Biologic activity of cyclic and caged phosphates: a review

Abstract

The recognition in the early 1960s by Morifusa Eto that tri-o-cresyl phosphate (TOCP) is hydroxylated by the cytochrome P450 system to an intermediate that spontaneously cyclizes to a neurotoxic phosphate (saligenin phosphate ester) ignited the interest in this group of compounds. Only the ortho isomer can cyclize and clinically cause Organo Phosphate Induced Delayed Neurotoxicity (OPIDN); the meta and para isomers of tri-cresyl phosphate are not neuropathic because they are unable to form stable cyclic saligenin phosphate esters. This review identifies the diverse biological effects associated with various cyclic and caged phosphates and phosphonates and their possible use. Cyclic compounds that inhibit acetylcholine esterase (AChE), such as salithion, can be employed as pesticides. Others are neurotoxic, most probably because of inhibition of neuropathy target esterase (NTE). Cyclic phosphates that inhibit lipases, the cyclipostins, possibly represent promising therapeutic avenues for the treatment of type 2 diabetes mellitus and/or microbial infections; those compounds inhibiting β-lactamase may prevent bacterial resistance against β-lactam antibiotics. Naturally occurring cyclic phosphates, such as cyclic AMP, cyclic phosphatidic acid and the ryanodine receptor modulator cyclic adenosine diphosphate ribose, play an important physiological role in signal transduction. Moreover, some cyclic phosphates are GABA-antagonists, while others are an essential component of Molybdenum-containing enzymes. Some cyclic phosphates (cyclophosphamide, ifosfamide) are clinically used in tumor therapy, while the coupling of therapeutic agents with other cyclic phosphates (HepDirect® Technology) allows drugs to be targeted to specific organs. Possible clinical applications of these compounds are considered. Copyright © 2016 John Wiley & Sons, Ltd.

Melatonin Protects Neural Stem Cells Against Tri-Ortho-Cresyl Phosphate-Induced Autophagy

“…Numerous investigations have been conducted on TOCP toxicity, which include various mechanism studies such as acetyl cholinesterase inhibition, neuropathy target esterase inhibition, or γ-aminobutyric acid antagonization (Lorke et al, 2017) in the neural system (Craig and Barth, 1999;Zhang et al, 2007), immune system (Foil et al, 1980;Brinkerhoff et al, 1981), or reproductive system (Xu et al, 2016), but consensus regarding this topic has not been reached. The definite effects and potential mechanisms of TOCP on NSCs, which are essential in the nervous system, still remain to be explored and verified.…”

“…In addition to poisoning of acute organophosphorus compounds, TOCP can also cause severe and irreversible delayed neuropathy, OPIDN, in sensitive animals and humans. Although the OPIDN incidents were first reported in the 1930's in America, there are still various theories on the pathogenesis of OPIDN (Wolkoff et al, 2016;Lorke et al, 2017). Current clinical treatments have no specific effects, and the prognosis has been poor until now, which not only significantly influenced patient health but also caused a heavy societal burden (Abdollahi and Karami-Mohajeri, 2012;Emerick et al, 2012).…”

“…Tricresyl phosphate (TCP), an extensively used organophosphate compound, widely acts as plasticizers, flame retardants, components of jet engine oil, and phosphorus-containing pesticides in industry, even in chemical fibers, textiles, and leather. TOCP is the most toxic compound among three isomers of TCP and has caused several poisoning incidents (Wolkoff et al, 2016;Lorke et al, 2017). TOCP has already been demonstrated to induce neurotoxicity, immunotoxicity (Brinkerhoff et al, 1981), and reproductive toxicity such as inhibition of spermatogonial stem cells and ovarian failure (Xu et al, 2016) in animals.…”

Catalytic Hydrolysis of Tricresyl Phosphate by Ruthenium (III) Hydroxide and Iron (III) Hydroxide towards Sensing Application

“…The commercial TCP products consist of various isomers, in which tri-ortho-cresyl phosphate (ToCP) has been proved most neuroxic due to its irreversible damage to a human's peripheral nerve and spinal cord [2][3][4][5]. ToCP inhibits several vital enzymes, such as acetylcholine esterase [6][7][8] and carboxyesterase [9][10][11]. Acute exposure to ToCP induces nausea, vomiting, diarrhea and abdominal pain, followed by a long asymptomatic period of up to a month.…”

Bis(dimethylamino)phosphorodiamidate: A Reagent for the Regioselective Cyclophosphorylation of cis-Diols Enabling One-Step Access to High-Value Target Cyclophosphates

“… , Although these phosphate esters are kinetically stable in aqueous solution at physiological pH, they are easily hydrolyzed by appropriate enzymes, , proceeding through the assistance of an adjacent hydroxyl group, resulting in cyclophosphate (cP) ester intermediates (Figure ). Many cyclophosphate intermediates play very important roles in modern biology . For example, myo -inositol-1,2-cyclophosphate, produced by the action of enzyme phosphoinositide specific phospholipase C (PI-PLC) on the sn -3-phosphodiester bond of phosphatidylinositol, gives rise to inositol based signaling metabolites crucial to signal transductions and metabolic circuits. − …”