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Bulky Residues (bulky + residue)
Selected AbstractsFine-Tuning the Dimerization of Tetraureacalix[4]arenesCHEMISTRY - A EUROPEAN JOURNAL, Issue 15 2010Yuliya Rudzevich Dr. Abstract Calix[4]arenes substituted by four urea residues at their wide rim form hydrogen-bonded homo- and heterodimeric capsules in apolar solvents. If urea groups are covalently connected to loops or substituted by bulky residues, the dimerization may be restricted to those pairs in which the loops do not overlap and for which the residues are small enough to pass the loops. In the present study, we describe the dimerization properties of tetraureas with one, two (adjacent or opposite), three, or four loops and those bearing (additionally) up to four residues of different size: a=tolyl, b=3,5-di- tert -butylphenyl, c=4-propyloxy-3,5-di-(tert -butylphenyl)phenyl, and d=4-[tris-(4- tert -butylphenyl)methyl]phenyl. For compounds with four loops of different size (O(CH2)nO-chains with n=10, 14, and 20 connecting the m -positions of the urea phenyl residues) a clear "stepwise" sorting scheme could be established, in which the bulkiest residue d is excluded by all tetraloop compounds and the smallest residue a can pass only the smallest loops (n=10). The medium-sized residues b or c are tolerated by n=14 and 20 or only by n=20. Selectivities can be built up also on geometrical factors. A trisloop compound, for instance, combines only with a tetraurea bearing a single bulky residue and tetraureas with two bulky substituents in adjacent or opposite position are distinguished by the bisloop derivatives with adjacent or opposite loops. The impossibility to form a homodimer of a monoloop compound containing two bulky residues leads to its selective heterodimerization with a derivative bearing three bulky groups. Subtle effects for "borderline" cases, in which the dimerization or reorganization takes a longer time, are also discussed. [source] Molecules with New Topologies Derived from Hydrogen-Bonded Dimers of Tetraurea Calix[4]arenesCHEMISTRY - A EUROPEAN JOURNAL, Issue 28 2008Anca Bogdan Dr. Abstract Tetraurea calix[4]arenes 2 have been synthesized in which two adjacent aryl urea residues are connected to a loop by an aliphatic chain -O-(CH2)n -O-. The remaining urea residues have a bulky 3,5-di- tert -butylphenyl residue and an , -alkenyloxyphenyl residue. Since this bulky residue cannot pass through the loop, only one homodimer (2,2) is formed in apolar solvents, for steric reasons, in which the two alkenyl residues penetrate the two macrocyclic loops. Covalent connection of these alkenyl groups by olefin metathesis followed by hydrogenation creates compounds 3, which consist of molecules with hitherto unknown topology. Their molecular structure was confirmed by 1H,NMR spectroscopy and ESIMS, and for one example by single-crystal X-ray analysis. [source] The Nonchiral Bislactim Diethoxy Ether as a Highly Stereo-Inducing Synthon for Sterically Hindered, , -Branched , -Amino Acids: A Practical, Large-Scale Route to an Intermediate of the Novel Renin Inhibitor AliskirenHELVETICA CHIMICA ACTA, Issue 8 2003Richard Göschke The diastereoselective synthesis of the sterically hindered, , -branched , -amino acid derivative (2S,4S)- 24a and its N -[(tert -butoxy)carbonyl](Boc)-protected alcohol (2S,4S)- 19, both key intermediates of a novel class of nonpeptide renin inhibitors such as aliskiren (1), is described. Initially, the analogous methyl ester (2S,4S)- 17 was obtained by alkylation of the chiral Schöllkopf dihydropyrazine (R)- 12a with the dialkoxy-substituted alkyl bromide (R)- 11a, which proceeded with explicitly high diastereofacial selectivity (ds ,98%) to give (2S,5R,2,S)- 13a (Scheme,4), followed by mild acid hydrolysis and N -Boc protection (Scheme,5). Conversely, the complete lack of stereocontrol and poor yields for the reaction of (R)- 11a with the enantiomeric (S)- 12b suggested, in addition to the anticipated shielding effect by the iPr group at C(2) of the auxiliary, steric repulsion between the MeOC(6) and the bulky residues of (R)- 11a in the proposed transition state, which would strongly disfavor both the Si and Re attack of the electrophile (see Fig.). Based on this rationale, alkylation of the readily accessible achiral diethoxy-dihydropyrazine 21 with (R)- 11a was found to provide a 95,:,5 mixture of diastereoisomers (2S,2,S)- 22a and (2R,2,S)- 