Comparative Assessment of Changes in the Blood Coagulation System in Rats When Exposed to Organic Boron Compounds of Various Chemical Structures

Background. Despite the available information on the clinical manifestations of acute and chronic intoxication with boron compounds, no clear evidence was found among studies to research the effect of boron compounds with different chemical structures on key factors of the blood coagulation system. The data are presented in full for the first time. Aim of the study. Identification of possible signs of the effect of boron compounds on selected indicators of hemostasis in laboratory animals and their characteristics depending on the chemical structure of the compounds. Methods. Modern methods of studying hemostasis are used. Nonlinear rats were chosen as the experimental biological model. Once through the mouth, in the maximum tolerated dose, the following drugs were administered: isopropylmethacarborane, 1,2-di(oxymethyl)orthocarborane, 1,7-di(oxymethyl)methacarborane, polyethylammonium triethylammonium salt, boric acid. Research conducted against a background of dynamic control. Results. Materials were obtained that testify to the effect of boron compounds under the conditions of this experiment on factors of the blood coagulation system. The differences in this effect are established in connection with the chemical structure of the compounds, which are especially pronounced after the introduction of methacarboranes. The effect of orthocarborane and the polyethylammonium triethylammonium salt on factors was less significant. An important fact is that boric acid per se, by its effect on the blood coagulation system, turned out to be less effective than other compared compounds. Conclusion. The polytropy of the toxic effect of boron compounds of different chemical structures was confirmed, including with the involvement of the blood coagulation system, but with the essential features of each of them under conditions of a single exposure to laboratory animals in the maximum tolerated dose.

Crystal structure of the triethylammonium salt of 3-[(4-hydroxy-3-methoxyphenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2-oxo-2H-chromen-4-olate

The reaction between 3,3′-[(3-methoxy-4-hydroxyphenyl)methanediyl]bis(4-hydroxy-2H-chromen-2-one) and triethylamine in methanol yielded the title compound triethylammonium 3-[(4-hydroxy-3-methoxyphenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2-oxo-2H-chromen-4-olate, C6H16N+·C26H17O8−or (NHEt3)+(C26H17O8)−, which crystallized directly from its methanolic mother liquor. The non-deprotonated coumarol substituent shares its H atom with the deprotonated coumarolate substituent in a short negative charge-assisted hydrogen bond in which the freely refined H atom is moved from its parent O atom towards the acceptor O atom, elongating the covalent O—H bond to 1.18 (3) Å. The respective H atom can therefore be described as being shared by two alcohol O atoms, culminating in the formation of an eight-membered ring.

The P2Y12 Antagonists, 2-Methylthioadenosine 5′-Monophosphate Triethylammonium Salt and Cangrelor (ARC69931MX), Can Inhibit Human Platelet Aggregation through a Gi-independent Increase in cAMP Levels

ADP plays an integral role in the process of hemostasis by signaling through two platelet G-protein-coupled receptors, P2Y1 and P2Y12. The recent use of antagonists against these two receptors has contributed a substantial body of data characterizing the ADP signaling pathways in human platelets. Specifically, the results have indicated that although P2Y1 receptors are involved in the initiation of platelet aggregation, P2Y12 receptor activation appears to account for the bulk of the ADP-mediated effects. Based on this consideration, emphasis has been placed on the development of a new class of P2Y12 antagonists (separate from clopidogrel and ticlopidine) as an approach to the treatment of thromboembolic disorders. The present work examined the molecular mechanisms by which two of these widely used adenosine-based P2Y12 antagonists (2-methylthioadenosine 5′-monophosphate triethylammonium salt (2MeSAMP) and ARC69931MX), inhibit human platelet activation. It was found that both of these compounds raise platelet cAMP to levels that substantially inhibit platelet aggregation. Furthermore, the results demonstrated that this elevation of cAMP did not require Gi signaling or functional P2Y12 receptors but was mediated through activation of a separate G protein-coupled pathway, presumably involving Gs. However, additional experiments revealed that neither 2MeSAMP nor ARC69931MX (cangrelor) increased cAMP through activation of A2a, IP, DP, or EP2 receptors, which are known to couple to Gs. Collectively, these findings indicate that 2MeSAMP and ARC69931MX interact with an unidentified platelet G protein-coupled receptor that stimulates cAMP-mediated inhibition of platelet function. This inhibition is in addition to that derived from antagonism of P2Y12 receptors.