Terminal substituent effects on the reactivity, thermodynamics, and stereoselectivity of the 8π-6π electrocyclization cascades of 1,3,5,7-tetraenes.

M06-2X/6-31+G(d,p) computations are reported for the 8π-6π electrocyclization cascades of 1,3,5,7-tetraenes. The rate-determining step for these cascades is typically the second (6π) ring closure. According to experiment and theory, un- and monosubstituted tetraenes readily undergo 8π electrocyclic ring closure to form 1,3,5-cyclooctatrienes; however, the 6π electrocyclizations of these cyclooctatriene intermediates are slow and reversible, and mixtures of monocyclic and bicyclic products are formed. Computations indicate that di- and trisubstituted tetraenes undergo facile but less exergonic 8π electrocyclization due to a steric clash that destabilizes the 1,3,5-cyclooctatriene intermediates. Relief of this steric clash ensures the subsequent 6π ring closures of these intermediates are both kinetically facile and thermodynamically favorable, and only the bicyclic products are observed for the cascade reactions of naturally occurring tri- and tetrasubstituted tetraenes (in agreement with computations). The 6π electrocyclization step of these cascade electrocyclizations is also potentially diastereoselective, and di- and trisubstituted tetraenes often undergo cascade reactions with high diastereoselectivities. The exo mode of ring closure is favored for these 6π electrocyclizations due to a steric interaction that destabilizes the endo transition state. Thus, theory explains both the recalcitrance of the unsubstituted 1,3,5,7-octatetraene and 1-substituted tetraenes toward formation of the bicyclo[4.2.0]octa-2,4-diene products, as well as the ease and the stereoselectivity with which terminal di- and trisubstituted tetraenes are known to react biosynthetically.

Adrenal medulla imaging agents: a structure-distribution relationship study of radiolabeled aralkylguanidines.

Fourteen 125I-labeled aralkylguanidines were synthesized and evaluated as potential imaging agents for the adrenal medullae and tumors of adrenomedullary origin. These guanidines are radiotracer analogues of guanethidine, an antihypertensive agent thought to mediate neuron blockade by uptake into adrenergic nerves. Dog adrenal medullae were used as a model to test radiotracer affinity for catecholamine storage tissue. Tissue distribution studies revealed that a number of radioiodinated guanidines showed pronounced localization in the adrenal medullae following intravenous injection, in certain cases exceeding that of either (-)-[3H]norepinephrine or [14C]guanethidine. (m-[125I]Iodobenzyl)guanidine (m-IBG, 2b) gave the best combination of high concentration and selectivity. The low adrenomedullary affinity observed with [14C]guanidine and m-[125I]iodobenzylamine demonstrates the uniqueness of the aralkylguanidine structure. Preliminary evidence suggests that 2b is a storage analogue of norepinephrine. [125I]2a is now being used clinically in imaging and radiotherapy of catecholamine tumors, such as pheochromocytoma.

Conformational analogues of antihypertensive agents related to guanethidine.

In an effort to clarify the conformational requirements, if any, of agents producing adrenergic neuronal blockade through mechanisms similar to guanethidine, the synthesis and pharmacological evaluation of 15 analogues of cinnamylguanidine are described. These analogues represent derivatives in which the distance between the center of the ring system and the guanidinium nitrogen atom varies from 3.9 to 6.2 A. While conformational relationships could not be defined in this study, three analogues (3, 4, and 5) were apparently more potent than guanethidine in the in vitro assay employed.

Prevention by guanethidine analogues of output of noradrenaline induced by sodium reduction in rabbit ventricular slices.

