Molecular Bilateral Symmetry of Natural Products:  Prediction of Selectivity of Dimeric Molecules by Density Functional Theory and Semiempirical Calculations

Abstract

A literature survey and theoretical calculations have been applied to explore bilateral symmetry in natural product systems. Molecular bilateral symmetry is defined to include C(2) (sigma plane or axis), C(s)(), and C(2)(v)() point groups in molecules. Natural products that possess chirality in the form of C(2)-axes or sigma planes of symmetry are present in higher proportions (69%) compared to molecules bearing achiral C(s)() or C(2)(v)() point groups (14% and 16%, respectively). Density functional theoretical and semiempirical calculations indicate that the dimers 3,3'-dibromo-5,5'-[N-(2-(3-bromo-4-hydroxyphenyl)ethyl)-2-hydroxyiminoacetamide]biphenyl-2,2'-diol (1), (S,S)-1,2-bis(2-amino-3H-imidazol-4-yl)-(R,R)-3,4-bis(1H-pyrrole-2-amido)cyclobutane (2), 2-oxo-dimethyl-1,3-bis(3,4-dibromobenzene-1,2-diol) (11), 1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (12), and bis(5-isopropyl-8-methylazulene)methane (13) evolve more energy per connecting bond than the corresponding trimers or tetramers would. This we propose is a guiding parameter that may adjust molecule growth. The corresponding trimers, tetramers, or higher oligomers of 1, 2, and 11-13 appear to represent "missing" compounds in nature. Natural products 1, 2, and 11-13, having 3-fold and higher levels of symmetry, would founder on the lack of a facile method of synthesis and on the prohibitively high-energy costs caused by steric crowding at their core.

Residual Dipolar Coupling Enhanced NMR Spectroscopy and Chiroptics: A Powerful Combination for the Complete Elucidation of Symmetrical Small Molecules

“…According to the 2004 Greers analysis of natural products, which includes over 3000 literature entries, [1] up to 7 % of them are homodimeric full bilaterally symmetric compounds exhibiting remarkable pharmacological profiles, although the biological role of symmetry in these structures is not yet fully understood. [2] NMR-spectroscopy-based structure elucidation of homodimers is challenging, since the two monomeric parts provide the same set of NMR signals and therefore NOEs between equivalent protons cannot be observed, unless the symmetry is broken in 13 C, 1 H-HSQC-NOESY experiments. [3] In addition, intra-and intermonomer NOE correlations are difficult to discern.…”

Paradigms and paradoxes: Mechanisms for possible enhanced biological activity of bilaterally symmetrical chemicals

“…Enzyme recognition . Receptor-ligand interactionsRecent interest has focused on natural product bilateral symmetry and the prediction of selectivity of dimeric molecules by density functional theory (DFT) and semiempirical calculations [1]. It has been shown that bilateral symmetry [defined as including C 2 (sigma mirror or rotation axis), C s , and C 2v point groups in molecules] is present in a number of natural product structures.…”

Evaluation of Biosynthetic Pathway and Engineered Biosynthesis of Alkaloids

“…Dimerization is found relatively frequently among natural products, as it is considered to be an efficient way of enhancing the chemical complexity and diversity of metabolites being biosynthesized. It can also increase the valency of a compound, affording the molecule a higher affinity for its target or higher stability upon forming a complex with its target [6]. Compound 1 [7] and its related compound WIN 64821 ( Figure 2) [8] originally isolated from Aspergillus versicolor exhibit useful biological activities, such as an inhibition of substance P receptor for potential analgesic and anti-inflammatory activities.…”