-cyclohexadiene with acrolein in good selectivity. Complexes 2-5, 9-11, and 13 have been characterized by X-ray crystallography.     

Efficient synthesis of 3-oxygenated benzothiophene derivatives

An efficient synthesis of 2-bromo-3-aryloxybenzothiophene derivatives by a conjugate addition-elimination sequence of 2,3-dibromo benzothiophene dioxides with phenolic nucleophiles has been developed. These benzothiophene derivatives serve as important intermediates for the synthesis of SERM analogues.     

Tracking radical migration in large hydrogen deficient peptides with covalent labels: Facile movement does not equal indiscriminate fragmentation

Photodissociation of iodo-tyrosine modified peptides yields localized radicals on the tyrosine side chain, which can be further dissociated by collisional activation. We have performed extensive experiments on model peptides, RGYALG, RGYG, and their derivatives, to elucidate the mechanisms underlying backbone fragmentation at tyrosine. Neither acetylation nor deuteration of the tyrosyl phenolic hydrogen significantly affects backbone fragmentation. However, deuterium migration from the tyrosyl β carbon is concomitant with cleavage at tyrosine. Substitution of tyrosine with 4-hydroxyphenylglycine, which does not have β hydrogens, results in almost complete elimination of backbone fragmentation at tyrosine. These results suggest that a radical situated on the β carbon is required for a-type fragmentation in hydrogen-deficient radical peptides. Replacement of the αH of the residue adjacent to tyrosine with methyl groups results in significant diminution of backbone fragmentation. The initial radical abstracts an αH from the adjacent amino acid, which is poised to “rebound” and abstract the βH of tyrosine through a six-membered transition-state. Subsequent β-scission leads to the observed a-type backbone fragment. These results from deuterated peptides clearly reveal that radical migration in peptides can occur and that multiple migrations are not infrequent. Counterintuitively, close examination of all experimental results reveals that the probability for fragmentation at a particular residue is well correlated with thermodynamic radical stability. A-type fragmentation therefore appears to be most likely when favorable thermodynamics are combined with the relevant kinetic control. These results are consistent with ab initio calculations, which demonstrate that barriers to migration are significantly smaller in magnitude than probable dissociation thresholds.     

On information pooling, adaptability and superefficiency in nonparametric function estimation

The connections between information pooling and adaptability as well as superefficiency are considered. Separable rules, which figure prominently in wavelet and other orthogonal series methods, are shown to lack adaptability; they are necessarily not rate-adaptive. A sharp lower bound on the cost of adaptation for separable rules is obtained. We show that adaptability is achieved through information pooling. A tight lower bound on the amount of information pooling required for achieving rate-optimal adaptation is given. Furthermore, in a sharp contrast to the separable rules, it is shown that adaptive non-separable estimators can be superefficient at every point in the parameter spaces. The results demonstrate that information pooling is the key to increasing estimation precision as well as achieving adaptability and even superefficiency.     

Information Geometry of the Exponential Family of Distributions with Progressive Type-II Censoring

In geometry and topology, a family of probability distributions can be analyzed as the points on a manifold, known as statistical manifold, with intrinsic coordinates corresponding to the parameters of the distribution. Consider the exponential family of distributions with progressive Type-II censoring as the manifold of a statistical model, we use the information geometry methods to investigate the geometric quantities such as the tangent space, the Fisher metric tensors, the affine connection and the α-connection of the manifold. As an application of the geometric quantities, the asymptotic expansions of the posterior density function and the posterior Bayesian predictive density function of the manifold are discussed. The results show that the asymptotic expansions are related to the coefficients of the α-connections and metric tensors, and the predictive density function is the estimated density function in an asymptotic sense. The main results are illustrated by considering the Rayleigh distribution.