H. C. P. F. Roelen

An efficient approach toward the synthesis of phosphorothioate diesters via the schönberg reaction

Abstract Easily accessible phenacetyl or benzoyl disulfide proved to be very convenient reagents for a rapid P-sulfurization of phosphite-triesters and H-phosphonate diesters, respectively.

Selectivity of action of 8‐alkylamino analogues of N6‐cyclopentyladenosine in vivo: haemodynamic versus anti‐lipolytic responses in rats

A1 adenosine receptor agonists with reduced intrinsic activity may be therapeutically useful as result of an increased selectivity of action. In this study the tissue selectivity of three 8‐alkylamino substituted analogues of N6‐cyclopentyladenosine (CPA) was investigated for haemodynamic and anti‐lipolytic effects using an integrated pharmacokinetic‐pharmacodynamic approach. Chronically instrumented male Wistar rats received intravenous infusions of 4.0 mg kg−1 8‐methylaminoCPA (8MCPA), 12.0 mg kg−1 8‐ethylaminoCPA (8ECPA), 20.0 mg kg−1 8‐butylaminoCPA (8BCPA) or vehicle during 15 min. During experimentation, serial arterial blood samples were drawn for the determination of agonist concentrations and plasma non‐esterified fatty acid (NEFA) levels. Blood pressure and heart rate were monitored continuously. In addition to the CPA analogues, each rat received a rapid bolus infusion of CPA to determine the maximal effects of the full agonist. The concentration‐time profiles of the CPA analogues could be described by a bi‐exponential function. Values for clearance, volume of distribution at steady state and elimination half‐life were 44±5, 48±6 and 39±2 ml min−1 kg−1, 0.97±0.09, 0.84±0.10 and 1.05±0.07 1 kg−1 and 25±2, 28±2 and 40±2 min for 8MCPA, 8ECPA and 8BCPA, respectively (mean±s.e.mean, n=6–8). Different models were used to derive the concentration‐effect relationships for heart rate and NEFA, yielding estimates of potency (EC50) and instrinsic activity (Emax) for both effects of the compounds in vivo. On heart rate the compounds acted as partial agonists, with Emax values of −173±14, −131±11 and −71±6 beats min−1 for 8MCPA, 8ECPA and 8BCPA, respectively. These Emax values were significantly lower than the maximal effect of CPA (−208±8 beats min−1). With regard to the anti‐lipolytic effect all three compounds were full agonists and lowered NEFA levels to the same extent as CPA (69%). The estimated Emax values were 63±5, 63±4 and 68±2%, respectively. Furthermore, the compounds were more potent in causing anti‐lipolytic than cardiovascular effects. The EC50 values for the NEFA and heart rate lowering effects were 37±15, 68±22 and 659±108 ng ml−1 and 164±22, 341±76 and 975±190 ng ml−1 for 8MCPA, 8ECPA and 8BCPA, respectively (mean±s.e.mean, n=6–8). This study demonstrates that partial agonists for the A1 adenosine receptor have increased selectivity of action in vivo. The 8‐alkylamino analogues of CPA may be useful anti‐lipolytics with less pronounced haemodynamic side effects.

8-substituted adenosine and theophylline-7-riboside analogues as potential partial agonists for the adenosine A1 receptor

A series of 8-substituted adenosine and theophylline-7-riboside analogues (28 and 9 compounds, respectively) was tested on adenosine A1 and A2A receptors as an extensive exploration of the adenosine C8-region. Alkylamino substituents at the 8-position cause an affinity decrease for adenosine analogues, but an affinity increase for theophylline-7-riboside derivatives. The affinity decrease is probably due to a direct steric hindrance between the C8-substituent and the binding site as well as to electronic effects, not to a steric influence on the ribose moiety to adopt the anti conformation. The 8-substituents increase the affinity of theophylline-7-riboside analogues probably by binding to a lipophilic binding site. The intrinsic activity was tested in vitro for some 8-substituted adenosine analogues, by determining the GTP shift in receptor binding studies and the inhibition of adenylate cyclase in a culture of rat thyroid FRTL-5 cells, and in vivo in the rat cardiovascular system for 8-butylaminoadenosine. Thus, it was shown that 8-ethyl-, 8-butyl-, and 8-pentylamino substituted analogues of adenosine may be partial agonists in vitro, and that 8-butylaminoadenosine is a partial agonist for the rat cardiovascular A1 receptor in vivo.

