Crystal structure of a novel synthetic inhibitor of HIV-1 protease

The crystal structure of a novel non-peptidic HIV-1 protease inhibitor derived by simple solid-state dimerization of 4-aryl-1,4-dihydropyridines, reveals a strained central cage and the conformation of its phenyl, benzyl, and hydroxymethylene substituents. The polycyclic cage includes two nearly flat cyclobutane rings and four fused piperidine rings in boat conformations. The cage geometry reveals two unexpected features, namely marked distortions of the valence angles in every second piperidine and a shortening of one of the cyclobutane bonds. The molecule displays exact centrosymmetry, but the central cage and the hydroxymethylene substituents also approximate the C₂-symmetry of the target enzyme. The two independent hydroxyl groups are involved in intermolecular hydrogen bonding, one as a donor, the other as an acceptor. The disposition of the hydroxyl groups in the molecular framework is compatible with the dual role of the inhibitor in the active-site cavity of HIV-1 protease, whereby one OH group is hydrogen-bonded to the catalytic aspartates, whereas another one provides an interface to the locked flaps of the enzyme.     

Synthesis of a PNA-encoded cysteine protease inhibitor library

Peptide nucleic acids (PNAs) have been used to encode a combinatorial library whereby each compound is labeled with a PNA tag which reflects its synthetic history and localizes the compound upon hybridization to an oligonucleotide array. We report herein the full synthetic details for a 4000 member PNA-encoded library targeted towards cysteine protease.     

Identification of novel malarial cysteine protease inhibitors using structure-based virtual screening of a focused cysteine protease inhibitor library

Malaria, in particular that caused by Plasmodium falciparum , is prevalent across the tropics, and its medicinal control is limited by widespread drug resistance. Cysteine proteases of P. falciparum , falcipain-2 (FP-2) and falcipain-3 (FP-3), are major hemoglobinases, validated as potential antimalarial drug targets. Structure-based virtual screening of a focused cysteine protease inhibitor library built with soft rather than hard electrophiles was performed against an X-ray crystal structure of FP-2 using the Glide docking program. An enrichment study was performed to select a suitable scoring function and to retrieve potential candidates against FP-2 from a large chemical database. Biological evaluation of 50 selected compounds identified 21 diverse nonpeptidic inhibitors of FP-2 with a hit rate of 42%. Atomic Fukui indices were used to predict the most electrophilic center and its electrophilicity in the identified hits. Comparison of predicted electrophilicity of electrophiles in identified hits with those in known irreversible inhibitors suggested the soft-nature of electrophiles in the selected target compounds. The present study highlights the importance of focused libraries and enrichment studies in structure-based virtual screening. In addition, few compounds were screened against homologous human cysteine proteases for selectivity analysis. Further evaluation of structure-activity relationships around these nonpeptidic scaffolds could help in the development of selective leads for antimalarial chemotherapy.     

Crystal and molecular structure of 13-diethanolamino-deacetyllaurenobiolide. Macrocycle conformation in linear germacrolides

An x-ray structure analysis of the 13-diethanolamino derivative of deacetyllaurenobiolide, a germacrane sesquiterpene lactone, was performed. The germacrane macrocycle has the chairchair conformation with the ¹⁵D_5,1D¹⁴ configuration. The conformation of the macrocycle in linear germacrolides was analyzed.Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 454–457, November–December, 2004.This revised version was published online in April 2005 with a corrected cover date.     

Crystal structure and conformation of 10-aryl-bilatrienes-abc

Summary Crystal structure determinations of etiobiliverdin-IV (1) and of twomeso-substituted arylbilatrienes-abc (the 2-imidazolylderivative2 and the 4-nitrophenylderivative3) are reported. All three molecules have aZ,Z,Z configuration and occur in the crystal in anall-syn conformation, which results in a helical overall molecular shape. As a consequence of the steric repulsion between the aryl substituent and the two methyl groups on positions 8 and 12, the pitch and the curvature of the helix are larger in the twomeso-substituted derivatives2 and3 compared to1. In each structure, the packing is dominated by the formation of centrosymmetric, S-shaped dimers via two hydrogen bonds between the pyrrolic H-atom and the carbonyl oxygen of ring A of two molecules related by the operation of an inversion center.

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Kristallstruktur und Konformation von 10-Aryl-bilatrienen-abc

Zusammenfassung Es wird über Kristallstrukturbestimmungen von Aetiobiliverdin-IV (1) sowie zweiermeso-substituierter Arylbilatriene-abc (dem 2-Imidazolylderivat2 und dem 4-Nitrophenylderivat3) berichtet. Alle drei Moleküle liegen im Kristall in einerZ,Z,Z Konfiguration vor und nehmen eineall-syn-Konformation ein, woraus sich eine helikale Molekülgestalt ergibt. Als Folge der sterischen Abstoßung zwischen dem Arylsubstituenten und den beiden Methylgruppen an den Positionen 8 und 12 sind die Ganghöhe und die Krümmung der Helix in den beidenmeso-substituierten Derivaten2 und3 gegenüber1 vergrößert. Die Kristallpackung wird in den drei Kristallstrukturen bestimmt durch die Ausbildung S-förmiger, zentrosymmetrischer Dimeren, die durch zwei intermolekulare Wasserstoffbrücken zwischen dem pyrrolischen Wasserstoffatom und dem Carbonylsauerstoff von Ring A zweier zentro-symmetrieäquivalenter Moleküle zusammengehalten werden.

     

Asymmetric synthesis of a potent azepanone-based inhibitor of the cysteine protease cathepsin K

In this account we detail the asymmetric synthesis of 1, a potent azepanone-based inhibitor of cathepsin K (K_i = 0.16 nM), which has been shown to inhibit the production of biomarkers of bone resorption in monkeys. The key steps in the synthesis sequence were the utility of the Evans aldol reaction coupled with the ring closing olefin metatheses to assemble the azepanone core contained within 1.     

Proteomic profiling and potential cellular target identification of K11777, a clinical cysteine protease inhibitor, in Trypanosoma brucei

We report herein the design, synthesis and application of K11777-derived activity-based probes (ABPs) allowing in situ profiling and identification of potential cellular targets of K11777 in Trypanosoma brucei.     

Crystal and molecular structure of isogarcinol

The controversy with regard to the structures of the closely related polyisoprenylated phenolic compounds, garcinol, isogarcinol, camboginol, cambogin, xanthochymol and isoxanthochymol is cleared by X-ray crystallographic analysis of the naturally occurring isogarcinol. The unusual UV spectral characteristics of the chromophore of isogarcinol are discussed.