1 The prevention by guanethidine and related agents of the output of noradrenaline induced by low sodium was investigated in rabbit ventricular slices. When external NaCl was reduced, the output of noradrenaline into the medium collected at 30 min intervals, increased and the endogenous levels decreased. These changes induced by replacing sodium with sucrose or choline were not affected either by the omission of calcium and addition of 0.5 mM ethylene glycol-bis(aminoethylether)N,N,N',N' tetra-acetic acid (EGTA) or by an increase in the calcium concentration to 10 mM 30 min before sodium deprivation.2 Guanethidine 4 x 10(-6) and 4 x 10(-5) M and 4-7-exo-methylene-hexahydroisoindoline-ethyl guanidine (No. 865-123) 4 x 10(-5) to 8 x 10(-4) M inhibited, in a dose-dependent manner, increases in output of noradrenaline induced by reduction of sodium to 18 mM, while guanethidine 8 x 10(-5) M and high doses of bretylium produced no inhibition: the latter two released noradrenaline.3 The inhibitory actions of guanethidine 4 x 10(-5) M and No. 865-123 4 x 10(-4) M were prevented by tetracaine 3.3 x 10(-4) M, which per se did not modify the output of noradrenaline induced by 18 mM sodium.4 Accumulation of guanethidine and No. 865-123 in ventricular slices was greater than that noted in striated muscle slices and was dose-, time- and temperature-dependent. Tetracaine 3.3 x 10(-4) M did not prevent the accumulation of guanethidine 4 x 10(-5) M and No. 865-123 1.1 x 10(-6) to 4 x 10(-4) M.5 The guanidine derivatives appear to increase the permeability of adrenergic nerve endings to sodium ions.

Influence of sodium ions on detergent solubilization of pig brush border D-glucose transport system for reconstitution experiments.

The D-glucose uptake by liposomes resulting from the association of egg lecithins with solubilized membrane proteins was measured in order to assess their sodium dependent D-glucose transport activity. Membrane proteins were extracted by Triton X-100 solubilization of pig kidney brush border membrane vesicles, which were suspended either in KCl medium or in NaCl medium. When measured by equilibrium isotope exchange procedure in sodium conditions, the D-glucose uptake by sodium detergent extract associated to liposomes occurred with a higher velocity than that obtained with liposomes reconstituted from potassium detergent extract. No differences were observed in the permeability or in the protein content of two types of liposomes. These results are discussed in terms of activation of D-glucose transport system induced by sodium ions before membrane protein solubilization.

Synthesis and pharmacology of alkanediguanidinium compounds that block the neuronal nicotinic acetylcholine receptor.

Taking as models the polyamine toxin fraction FTX from the funnel-web spider venom, and the guanidinium moiety of guanethidine, a series of azaalkane-1, omega-diguanidinium salts were obtained. Some of them blocked ion fluxes through the neuronal nicotinic receptors for acetylcholine (nAChR). The blockade was exerted at submicromolar concentrations, suggesting a highly selective interaction with the nAChR. In fact, the active compounds on the nAChR ion channel did not recognize the voltage-dependent Na+ or Ca2+ channels of bovine adrenal chromaffin cells. Therefore, these compounds may be useful tools to clarify the functions of nAChR receptors in the central and peripheral nervous systems.

Action of new organometallic complexes against Leishmania donovani.

The action of 16 newly synthesized metal complexes having the general structure cis-Pt-(II)-Xn-Ln have been tested in vitro against the promastigote forms of Leishmania donovani. The metal complexes at 24 h and maximum dosages inhibited growth from 0%, e.g. in cis-Pt-nifurtimox, to 100%, e.g. in cis-Pt-(2,3,4,5,6-pentafluoroaniline)2Br2 or cis-Pt-pentamidine-I2. A study of the cytotoxicty of these latter complexes on the phagocytic cell line J-774 showed neither high cytotoxicity nor cytolysis. At the maximum dosage after 24 h of permanent contact with the cells (extreme, non-physiological conditions), cytolysis did not exceed 30%. For most of the compounds, cytolysis ranged from 0%, for cis-Pt-oxamniquine-Cl2 to 27.7%, for cis-Pt-pentamidine-I2. The compound cis-Pt-(2,3,4,5,6-pentafluoroaniline)2-Br2 caused up to 1.4% cytolysis under the above conditions. Parasites exposed to cis-Pt-pentamidine-I2 showed notably reduced DNA, RNA and protein synthesis, unlike those exposed to other compounds. Parasites examined by electron microscopy showed effects mainly on the nucleus, though in some cases the mitochondria were affected, altering the internal membranes of the cytoplasmic organelles. The in-vivo activity of the complex cis-Pt-guanethidine-Cl2 was evaluated in parasitized Wistar rats, in which the number of amastigotes per gram of spleen was reduced by 75% compared with controls.