An expeditious synthesis of biological important myo-inositol phosphorothioates

Abstract The myo -inositol phosphorothioates 6 , 9 , 12 , and 17 were readily accessible from properly protected precursors by phosphitylation with N,N -diisopropyl dibenzyl phosphoramidite ( 1 ), subsequent in situ sulfurization of the intermediate phosphite triesters with phenacetyl disulfide ( 3 ), and removal of all benzyl protecting groups.

A monogalactosylated cholesterol derivative that specifically induces uptake of LDL by the liver

We described earlier the effect of tris-gal-chol (a triantennary galactose structure coupled to cholesterol) on the fate of low density lipoprotein (LDL) and high density lipoprotein (HDL). Tris-gal-chol-loaded LDL and HDL are both efficiently cleared from blood by hepatic galactose-specific receptors. Thus, tris-gal-chol combines a beneficial LDL-reducing effect with an equally effective but undesirable HDL-lowering effect. We recently synthesized a cholesterol derivative with a single terminal galactose residue, denoted mono-gal-chol. In the present study we show that this compound, which incorporates readily into both LDL and HDL, induces rapid association of LDL and HDL to the liver. The mono-gal-chol-stimulated hepatic association of HDL, however, was about fivefold lower than that of LDL. In the liver, Kupffer cells were mainly (90%) responsible for the liver uptake of mono-gal-chol-loaded LDL, whereas the complex of mono-gal-chol with HDL was predominantly (95%) taken up by parenchymal cells. Uptake by both cell types proceeded via galactose-specific receptors and was followed by degradation of the apolipoproteins in the lysosomes. Thus, compared with tris-gal-chol, mono-gal-chol is equally effective in the induction of galactose-specific uptake of LDL by Kupffer cells. However, the galactose-specific receptor on parenchymal cells recognizes mono-gal-chol-loaded HDL less efficiently than tris-gal-chol-containing HDL. These results indicate that mono-gal-chol might be used to specifically lower LDL levels in patients with a high LDL cholesterol level.

Partial agonists for adenosine receptors

Publisher Summary This chapter discusses the partial agonists for adenosine receptors. Adenosine is generally considered as a “local hormone” with profound physiological activity. It is thought to mediate a large variety of effects, as diverse as vasodilation in the cardiovascular system, inhibition of lipolysis in fat cells, and depression of neuronal activity in the central nervous system (CNS). Most of its effects are mediated by membrane-bound receptors, called P i -purinoceptors, of which currently three subclasses are defined: A l , A 2 and A 3 . All three classes have been cloned, and are coupled to the enzyme adenylate cyclase, A 1 and A 3 adenosine receptors in an inhibitory, and A 2 receptors, of which two further subtypes A 2a and A 2b exist, in a stimulatory fashion. The chapter discusses some methods for screening partial agonists as well as application of these screening methods to adenosine receptors. There is also a description of how partial agonists for adenosine receptors were obtained for the purpose of this chapter. In view of the overwhelming number of therapeutic strategies already in clinical practice, the hypotensive effects of adenosine receptor agonists are probably of limited use. On the contrary, the potentially beneficial metabolic, antiarrhythmic, and CNS effects elicited by these compounds are confounded by the cardiovascular actions.

Stereoselective Synthesis of Ribonucleoside 3′,5′-Cyclic Methyl(phenyl)phosphonates and Phosphonothioates

Abstract Monophosphonylation of 2′-protected ribonucleosides (i.e. 2′-O-THP-uridine and 2′-O-THP-N 6-levulinoyl-adenosine) with the bifunctional reagents bis[(6-trifluoromethyl)benzotriazol-1-yl] methyl(phenyl)phosphonates or the analogous phosphonothioates, and subsequent addition of N-methylimidazole, gave the chirally pure 3′,5′-cyclic methyl(phenyl)phosphonate or phosphonothioate derivatives, respectively. Deblocking of the fully protected compounds yielded, as evidenced by X-ray analysis, the corresponding pure Sp-diastereoisomers.