23a in high yield (Scheme,6), which afforded in two steps and after recrystallization enantiomerically pure (2S,4S)- 24a. Similarly, the stereochemical course for the alkylation reactions of the related alkyl bromides (S)- 28a and (R)- 28b with both (R)- 12a and (S)- 12b as well as with the achiral 21 was investigated (Schemes,7,9). The precursor bromides (R)- 11a, (S)- 11b, (R)- 28a, and (S)- 28b were efficiently synthesized via the diastereoselective alkylation of the Evans 3-isovaleroyloxazolidin-2-ones (R)- 7a and (S)- 7b either with bromide 6 or with benzyl chloromethyl ether, and subsequent standard transformations (Schemes,3 and 7). A practical and economical protocol of the preparation of (2S,4S)- 24a on a multi-100-g scale is given. This is the first report of the application of an achiral dihydropyrazine, i.e., in form of 21, as a highly stereo-inducing synthon providing rapid access to a N -protected , -branched , -amino acid with (2S) absolute configuration. [source] Breaking symmetry in protein dimers: Designs and functionsPROTEIN SCIENCE, Issue 1 2006Jerry H. Brown Abstract Symmetry, and in particular point group symmetry, is generally the rule for the global arrangement between subunits in homodimeric and other oligomeric proteins. The structures of fragments of tropomyosin and bovine fibrinogen are recently published examples, however, of asymmetric interactions between chemically identical chains. Their departures from strict twofold symmetry are based on simple and generalizable chemical designs, but were not anticipated prior to their structure determinations. The current review aims to improve our understanding of the structural principles and functional consequences of asymmetric interactions in proteins. Here, a survey of >100 diverse homodimers has focused on the structures immediately adjacent to the twofold axis. Five regular frameworks in ,-helical coiled coils and antiparallel ,-sheets accommodate many of the twofold symmetric axes. On the basis of these frameworks, certain sequence motifs can break symmetry in geometrically defined manners. In antiparallel ,-sheets, these asymmetries include register slips between strands of repeating residues and the adoption of different side-chain rotamers to avoid steric clashes of bulky residues. In parallel coiled coils, an axial stagger between the ,-helices is produced by clusters of core alanines. Such simple designs lead to a basic understanding of the functions of diverse proteins. These functions include regulation of muscle contraction by tropomyosin, blood clot formation by fibrin, half-of-site reactivity of caspase-9, and adaptive protein recognition in the matrix metalloproteinase MMP9. Moreover, asymmetry between chemically identical subunits, by producing multiple equally stable conformations, leads to unique dynamic and self-assembly properties. [source] A statistically derived parameterization for the collagen triple-helixPROTEIN SCIENCE, Issue 11 2002Jan K. Rainey Abstract The triple-helix is a unique secondary structural motif found primarily within the collagens. In collagen, it is a homo- or hetero-tripeptide with a repeating primary sequence of (Gly-X-Y)n, displaying characteristic peptide backbone dihedral angles. Studies of bulk collagen fibrils indicate that the triple-helix must be a highly repetitive secondary structure, with very specific constraints. Primary sequence analysis shows that most collagen molecules are primarily triple-helical; however, no high-resolution structure of any entire protein is yet available. Given the drastic morphological differences in self-assembled collagen structures with subtle changes in assembly conditions, a detailed knowledge of the relative locations of charged and sterically bulky residues in collagen is desirable. Its repetitive primary sequence and highly conserved secondary structure make collagen, and the triple-helix in general, an ideal candidate for a general parameterization for prediction of residue locations and for the use of a helical wheel in the prediction of residue orientation. Herein, a statistical analysis of the currently available high-resolution X-ray crystal structures of model triple-helical peptides is performed to produce an experimentally based parameter set for predicting peptide backbone and C, atom locations for the triple-helix. Unlike existing homology models, this allows easy prediction of an entire triple-helix