ALBERT

Notes: Summary Structurally guided design approaches to low-molecular-weight platelet aggregation antagonists addressing the platelet-associated heterodimeric cell surface receptor gpIIb/IIIa rely on comparative studies of an ensemble of conformationally and biologically characterized compounds, since no high-resolution structure of the receptor system is available. We report a classical indirect and comparative pharmacophore refinement approach based on a series of small cyclic Arg-Gly-Asp (RGD) peptides as gpIIb/IIIa-fibrinogen interaction antagonists. These peptides have previously been investigated as potent and selective tumor cell adhesion inhibitors. The definition of geometrical descriptors classifying the RGD peptide conformations and their subsequent analysis over selected RGD- and RXD-containing protein structures allows for a correlation of distinct structural features for platelet aggregation inhibition. An almost parallel alignment of the Arg and Asp side chains was identified by a vector analysis as being present in all active cyclic hexa-and pentapeptides. This orientation is induced mainly by the constraint of backbone cyclization and is not of any covalent tripeptide-inherent origin, which was rationalized by a 500 ps high-energy MD simulation of a sequentially related linear model peptide. The incorporation of the recognition tripeptide Arg-Gly-Asp into the cyclic peptide templates acted as a filter mechanism, restricting the otherwise free torsional relation of both side chains to a parallel orientation. Based on the derived results, several detailed features of the receptor binding site could be deduced in terms of receptor complementarity. These findings should govern the design of next-generation compounds with enhanced activities. Furthermore, the complementary stereochemical characteristics of the substrate can be used as boundary conditions for pseudoreceptor modelling studies that are capable of reconstructing a hypothetical binding pocket, qualitatively resembling the steric and electronic demands of gpIIb/IIIa. It is interesting to note that these features provide clear differentiation to requirements for inhibition of % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9qq-f0-yqaqVeLsFr0-vr% 0-vr0db8meaabaqaciGacaGaaeqabaWaaeaaeaaakeaacaqGXoWaaS% baaSqaaiaabAfadaWgaaadbaaabeaaaSqabaGccaqGYoWaaSbaaSqa% aiaaiodaaeqaaaaa!3DDC!\[{\text{\alpha }}_{{\text{V}}_{} } {\text{\beta }}_3 \] substrate binding. This can account for the extremely high selectivity and activity of some of our constrained peptides for either the % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9qq-f0-yqaqVeLsFr0-vr% 0-vr0db8meaabaqaciGacaGaaeqabaWaaeaaeaaakeaacaqGXoWaaS% baaSqaaiaab+bbcaqGIbaabeaakiaabk7adaWgaaWcbaGaaG4maaqa% baaaaa!3E56!\[{\text{\alpha }}_{{\text{b}}} {\text{\beta }}_3 \] or the % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9qq-f0-yqaqVeLsFr0-vr% 0-vr0db8meaabaqaciGacaGaaeqabaWaaeaaeaaakeaacaqGXoWaaS% baaSqaaiaabAfaaeqaaOGaaeOSdmaaBaaaleaacaaIZaaabeaaaaa!3DA4!\[{\text{\alpha }}_{\text{V}} {\text{\beta }}_3 \] receptor.

Notes: 1,2,4,5-Tetramethyl-and pentamethylbenzene from stable 1:2 complexes with SbCl3 of the type (C6H6-Men) · 2SbCl3(1,2) with an inverse sandwich structure. The compounds crystallize isotypically and are isostructural to the (hexamethylbenzene)antimony and -bismuth complexes.They are thus built of tetrameric chlorine-bridged Sb4Cl12 units, which are crosslinked at the metal centers with four other tetramers by double-sided arene coordination (X-ray structure analysis of 1). The Sb atoms, which are in a distorted trigonal bipyramidal environment, show a slight deviation from a centric (η6) coordination. The same stoichiometry and the same structural principle are found for the complex (C6Me6 · 2 AsCl3 (4), which is obtained from solutions of hexamethylbenzene and AsCl3 in toluene. In 4 the arsenic atoms are η6-coordinated to the hexamethylbenzene ring from both sides (X-ray analysis). Treatment of AsBr3 with hexamethylbenzene leads to a product of the composition 5 (C6Me6) · AsBr3. Reaction of hexaethylbenzene with AsCl3 in petroleum ether leads to the formation of the 1:2 complex (C6Et6) · 2 AsCl3 (5), built of discrete inverse sandwich units, which are arranged in strings parallel to the crystallographic c axis. From solutions of AsCl3 (AsBr3), SbCl3 (SbBr3) and hexaethylbenzene in petroleum ether ternary compounds are isolated with an As:Sb ratio of 1:5.2 and 1:1.86, respectively. Single crystal X-ray structure determinations failed as a consequence of severe disorder.