The Influence of Fluorinated Molecules (Semiochemicals and Enzyme Substrate Analogues) on the Insect Communication System

Abstract

Can the introduction of fluorine atoms affect the bioactivity of natural semiochemicals? Can fluorine contribute in the creation of specific enzyme inhibitors to interrupt or disrupt the insect communication system? The first step for the bioactivity of a molecule is interaction with the biological sensor. Hydrogen and fluorine are almost bioisosteric and the receptor site of the enzyme can still recognize and accept the fluoro analogue of its natural substrate. However, the peculiar electronegativity of the fluorine atom can affect the binding, absorption, and transport of the molecule. The differences in the molecule's electronic properties can lead to differences in the chemical interactions between the receptor and the fluorinated substrate. Fluorine introduction can modify the metabolic stability and pathway of the semiochemicals in many different ways. Fluorinated analogues can show synergism, inhibition, or hyperagonism effects on insect behaviors, that is, the activity of the nonfluorinated parent compounds can be mimicked, lost, or increased. In any case, the fluorinated molecules can interact with the bioreceptors in a new and disrupting way. The semiochemicals are olfactory substances: fluorine can affect their volatility or smell. Production of semiochemicals from exogenous substances, perception at antennal receptors, and processing of biological responses are the main steps of communication among insects. In the production step, the fluorinated molecules can interact with enzymes that catalyze the biosynthesis of the natural pheromones. In the perception step, fluorinated semiochemicals can interact with the olfactory receptor cells; this often leads to totally unpredictable behaviors. Fluorinated molecules have been developed as probes to elucidate the complex chemorecognition processes of insects. Many of these molecules have been tested to find highly effective behavior-modifying chemicals. New analogues have been synthesized to investigate the metabolic pathway of a pheromone molecule and many of them are promising disrupting agents. Despite such titanic research efforts, the results have often been random, rational trends in the induced behaviors have sometimes been impossible to find, and practical applications of the fluorinated semiochemicals are still uncertain.

Halogenated ligands and their interactions with amino acids: Implications for structure–activity and structure–toxicity relationships

“…A recent study by Carosati et al [35] described the nature and geometry of hydrogen bonds with different types of fluorine atoms in biological systems. Pesenti and Viani [36] described the effective use of fluorinated analogs in intercepting insect communication systems. The SAR for interactions of the pheromone receptor includes a polar functional group, a carbon-carbon double bond and the terminal alkyl group.…”

Preparation of 9α‐Fluorinated Sesquiterpenic Drimanes and Evaluation of Their Antifeedant Activities

“…This compound may be considered an appropriate intermediate for the preparation of the 9α-fluoro analogues of polygodial (16), drimenin (17) and cinnamolide (18). In fact, these natural compounds have been successfully prepared from the corresponding hydrogen analogue diol.…”

“…As substituent it is rarely boring, always good for a surprise, but often completely unpredictable". [5] Over the last few years there has been a growing interest in the synthesis of fluorine-containing analogues of natural products and a large number of fluorinated natural products with biological significance such as amino acids, [6] peptides, [7] glycosides, [8] nucleosides, [9] lipids, [10] oligosaccharides, [11] steroids, [12] prostaglandins, [13] vitamins, [14] antibiotics, [15] pheromones [16] alkaloids [17] and others [18] have been synthesized and some have subsequently been developed as pharmaceuticals and are marketed, registered or at the clinical development stage. [19] Also, a relatively significant number of fluoro derivatives of bioactive terpene-type compounds have bee reported and in many cases these show an increase in activity with respect to the corresponding hydrogen analogue.…”

Stereoselective synthesis of insect sex pheromone analogs having a fluorine atom on their double bonds

“…In this context, substitution of fluorine atoms for hydrogen in insect sex pheromones could be expected to disturb the perception of the natural pheromone by competitive binding of the fluorinated analogs with specific pheromone receptors, eventually leading to disruption of the mating communication system. Furthermore, the above substitution could increase the thermal and oxidative stability of the parent compounds, which might be of potential interest in field trials [3].…”

“…Many fluorinated analogs of insect pheromones have been synthesized and applied to field tests [3]. However, only a few analogs having a fluorine atom on their double bond have been reported [4][5][6].…”