Intermolecular interactions involving aromatic rings are key processes in both chemical and biological recognition. Their understanding is essential for rational drug design and lead optimization in medicinal chemistry. Different approaches-biological studies, molecular recognition studies with artificial receptors, crystallographic database mining, gas-phase studies, and theoretical calculations-are pursued to generate a profound understanding of the structural and energetic parameters of individual recognition modes involving aromatic rings. This review attempts to combine and summarize the knowledge gained from these investigations. The review focuses mainly on examples with biological relevance since one of its aims it to enhance the knowledge of molecular recognition forces that is essential for drug development.

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Zwischenmolekulare Wechselwirkungen unter Beteiligung aromatischer Ringe sind Schlüsselvorgänge sowohl in chemischen als auch in biologischen Erkennungsprozessen. Ihr Verständnis ist für das rationale Wirkstoffdesign und für die Leitstrukturoptimierung in der Medizinischen Chemie essenziell. Unterschiedliche Ansätze werden für ein tiefergehendes Verständnis der strukturellen und energetischen Parameter einzelner Erkennungsarten mit aromatischen Substraten verfolgt: erwähnt seien biologische Untersuchungen, Studien der molekularen Erkennung mit künstlichen Rezeptoren, Suchen in kristallographischen Datenbanken, Gasphasenstudien und theoretische Untersuchungen. Dieser Aufsatz versucht, diese Wissensgebiete zu vereinen und die aus zahlreichen Untersuchungen gewonnenen Erkenntnisse zusammenzufassen. Er widmet sich hauptsächlich Beispielen mit biologischer Relevanz mit dem Ziel, die für die Wirkstoffentwicklung wichtigen Kenntnisse der molekularen Erkennung zu vertiefen.

Rationale: It has been proposed that an activated renin angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that angiotensin-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT1R) to the vasoprotective axis [ACE2-Ang-(1-7)-Mas] of the RAS, resulting in the prevention of PH. Objectives: We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis. Methods: The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model. Measurements and Main Results: A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, angiotensinogen, AT1 receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-10. Conclusions: These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.Keywords: renin angiotensin system; angiotensin-converting enzyme 2; pulmonary heart disease.Pulmonary hypertension (PH) presents a diverse etiology and is defined by a mean pulmonary arterial pressure of greater than 25 mm Hg at rest, or greater than 30 mm Hg with exercise (1). The most common causes of PH include chronic obstructive pulmonary disease (often caused by smoking), left heart failure, substance abuse, schistosomiasis, high altitude exposure, drugs, toxins (e.g., chemical warfare), and HIV infection (2, 3). It has been proposed that these risk factors, coupled with predisposing genetic factors, lead to an imbalance between vasoconstrictor and vasodilator mechanisms. This imbalance initiates a cascade of pathophysiological events in the lungs leading to PH (4). These events are suggested to be set in motion by pulmonary vascular endothelial dysfunction causing enhanced proliferation and activation of lung fibroblasts, leading to extracellular matrix formation and fibrosis, infiltration of inflammatory cells, increased production of proinflammatory cytokines, exaggerated pulmonary vascular remodeling, and smooth muscle hypertrophy (5, 6). Vasodilatory ther...

Abstract-Angiotensin-converting enzyme 2 (ACE2) is a key renin-angiotensin system enzyme involved in balancing the adverse effects of angiotensin II on the cardiovascular system, and its overexpression by gene transfer is beneficial in cardiovascular disease. Therefore, our objectives were 2-fold: to identify compounds that enhance ACE2 activity using a novel conformation-based rational drug discovery strategy and to evaluate whether such compounds reverse hypertension-induced pathophysiologies. We used a unique virtual screening approach. In vitro assays revealed 2 compounds (a xanthenone and resorcinolnaphthalein) that enhanced ACE2 activity in a dose-dependent manner. Acute in vivo administration of the xanthenone resulted in a dose-dependent transient and robust decrease in blood pressure (at 10 mg/kg, spontaneously hypertensive rats decreased 71Ϯ9 mm Hg and Wistar-Kyoto rats decreased 21Ϯ8 mm Hg; PϽ0.05). Chronic infusion of the xanthenone (120 g/day) resulted in a modest decrease in the spontaneously hypertensive rat blood pressure (17 mm Hg; 2-way ANOVA; PϽ0.05), whereas it had no effect in Wistar-Kyoto rats. Strikingly, the decrease in blood pressure was also associated with improvements in cardiac function and reversal of myocardial, perivascular, and renal fibrosis in the spontaneously hypertensive rats. We conclude that structure-based screening can help identify compounds that activate ACE2, decrease blood pressure, and reverse tissue remodeling. Administration of ACE2 activators may be a valid strategy for antihypertensive therapy. T he recent discovery of angiotensin-converting enzyme (ACE) 2 1,2 and its role in the control of renin-angiotensin system activity is relevant as a potentially valuable target for antihypertensive therapies. ACE2 is a zinc-dependent monocarboxypeptidase that plays a central role in balancing vasoconstrictor and proliferative actions of angiotensin (Ang) II with the vasodilatory and antiproliferative effects of Ang-(1-7). 3 Altered expression of this enzyme is associated with cardiac, vascular, and renal dysfunctions. 4,5 In addition, blocking the synthesis of Ang II by Ang-converting enzyme inhibitors or its actions by Ang II receptor blockers has been shown to increase cardiac ACE2 expression. 6,7 Furthermore, overexpression of ACE2 by gene transfer 8 protects the heart from hypertension-induced cardiac remodeling. It was demonstrated that ACE2 is an effective enzyme in attenuating fibrosis and structural remodeling. 8 Based on these observations, we hypothesize that pharmacological enhancement of ACE2 activity would have beneficial effects on the cardiovascular system and would protect against hypertensioninduced pathophysiology. Therefore, our objectives in this study were 2-fold: to identify compounds that enhance ACE2 activity and to determine the effects of ACE2 enhancers on hypertension and associated pathophysiology. Materials and MethodsSynthesis of xanthenone, measurement of ACE2 activity, histological analysis, and statistical analysis are described in the sup...

