Nonbiaryl and Heterobiaryl Atropisomers: Molecular Templates with Promise for Atropselective Chemical Transformations

Modulators of leukotriene biosynthesis and receptor activation.

In silico studies for the rational discovery of anticonvulsant compounds.

Steroid research at Syntex: "the pill" and cortisone.

The “through-space” mechanism in spin spin coupling

Early history of steroid chemistry in Mexico: the story of three remarkable men.

Herein we describe a Free-Wilson/Fujita-Ban QSAR (quantitative structure-activity relationship) analysis of the analgesic potency of over 50 semisynthetic opioid narcotics. The 3-hydroxy- and 3-methoxy-N-alkyhorphinan-6-ones of B/C-cis and -trans stereochemistry include compounds exhibiting structural variation at five positions [N-methyl ((217)) oxygen at C3, C4-C5 oxygen bridge, alkyl substituents at C7 and C8]. The pharmacological parameter correlated was the analgesic potency (-log EDN) exhibited on abdominal contractions produced by acetylcholine injection in mice. A satisfactory correlation was obtained only by assuming interdependent contributions of the substituents on C17 and O(C3), with which it was possible to explain 75% of the variance. Phenolic compounds (3-OH) behave somewhat differently from the methyl ethers (3-OCH3), and in both series the substituents on C8 have a size-dependent negative contribution, implying steric hindrance at their contact point on the receptor. With use of this correlation the potency of five further members of the series was predicted. Subsequent testing fully confirmed the validity of the correlation since the measured potencies were, within experimental error, equal to those calculated. In a further refinement, phenolic compounds were considered separately from the ethers, and it was found that the contribution of the substituents on (217, C7, and C8 remained similar in sign and magnitude but not that of the furan oxygen. This analysis allows us to conclude that if both phenolic and nonphenolic members of this series act on the same receptor they must bind at different subsites or in alternate modes, supporting an earlier proposal in the literature.

A Free-Wilson/Fujita-Ban analysis and prediction of the analgesic potency of some 3-hydroxy- and 3-methoxy-N-alkylmorphinan-6-one opioids.

PMR studies of a series of 2,4- and 2,6- dinitrophenyl- and 2,4-dinitronaphthyl- aryl ethers strongly indicate the existence of preferred conformations. Extensive conjugation of the ether linkage with the dinitro ring, resulting in their coplanarity, is an important stereochemical influence. In the ensuing skew conformation the dinitro ring is positioned in such a way that the 6-substituent is proximal to the other ring. In the case of the 2,4-dinitrophenyl ethers (1) this is the 6-proton, which shows the expected shielding due to the ring current in the other ring. In the 2,6-dinitrophenyl-(2) and 2,4-dinitronaphthyl-(3) ethers, this is a nitro group, twisted out of coplanarity to fit over the other ring, whose magnetic anisotropy is reflected in the shielding experienced by the 6′-protons. When there is a 2′-substituent 






present the ring which bears it twists in such a way as to bring the 6′-proton closer to the proximal nitro-group, explaining the greater shielding observed in these cases. Variable temperature studies provided further evidence in favor of these conformations since no significant changes were observed from −55° to + 155°, even for compounds with four substituents flanking the ether linkage. Nevertheless, the compounds studied here are not frozen in these conformations, but probably inter-convert via concerted rotation with others.

Conformations of highly hindered aryl ethers—IV PMR studies of 2,4‐ and 2,6‐ dinitroaryl ethers

A novel type of interannular coupling (6JH,F = 1.0 to 1.3 Hz) has been observed in some fluorodinitrodiphenyl ethers between the fluorine(s) on one ring ortho to the ether linkage and a proton ortho to it on the other ring. 1H and 19F chemical shift and coupling constant data support the previous conclusion that these ethers preferentially adopt a twist (propeller) conformation. On account of the geometrical disposition of the six bonds between the interacting nuclei and the latter's spatial proximity in this conformation, direct coupling through-space is indicated. Concerted libration around the ether bonds brings about magnetic equivalence of the o-fluoro substituents on one ring and causes equal coupling to be observed to the o-proton on the other ring. The possiblity that the coupling is mediated by an intervening π-cloud is suggested as an alternate mechanism for indirect coupling. The observed interannular transmission of spin information provides evidence in favor of a recent proposal made concerning the mode of action of the thyroid hormones.

Conformations of highly hindered aryl ethers—VIII Interannular HF coupling in diphenyl ethers

A simple computerized molecular structure scanning method was developed for generating a large, fixed number of calculated structural variables based on model structures derived from force-field and quantum mechanics methods. These were reduced to one or a few parameters for QSAR studies by means of principal component analysis. When analyzed by principal component regression, the resulting descriptors summarize such gross features as electron distribution and substituent shape and volume very well. For two data sets (some substituted amphetamine hallucinogens and some dihydropyridine vasodilators), these calculated parameters were at least equivalent in their ability to model drug potency to those commonly used in QSAR.

A F Pedro Lehmann

Papers

Early history of steroid chemistry in Mexico: the story of three remarkable men.

A Free-Wilson/Fujita-Ban analysis and prediction of the analgesic potency of some 3-hydroxy- and 3-methoxy-N-alkylmorphinan-6-one opioids.

Conformations of highly hindered aryl ethers—IV PMR studies of 2,4‐ and 2,6‐ dinitroaryl ethers

Conformations of highly hindered aryl ethers—VIII Interannular HF coupling in diphenyl ethers

The Use of Computerized Molecular Structure Scanning and Principal Component Analysis to Calculate Molecular Descriptors for QSAR