Norman E. Sharpless

Study on the Quinquevalent Chromium Complex

Accurate values of the parallel and perpendicular components of g‐factor and hyperfine coupling tensor were determined for [CrOCln]—(n−3) where n=4 and 5, by the ESR line shape analysis. It was shown by a molecular orbital treatment that these magnetic parameters can be explained consistently by taking into account of an excited electronic configuration in which an electron in a filled orbital is excited to the half‐filled level. An assignment of a hitherto unexplained visible absorption band was proposed on the same ground.

Structure-activity studies of aldose reductase inhibitors containing the 4-oxo-4H-chromen ring system

Various 4-oxo-4H-chromen-2-carboxylic acids and their derivatives were screened for aldose reductase inhibitory activity. Their inhibitory response along with that of several flavonoids has been correlated with simple Hückel molecular orbital calculations. From these results a possible mode of action is postulated.

Nature of the Unpaired Electron Orbital in Some Low Spin Oxygen-Co Complexes

Abstract The CoII complexes, Co(II)-bissalicylal-3,3′-diimino-di-n-propylamine peroxide I and decaammine-μ-peroxodicobalt cation II, were investigated by the electron spin resonance (esr). On the basis of the observed esr parameters, it was concluded that the unpaired electron is largely localized on the O2 group and, therefore, these complexes are better described as super-oxides. The equilibrium in solution of I between the paramagnetic and dia-magnetic forms implied by the previous studies was also demonstrated.

The aldose reductase inhibitor site

Evidence linking the enzyme aldose reductase (alditol:NADP+ oxidoreductase, EC 1.1.1.21) to the pathogenesis of several diabetic complications is rapidly mounting. The results of several animal studies combined with preliminary reports of ongoing clinical trials indicate that inhibition of aldose reductase produces a beneficial effect against such diabetic complications as neuropathy, cataract, corneal epitheliopathy, retinopathy, microangiopathy, and possibly nephropathy. The observations that aldose reductase inhibitors appear to provide a new direct mode of treatment for the control of diabetic complications--a method independent of the insulin-related control of blood glucose levels--has spurred interest in the development of more potent and selective inhibitors. That goal can be more easily realized through an understanding of how these inhibitors interact with the aldose reductase protein. This requires insight into the steric and electronic requirements of both the inhibitors and the enzyme site where they bind (inhibitor site). Through the use of computer molecular modeling, molecular orbital calculations, known structure-activity relationships (SAR), protein modification reagents, and irreversible inhibitors, specific structural, and electronic similarities among the apparently structurally diverse aldose reductase inhibitors (ARIs) have been observed. In turn, these studies have led us to postulate the pharmacophor requirements of the ARI site.

Physical State Influences on the Intensity of Infrared Absorption Bands

Using chloranil as a model, the intensities of various bands in the infrared spectrum have been investigated as functions of the particle size of the crystals. As the particles become larger, the values of molar absorptivity appear to approach the value found for a single crystal As the particle size approaches zero, the values increase. The molar absorptivities in solution are higher than those observed for the smallest particles investigated, and the plots of molar absorptivity as function of size may be extrapolated to the solution values as possible limits It appears that there is no orientation of particles in the pellets, while x-ray diffraction data indicate no changes in crystal structure but do show some evidence of the formation of a solid solution. The frequencies of the various bands are independent of the sizes of the particles.

Nuclear Magnetic Resonance of Compounds Related to DDT: Part II. Aromatic Protons

The nuclear magnetic resonance spectra of the aromatic protons of DDT and 31 of its analogs and derivatives have been analyzed. Chemical shifts of these molecules are functions of the electronegativities of the substituents on the ring, as well as those in the aliphatic portion, although substitution of the ring chlorine in DDT by either a nitro or a t-butyl group leads to anomalous values. Molecular orbital calculations show that the chemical shift of the proton ortho to the ring substituent depends upon the π electron density at the corresponding carbon, but the chemical shift of the proton meta to this substituent is independent of the π electron density at the corresponding carbon. The data also indicate that the two aromatic rings in DDT are independent of each other.

The Nuclear Magnetic Resonance Spectra of Compounds Related to DDT. I. Non-Aromatic Protons:

The nuclear magnetic resonance spectra of a series of compounds related to DDT have been studied as they are influenced by ring or aliphatic substituents or by aliphatic structural changes The chemical shift of the benzylic or α proton follows the Hammett equation for ring substituents and the Taft variation of this equation for aliphatic substituents. Alkoxy substituents on the ring show alternation of chemical shift of the —OCH2— group protons with chain length and limiting behavior of the terminal methyl group with chain length. Dehydrochlorination of o,p-DDD produces cis-trans isomers. Coupling constants are shown to be influenced by ring substitution, particularly ortho chlorine.

Influence of structural factors in the acridines upon their therapeutic effectiveness. Quantum mechanical parameters

Abstract The electron density at the ring nitrogen ( q ), the energy of the highest occupied molecular orbital (HOMO) and the energy of the lowest empty molecular orbital (LEMO) of a large series of acridine compounds have been calculated by the LCAO method These have been studied in relation to the p K a and to the therapeutic indices of these compounds. For three gram-positive organisms ( Clostridium welchii, Streptococcus pyogenes , and Staphylococcus aureus ) the toxicities of the compounds correlate well with q and LEMO. The correlation for two gram-negative organisms ( Bacterium coli and Proteus ) is not as good. q , HOMO, and LEMO are discussed in terms of the p K a and molecular structures. The correlations of the quantum values and toxicity have been viewed in relation to the possible interaction of the acridines and the cell membrane and DNA in bacteria and trypanosomes.

Interactions between acridines and triphenyl methane dyes: Their possible role in therapeutic interference

Abstract The interaction of trypaflavine, or its N-ethyl analog, with the triphenyl methane dyes, Crystal Violet and parafuchsin, has been investigated. Molecular orbital calculations indicate that interaction between the two species is feasible and likely. Experimental evidence from X-ray diffraction determination, spectrophotometry in the visible region and fluorescence quenching confirms the existence of a complex between the species, with a 1:1 ratio of dyes, and the lack of fluorescence quenching with the model quencher methylene blue indicate that this 1:1 complex forms only when both molecules are flat. The formation of this complex is discussed as a possible explanation of the therapeutic interference by triphenyl methane dyes on the action of the acridines.

A MOLECULAR MODEL FOR A PHOSPHOLIPID-RETINALDEHYDE COMPLEX ABSORBING AT 500 nm

Abstract— –The structure of a complex formed from retinaldehyde and ethanolamine phosphoglyceride has been proposed as a Schiffs base stabilized byπ–πinteraction between the double bond of an oleic acid group (Δ9) and the 9–10 double bond of the retinaldehyde chain. Considerations of stereochemistry and simple MO theory indicate the proposed structure to be energetically favored, and its absorption maximum is predicted by free electron theory.