Described are assemblies consisting of polymeric capsules, ''polycaps,'' formed from two calix[4]arene tetraureas covalently connected at their lower rims. In these structures self-assembly leads to reversibly formed capsule sites along a chain, reminiscent of beads on a string. Their dynamic behavior is characterized by 1 H NMR spectroscopy through encapsulation of guest species, reversible polymerization, and the formation of sharply defined hybrid capsules.Molecule-within-molecule complexes represent an unusual arrangement of matter (1) with promising applications in mechanistic and physical organic chemistry (2, 3). More complicated synthetic systems that begin to resemble complexes found in biology are molecules that assemble through weak intermolecular forces. Specifically, cup-shaped molecules with hydrogen bonding sites on their larger rims have interesting capacities for molecular assembly. When the hydrogen bonding sites are self-complementary, the molecules dimerize to form capsules. These assemblies reversibly encapsulate smaller guest species of suitable size and shape, but show dynamic qualities (4): the capsules form and dissipate at rates that vary from microseconds to hours-long enough for chemical reactions to occur within them (5). Several such systems derived from resorcinarenes and calixarenes have been extensively characterized (6-8).In the calix[4]arenes ( Fig. 1) the cup-like shape provides half of each capsule, while the ureas on its larger (upper) rim provide the hydrogen bonds that permit the molecules to assemble. The alkyl (R 1 ) groups on the phenolic oxygens of the lower rim maintain (on average) the cup-like conformation (9), and the R 2 groups on the distal urea nitrogen (N ␤ ) provide for reasonable solubility in organic media. Their ready synthetic accessibility has raised the possibility (8, 10) that covalent connection at their lower rims could lead to polymeric capsules, or polycaps, on assembly (Fig. 2). MATERIALS AND METHODSGeneral. All chemicals were used without further purification unless otherwise specified. p-Heptylphenyl isocyanate was prepared from the corresponding acid based on a literature procedure (11). 5,11,17,26,27,arene (1, R 1 ϭ n-propyl, R 2 ϭ n-octyl) was prepared from the known tetraamine (12) by treatment with octyl isocyanate in a manner similar to 6 and 7. The 5,11,17,26,arene 2 was prepared according to the literature (13). Proton ( 1 H) NMR spectra were recorded on Bruker (Billerica, MA) DRX-600 (600 MHz) or AM-300 (300 MHz) spectrometers. Carbon ( 13 C) spectra were recorded on a Bruker DRX-600 (151 MHz) spectrometer. IR spectra were recorded on a Perkin-Elmer Paragon 1000PC FT-IR spectrometer. The fast atom bombardment (FAB) positive ion mass spectra were obtained on a VG ZAB-VSE double-focusing high resolution mass spectrometer equipped with a cesium ion gun. Matrix-assisted laser desorption ionization mass spectrometry experiments were performed on a PerSeptive Biosystems (Cambridge, MA) Voyager-Elite mass spectrometer with delayed extra...

Calix[4]arenes substituted with ureas on their upper, wider rims form dimers in solution held together by a seam of 16 hydrogen bonds. The resulting molecular capsules have interiors capable of accommodating small-molecule guests. By virtue of the assembly process, a head-to-tail arrangement of ureas is formed that can assume either a clockwise or counterclockwise orientation around the equator of the capsule. Amino acids on the urea functions have a dramatic effect on the dimerization behavior of the calixarenes. First, the chiral derivatives display a preference for associating with calixarenes substituted with arylureas rather than with themselves. This selectivity for heterodimerization is exclusive with amino acids that have β-branched side chains such as isoleucine and valine. Second, the point chirality of the amino acids is transferred upon assembly giving rise to a chiral capsule with only one direction to its head-to-tail arrangement of ureas. Circular dichroic spectroscopy is used to assign the absolute configuration of these capsules. The chirality of the capsule can be sensed by chiral guests where enantioselective binding is observed.

Derivatives of the calix[4]arenes in the cone conformation featuring either aryl urea or sulfonyl urea functions on their larger (upper) rims dimerize through hydrogen bonding to give molecular capsules. The capsules act as hosts that reversibly bind smaller molecule guests in organic media. Heterodimers form when both aryl and sulfonyl ureas are present, and the heterodimers form exclusively with respect to the homodimers. The heterodimerization encodes information at the molecular level and allows the predictable formation of discrete aggregates of nanometer dimensions. Evidence for the reversible assembly of these structures is provided by 1H NMR, guest encapsulation studies, and gel permeation chromatography. Covalent attachment of these calixarene aryl and sulfonyl ureas at their smaller (lower) rims leads to polymeric assemblies in which the informational content is preserved.