Macrocyclic inhibitor 1 {methyl [cyclo-7[(2R)-((N-valyl) amino)-2-(hydroxyl-(1S)-1-methyoxycarbonyl-2-phenylethoxy)phosphinyloxyethyl]-1-naphthaleneacetamide] sodium salt} was designed according to the conformation of the acyclic analogue Iva-l-Val-l-Val-l-LeuP-(O)Phe-OMe [LeuP = the phosphinic acid and analogue of l-leucine; (O)Phe = l-3-phenyllactic acid; OMe = methyl ester] (4) bound to penicillopepsin, by linking the P1 and P3 side chains of the penicillopepsin inhibitor. This compound and its two acyclic derivatives, {methyl (2S)-[1-(((N-Formyl)-l-valyl)amino-2-(2-naphthyl)ethyl)hydroxyphosphinyloxy]-3-phenylpropanoate, sodium salt} (2) and {methyl (2S)-[1-(((N-(1-naphthaleneacetyl))-l-valyl)aminomethyl)hydroxyphosphinyloxy]-3-phenylpropanoate, sodium salt} (3), have been synthesized and evaluated as inhibitors of penicillopepsin. Their binding affinity to the enzyme was found to be inversely related to the predicted degree of conformational flexibility across the series: 3 (K i = 110 μM), 2 (K i = 7.6 μM), 1 (K i = 0.8 μM). The X-ray crystallographic structures of penicillopepsin complexed with the macrocyclic peptidyl phosphonate 1 and with its two derivatives 2 and 3 have been determined and refined to crystallographic agreement factors R (=Σ||F o| − |F c||/Σ|F o|) of 15.9%, 16.0%, and 15.2% and R free of 19.8%, 20.3%, and 21.4%, respectively. The intensity data for all complexes were collected to 1.5 Å resolution. One 1.25 Å resolution data set was obtained for the complex with 1 at 110 K; the structure was refined to an R factor of 15.0% (R free of 19.7%). The binding interactions that 1 and 2 make with penicillopepsin are similar to those that have been observed for other transition-state mimics with aspartyl proteinases. On the other hand, the acyclic linear inhibitor 3 exhibits distinctive binding to penicillopepsin with the phosphonate group shifted ∼3.0 Å from the average position observed for the other complexes. These structural results show that the macrocyclic constraint of 1 enhances its binding affinity over those of the acyclic analogues but the differences in the observed bound dispositions mean that the effect has yet to be quantified.
223Komplexe des Typs LAu-SiR3 mit L = PR; oder PhNC und SiR3 = Si(ar~l)~, Si(SiMe,), oder SiPhzMe wurden durch Umsetzung von L-Au-CI mit LiSiR3 dargestellt. Ihre Stabilitat sinkt in Abhingigkeit von L und R in der Reihenfolge R;P-Au-Si(aryl)3 > R;P-Au-Si(SiMe,), > R;P-Au-SiPhzMe x PhNC-Au-SiR3.Umsetzung von R;P-Au-CH3 oder R;P-Au-OAc rnit HSiR, ergibt keine Silyl-Komplexe, bei Verwendung chlorierter Silane, HSi-R2CI, lindet lediglich CHJCI-bzw. OAc/Cl-Austausch statt. Das MoBbauer-Spektrum von MePhzP-Au-SiPh3 (6) sowie NMRund IR-spektroskopische Untersuchungen zeigen, daB Silylreste als starke a-Donor-Liganden gegeniiber dem Goldatom wirken.MePh2P-Au-SiPh, (6) und MePh2P-Au-Si (SiMe3)3 (7) wurden durch Rontgenstrukturanalysen charakterisiert [Au -Si 235.4(4) und 235.6(2) pm]. Die Au-Si-Bindung in MePh2P-Au-SiPh2Tol (5) wird durch Xz (X = C1, Br, I), HCl oder Mel, nicht aber durch HzO oder MeOH gespalten.Im Unterschied zur ausfiihrlich untersuchten Chemie von Organogold-Verbindungen" ist iiber Komplexe rnit Gold -Silicium-Bindung fast nichts bekannt. In der Literatur ist nur die Verbindung Ph3P-Au-SiPh3 kurz erwihnt, die Baird durch Umsetzung von Ph,P-Au-CI mit LiSiPhl in THF bei 0 C darstellte-". Er beschrieb sie als einen besonders in Losung sehr luft-und lichtempfindlichen, leicht lohfarbenen Feststor. Uns interessicrte, wie sich eine elektronische d"-Konfiguration des Metallatoms auf die Metall -Silicium-Bindung und, damit verbunden, auf die Rcaktivitat der Komplexe auswirkt. Fur derartige Untersuchungen erschienen uns Gold(1)-Komplexe des Typs L-Au-SiR, besonders gut geeignet, da im Unterschied zu d"-Komplexen der Nickel-Gruppe sterische Effekte nur eine geringe Rolle spielen sollten und da im Unterschied zu M(SiR&-Komplexen der Zink-Gruppe durch den Neutralliganden L die Eigenschaften des Metallkomplex-Fragmentes modifizierbar sind.
Transition‐Metal Silyl Complexes, 34. – A Dinuclear Gold Silyl Complex with Gold‐ Gold Interaction Between an (R3P)2Au and an (R′3,Si)ClAu Unit Ph2MeP‐Au‐Cl reacts with Ph2MeP‐Au‐SiPh3 to form the dinuclear complex (Ph2MeP)2Au2(Cl)SiPh3, which is in equilibrium with its starting compounds. An X‐ray structure analysis reveals that it consists of a (Ph2MeP)2Au and a (Ph3Si)ClAu unit, which are held together by Au‐Au interaction [298.07(4) Pm]. The approximately linear AuL2 units are orthogonal to each other.
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