Synthesis of 2,2,5,5-tetrasubstituted 1,4-dioxa-2,5-disilacyclohexanes via organotin(IV)-catalyzed transesterification of (acetoxymethyl)alkoxysilanes.

(Acetoxymethyl)silanes 2, 7a-c, and 10a-c with at least one alkoxy group, of the general formula (AcOCH2 )Si(OR)3-n(CH3)n (R: Me, Et, iPr; n=0, 1, 2), were synthesized from the corresponding (chloromethyl)silanes 1, 6a-c, and 9a-c by treatment with potassium acetate under phase-transfer-catalysis conditions. These compounds were found to provide 2,2,5,5-organo-substituted 1,4-dioxa-2,5-disilacyclohexanes 3, 8a-c, and 11a-c if treated with organotin(IV) catalysts such as dioctyltin oxide. The reaction proceeds through transesterification of the acetoxy and alkoxy units followed by ring-closure to form a dimeric six-membered ring. The corresponding alkyl acetates are formed as the reaction by-products. With these mild conditions, the method overcomes the drawbacks of previously reported synthetic routes to furnish 2,2,5,5-tetramethyl-1,4-dioxa-2,5-disilacyclohexane (3) and even allows the synthesis of 1,4-dioxa-2,5-disilacyclohexanes bearing hydrolytically labile alkoxy substituents at the silicon atom in good yields and high purity. These new materials were fully characterized by NMR spectroscopy, elemental analysis, mass spectrometry, and X-ray analysis (trans-8a).

Silicon analogues of the nonpeptidic GnRH antagonist AG-045572: syntheses, crystal structure analyses, and pharmacological characterization.

AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.

Action of (R)-sila-venlafaxine and reboxetine to antagonize cisplatin-induced acute and delayed emesis in the ferret.

The chemotherapeutic drug cisplatin is associated with severe gastrointestinal toxicity that can last for several days. A recent strategy to treat the nausea and emesis includes the combination of a 5-HT3 receptor antagonist, a glucocorticoid, and an NK1 receptor antagonist. The present studies explore the use of the selective noradrenaline reuptake inhibitors, (R)-sila-venlafaxine, (R,R)-reboxetine and (S,S)-reboxetine to prevent cisplatin (5 mg/kg, i.p.)-induced acute (0-24 h) and delayed (24-72 h) emesis in ferrets. The positive control regimen of ondansetron and dexamethasone, both at 1 mg/kg/8 h, reduced acute and delayed emesis by 100 (P<0.001) and 61% (P<0.05). (R)-sila-venlafaxine at 5 and 15 mg/kg/4 h reduced acute emesis by 86 (P<0.01) and 66% (P<0.05), respectively and both enantiomers of reboxetine at 1 mg/kg/12 h also reduced the response by approximately 70-90% (P<0.05). Out of the reuptake inhibitors, only (R)-sila-venlafaxine at 15 mg/kg/4 h was active to reduce delayed emesis (a 57% reduction was observed (P<0.05)); its terminal plasma levels were positively correlated with an inhibition of emesis during the delayed phase (P<0.05). (R)-sila-venlafaxine was also examined against a higher dose of cisplatin 10 mg/kg, i.p. (3 h test) and it dose-dependently antagonized the response (maximum reduction was 94% at 10 mg/kg, p.o.; P<0.01) but it was ineffective against apomorphine (0.125 mg/kg, s.c.) and ipecacuanha (2 mg/kg, p.o.)-induced emesis (P>0.05). In conclusion, the studies provide the first evidence for an anti-emetic potential of noradrenaline reuptake inhibitors to reduce chemotherapy-induced acute and delayed emesis.

Silicon analogues of the retinoid agonists TTNPB and 3-methyl-TTNPB, disila-TTNPB and disila-3-methyl-TTNPB: chemistry and biology.

Twofold sila-substitution (C/Si exchange) in the saturated ring of the tetrahydronaphthalene skeleton of the retinoid agonists TTNPB (1 a) and 3-methyl-TTNPB (2 a) leads to disila-TTNPB (1 b) and disila-3-methyl-TTNPB (2 b), respectively. The silicon compounds 1 b and 2 b were synthesized in multiple steps, and their identities were established by elemental analyses, multinuclear NMR experiments, and single-crystal X-ray diffraction studies. Like TTNPB (1 a) and 3-methyl-TTNPB (2 a), the analogous silicon-based arotinoids 1 b and 2 b are strong pan-RAR agonists and display the same strong differentiation and apoptosis-inducing activity in NB4 promyelocytic leukemia cells as the parent carbon compounds. These results are in keeping with the nearly isomorphous structures of 1 a and 1 b bound to the complex of the RARbeta ligand-binding domain with the nuclear receptor (NR) box 2 peptide of the SRC-1 coactivator. The contacts within the ligand-binding pocket are identical except for helix H11, for which two turns are shifted in the disila-TTNPB (1 b) complex. This study represents the first comprehensive structure-function analysis of a carbon/silicon switch in a signaling molecule and demonstrates that silicon analogues can have the same biological functionalities and conserved structures as their parent carbon compounds, and it illustrates at the same time that silicon analogues of biologically active compounds have the potential to induce alternative allosteric effects, as in the case of helix H11, which might allow for novel options in drug design.

(R)-sila-venlafaxine: a selective noradrenaline reuptake inhibitor for the treatment of emesis.

Sila-substitution of drugs (the carbon/silicon switch) is a concept that is being successfully used for the development of new chemical entities. The (R)-sila-analogue of the antidepressant venlafaxine is devoid of the serotonin reuptake inhibition observed with the marketed drug, leading to a selective noradrenaline reuptake inhibitor displaying anti-emetic properties.