structure based on all existing high-resolution triple-helix structures, rather than only on a single structure or on idealized parameters. Furthermore, regional differences based on the helical propensity of residues may be readily incorporated. The parameter set is validated in terms of the predicted bond lengths, backbone dihedral angles, and interchain hydrogen bonding. [source] Fine-Tuning the Dimerization of Tetraureacalix[4]arenesCHEMISTRY - A EUROPEAN JOURNAL, Issue 15 2010Yuliya Rudzevich Dr. Abstract Calix[4]arenes substituted by four urea residues at their wide rim form hydrogen-bonded homo- and heterodimeric capsules in apolar solvents. If urea groups are covalently connected to loops or substituted by bulky residues, the dimerization may be restricted to those pairs in which the loops do not overlap and for which the residues are small enough to pass the loops. In the present study, we describe the dimerization properties of tetraureas with one, two (adjacent or opposite), three, or four loops and those bearing (additionally) up to four residues of different size: a=tolyl, b=3,5-di- tert -butylphenyl, c=4-propyloxy-3,5-di-(tert -butylphenyl)phenyl, and d=4-[tris-(4- tert -butylphenyl)methyl]phenyl. For compounds with four loops of different size (O(CH2)nO-chains with n=10, 14, and 20 connecting the m -positions of the urea phenyl residues) a clear "stepwise" sorting scheme could be established, in which the bulkiest residue d is excluded by all tetraloop compounds and the smallest residue a can pass only the smallest loops (n=10). The medium-sized residues b or c are tolerated by n=14 and 20 or only by n=20. Selectivities can be built up also on geometrical factors. A trisloop compound, for instance, combines only with a tetraurea bearing a single bulky residue and tetraureas with two bulky substituents in adjacent or opposite position are distinguished by the bisloop derivatives with adjacent or opposite loops. The impossibility to form a homodimer of a monoloop compound containing two bulky residues leads to its selective heterodimerization with a derivative bearing three bulky groups. Subtle effects for "borderline" cases, in which the dimerization or reorganization takes a longer time, are also discussed. [source] The Interaction of Highly Helical Structural Mutants with the NOP Receptor Discloses the Role of the Address Domain of Nociceptin/Orphanin FQCHEMISTRY - A EUROPEAN JOURNAL, Issue 7 2005Teodorico Tancredi Dr. Abstract Nociceptin is a heptadecapeptide whose sequence is similar to that of Dynorphin A, sharing a message domain characterized by two glycines and two aromatic residues, and a highly basic C-terminal address domain but, in spite of these similarities, displays no opioid activity. Establishing the relative importance of the message and address domains of nociceptin has so far been hampered by its extreme conformational flexibility. Here we show that mutants of this peptide, designed to increase the helical content in the address domain, can be employed to explain the mode of interaction with the NOP receptor. Nociceptin analogues in which Ala residues are substituted with aminoisobutyric acid (Aib) show a substantial increment of activity in their interaction with the NOP receptor. The increment of biological activity was attributed to the well-documented ability of Aib to induce helicity. Here we have verified this working hypothesis by a conformational investigation extended to new analogues in which the role of Aib is taken up by Leu. The NMR conformational analysis confirms that all Ala/Aib peptides as well as [Leu7,11]-N/OFQ-amide and [Leu11,15]-N/OFQ-amide mutants (N/OFQ=nociceptin/orphanin FQ) have comparable helix content in helix-promoting media. We show that the helical address domain of nociceptin can place key basic residues at an optimal distance from complementary acidic groups of the EL2 loop of the receptor. Our structural data are used to rationalize pharmacological data which show that although [Leu11,15]-N/OFQ-amide has an activity comparable to those of Ala/Aib peptides, [Leu7,11]-N/OFQ-amide is less active than N/OFQ-amide. We hypothesize that bulky residues cannot be hosted in or near the hinge region (Thr5 -Gly6 -Ala7) without severe steric clash with the receptor. This hypothesis is also consistent with previous data on this hinge region obtained by systematic substitution of Thr, Gly, and Ala with Pro. [source] | ||||||||||