AG-045572 (CMPD1, 1a) 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 (1b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (H-1, C-13, Si-29), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1a, 1b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1a 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 1a 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.

Twofold sila‐substitution (C/Si exchange) of the clinically used RXR‐selective retinoid agonist bexarotene leads to disila‐bexarotene, which displays pharmacological potency similar to that of the parent carbon compound, as shown in a HeLa‐cell‐based RXR assay. Formal exchange of the SiCH2CH2Si group in disila‐bexarotene with a SiCH2Si or SiOSi moiety leads to the disila‐bexarotene analogues 8 and 9. The silicon compounds 8 and 9 were synthesized in multistep syntheses, starting from HCC(CH3)2SiCH2Si(CH3)2CCH and HCC(CH3)2SiOSi(CH3)2CCH, respectively. The key step in the syntheses of 8 and 9 is a cobalt‐catalyzed [2+2+2] cycloaddition reaction that affords the 1,3‐disilaindane and 2‐oxa‐1,3‐disilaindane skeletons. Disila‐bexarotene and its analogues 8 and 9 were studied for their biological effects relative to all‐trans retinoic acid in cultured human pluripotent stem cells. The parent carbon compound bexarotene was included in some of these biological studies. Although the silicon‐containing bexarotene analogues disila‐bexarotene, 8, and 9 appear not to regulate the differentiation of TERA2.cl.SP12 stem cells, preliminary evidence indicates that these compounds may possess enhanced functions over the parent compound bexarotene, such as induction and regulation of cell death and cell numbers. The biological data obtained indicate that bexarotene, contrary to the silicon‐containing analogues disila‐bexarotene, 8, and 9, may partially act to induce cell differentiation.

This work aimed to investigate the use of an organically modified porous silica matrix (poly(methacryloxypropyl)–poly(silsesquioxane); P-MA–PS) as a release system for heparin. The matrices were obtained from methacryloxypropyltrimethoxysilane (MAS) via the sol–gel process under acidic conditions following photochemical polymerization and cross-linking of the organic matrix. Modulation of the polymerization degree of the organic matrix in the range 0–71% allowed adjusting the release kinetics of heparin according to therapeutic needs. It was demonstrated that higher drug loads and a decreasing polymerization degree resulted in a faster release profile of heparin, which followed a square root of time kinetic according to the Higuchi model. The hydrolytic degradation of hybrid xerogel was found to follow a zero-order kinetic whereas the heparin concentration did not show an influence on the degradation rate of the matrix. Since the released heparin retained its biological activity, the P-MA–PS matrices are of clinically interest, e.g. as coating on drug eluting coronary stents.

Background: Chemical bonding of the drug onto surfaces by means of spacer molecules is accompanied with a reduction of the biological activity of the drug due to a constricted mobility since normally only short spacer molecule like aminopropyltrimethoxysilane (APMS) are used for drug coupling. This work aimed to study covalent attachment of heparin to titanium(oxide) surfaces by varying the length of the silane coupling agent, which should affect the biological potency of the drug due to a higher mobility with longer spacer chains.Methods: Covalent attachment of heparin to titanium metal and TiO2 powder was carried out using the coupling agents 3-(Trimethoxysilyl)-propylamine (APMS), N- [3(Trimethoxysilyl) propyl] ethylenediamine (Diamino-APMS) and N-1- [3-(Trimethoxy- silyl)propyl] diethylenetriamine (Triamino-APMS). The amount of bound coupling agent and heparin was quantified photometrically by the ninhydrin reaction and the tolidine-blue test. The biological potency of heparin was determined photometrically by the chromogenic substrate Chromozym TH and fibrinogen adsorption to the modified surfaces was researched using the QCM-D (Quartz Crystal Microbalance with Dissipation Monitoring) technique.Results: Zeta-potential measurements confirmed the successful coupling reaction; the potential of the unmodified anatase surface (approx. -26 mV) shifted into the positive range (> + 40 mV) after silanisation. Binding of heparin results in a strongly negatively charged surface with zeta-potentials of approx. -39 mV. The retaining biological activity of heparin was highest for the spacer molecule Triamino-APMS. QCM-D measurements showed a lower viscosity for adsorbed fibrinogen films on heparinised surfaces by means of Triamino-APMS.Conclusion: The remaining activity of heparin was found to be highest for the covalent attachment with Triamino-APMS as coupling agent due to the long chain of this spacer molecule and therefore the highest mobility of the drug. Furthermore, the adsorption of fibrinogen on the differently heparinised surfaces in real time demonstrated that with longer spacer chains the Delta D/Delta f ratios became higher, which is also associated with better biocompatible properties of the substrates in contact with a biosystem.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The hexacoordinate silicon(IV) complexes [NEt4](2)-[Si(NCS)(6)] (2), [K(18-crown-6)](2)[Si(NCS)(6)].2CH(3)CN (3.2CH(3)CN), and cis-[(acac)(2)Si(NCS)(2)] (cis-4; acac = acetylacetonato-O,O) were synthesized, starting from Si(NCS)(4) (1). Compounds 1, 2, 3.2CH(3)CN, and cis-4 were structurally characterized in the solid state (C-13, N-15 (cis-4 only), and Si-29 MAS NMR; crystal structure analyses) and in solution (H-1, C-13, and Si-29 NMR; cis-4 only). The experimental investigations were complemented by computational studies (RI-MP2 geometry optimizations of 1, [Si(NCS)(6)](2-), cis-4, and trans-4; calculations of the Si-29 NMR chemical shifts using the optimized structures).