Alessandra Ricca

New types of spin-labelled sugar and nucleoside analogs: Pyrrolidine, morpholine and piperidine N-Oxyls

Abstract Analogs of blocked furanose ( 20 ) or pyranose sugars (i.e. 15 ) and of nucleosides (i.e. 23 ) in which the ring oxygen has been replaced with a -N(OH)-bridge have been prepared in generally good yields by a general reductive cyclization procedure preserving the configuration of the preexistant asymetric centers and proceedings stereoselectively (in more favorable cases stereospecifically) when creating a new asymetric center. The title compounds oxidized to nitroxide free radicals affording usable ESR spectra.

The shape of the ground and lowest two excited states of H2NO

The structure of the ground and lowest two excited states of H2NO have been determined in large scale configuration interaction calculations using a multiconfiguration self‐consistent description of the molecular orbitals. These treatments are based on a systematic building of the correlation contribution which has been designed to account for the characteristics of the nitroxide group. This approach shows that the aminoxyl functional group is more than a three electron group shared by two atoms, but, in fact, a nine electron entity. Our best estimate of the geometry of the ground electronic state, obtained after second‐order configuration interaction using a large basis of atomic natural orbitals, is pyramidal. However, since the potential depth between 0° and 40° is lower or of the same order of magnitude as the estimated inversion frequency, the conclusion that this molecule behaves like a planar system is totally justified. The structure of the excited (n−π*) and (π−π*) states have been determined and...

Conformational study of a sugar nitroxyl free radical

Abstract Ethyl2,3-dideoxy-2-isopropylamino-α- d - arabino -hexopyranoside N -oxyl and its 2′- d analogue have been studied by variable-temperature e.s.r. spectroscopy. At low temperature, two frozen conformers ( 5 , a H-2 = 15.5 G; and 6 , a H-2 = 1.8 G) were found. Semi-empirical quantum mechanics and molecular mechanics, using specially developed parameters by hydroxylamines and nitroxyls, helped to assign an almost eclipsed geometry (ONC-2C-1 ∼ 10°) to 5 and a compromise between a staggered and the nearest eclipsed conformation (ONC-2C-1 ∼ 80°) to 6 .

CONFORMATIONAL DEPENDENCE OF ELECTRONIC SPECTRA IN THE NITROXIDE SERIES : A MCSCF/CI STUDY

Abstract We report a systematic study of the relation between the electronic spectra of nitroxide free radicals and their deviation from planarity, taking H 2 NO as a model compound. Using a MCSCF/CI treatment specifically designed to account for the characteristics of the nitroxide group, we have shown that the bathochromic shift of the n -π ∗ electronic transition is a sensitive signature of the geometry of these radicals.

Spin labeled nucleoside analogues: 4'-Hydroxymorpholin-2'-ylpurines and pyrimidines

Abstract Upon borane-pyridine reduction, a series of nucleoside dialdehyde dioximes 2 underwent cyclization to the corresponding 4′-hydroxymorpholin-2′-ylpurines or pyrimidines 3 from which the peracetyl derivatives 4 were prepared. At room temperature, compounds 3 and 4 exist as a mixture of invertomers in which the 4′S (equatorial 4′-OH or 4′-OAc) predominates. A 14 kcal/mol, nitrogen inversion barrier was estimated from variable temperature experiments. N.O.E. and 3JCH measurements established the anti conformation of the base-“sugar” bond. Compounds 3 spontaneously oxidized to the corresponding aminoxyl free radicals, EPR spectra of which showed that they existed in a chair conformation.

Structure-activity relationship between the 3D distribution of the electrophilicity of sugar derivatives and their cytotoxic and antiviral properties

SummaryThe cytotoxic activities of a series of sugar derivatives bearing electrophilic groups (1-cyanovinyl, 4-cyanochromen-2-yl and 3-nitrochromen-2-yl) have been correlated with their electrophilic properties. To this end, an electrophilic index was defined as an isovalue surface where the interaction energy with an incoming model nucelophile (H−) was equal to a predefined value. This index, calculated from extended Hückel wave functions, allows one to quantify the electrophilic character of the substrates and to describe its spatial localization within the molecular volume (at Michael acceptor sites or on other parts of the molecules). Only sugars for which Michael acceptor reactivity was predicted were retained, and they were subdivided into two groups: those showing antiviral activity against a retrovirus and those devoid of such activity. Under these conditions, good correlations between cytotoxic activity and electrophilic reactivity-positive for the first group, negative for the second-were found. In addition, the ratio electrophilicity/sum of the absolute value of the dipole plus its projection along the principal axis of inertia, Z, of the molecule allows one to predict to which of these groups a sugar derivative belongs.

Spin Labelled C-Glycoside Analogs: Derivatives of 1,4-Anhydro-4-deoxy-2,3-O-cyclopentylidene-l,4-N-hydroxyimino-DL-erythrofuranose

A series of 2,3-O-cyclopentylidene C-glycoside analogs in which the furanose ring has been replaced with a N-hydroxypyrrolidine have been prepared. A structural study of these tricyclic compounds and the aminoxyl radicals thereof has been carried out using variable temperature 1H NMR, X-ray diffraction, molecular dynamics and EPR spectroscopy. Both types of compounds, N-hydroxypyrrolidines and pyrrolidine N-oxyls, fundamentally prefer - in solutions- N-endo conformations over the alternate, N-exo forms found by X-ray diffraction studies and computed to be more stable by molecular dynamics.

Spin-labelled sulfur containing neoglycolipids

A neoglycolipid of structure beta-D-Glcp-S-(CH2)3N(OH)(CH2)4-O-cholest-5-en-3 beta-yl has been prepared in fair overall yield by reduction of the nitrone obtained by condensation of beta-D-Glcp-S-(CH2)3NHOH and OCH-(CH2)3-O-cholest-5-en-3 beta-yl. This synthetic procedure is very flexible, allowing a large range of lengths for the spacer arm, different positions for the NOH group along the spacer arm chain and the replacement of the sulfur by other bio-isosteric groups. The new neoglycolipid spontaneously oxidized to the corresponding nitroxide free radical whose EPR spectrum gave information on its conformational equilibrium which was further studied by molecular mechanics.

Recent Developments in Molecular Graphics

Through their considerable versatility, molecular graphics techniques have become the indispensable complement of experimental chemical and biological tools. The construction, representation and manipulation of computerized molecular models using graphics systems is indeed employed in numerous applications ranging from drug design to protein engineering, the search for novel catalysts, etc. This paper presents several developments we have recently achieved in the following areas: (i) representation of molecular surfaces as 3D solid models, with simultaneous clipping of the envelope allowing to visualize the structural model; (ii) evaluation of intermolecular interaction energies for organometallics using a new theoretical model, which leads to a color-coded reactivity index representable both on dot surfaces and solid models. This latter application is particularly useful for understanding and predicting organometallic reactivity, as exemplified by several applications emphasizing the increasing importance of this new area of computer-assisted chemistry.

Derivatives of 3-Deoxy-3-(N-Hydroxyamino)-D-Ribose

Abstract A series of 3-(N-arylmethyl-N-hydroxyamino)-l,2-O-cyclopentylidene-3-deoxy-5-O-toluoyl-α-D-riboses has been prepared. The blocking groups used were chosen to allow an easy nucleosidation of these compounds to spin labelled analogs of natural nucleosides. The conformational behavior of the N-arylmethyl-N-hydroxyamino group has been studied using 3/CH NMR coupling data and molecular mechanics computations. Upon spontaneous oxidation, these hydroxylamines led to the corresponding aminoxyl free radicals which were submitted to EPR spectroscopy and quantum mechanical computations at a semiempirical level (PM3).