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The peptide hormone adrenomedullin (ADM) consists of 52 amino acids with a disulfide bond and an amidated C‐terminus. Due to the vasodilatory and cardioprotective effects, the agonistic activity of the peptide on the adrenomedullin 1 receptor (AM1R) is of high pharmacological interest. However, the wild‐type peptide shows low metabolic stability leading to rapid degradation in the cardiovascular system. Previous work by our group has identified proteolytic cleavage sites and demonstrated stabilization of ADM by lipidation, cyclization, and N‐methylation. Nevertheless, these ADM analogs showed reduced activity and subtype selectivity toward the closely related calcitonin gene‐related peptide receptor (CGRPR). Here, we report on the rational development of ADM derivatives with increased proteolytic stability and high receptor selectivity. Stabilizing motifs, including lactamization and lipidation, were evaluated regarding AM1R and CGRPR activation. Furthermore, the central DKDK motif of the peptide was replaced by oligoethylene glycol linkers. The modified peptides were synthesized by Fmoc/t‐Bu solid‐phase peptide synthesis and receptor activation of AM1R and CGRPR was measured by cAMP reporter gene assay. Peptide stability was tested in human blood plasma and porcine liver homogenate and analyzed by RP‐HPLC and MALDI‐ToF mass spectrometry. Combination of the favorable lactam, lipidation, ethylene glycol linker, and previously described disulfide mimetic resulted in highly stabilized analogs with a plasma half‐life of more than 144 h. The compounds display excellent AM1R activity and wild‐type‐like selectivity toward CGRPR. Additionally, dose‐dependent vasodilatory effects of the ADM derivatives lasted for several hours in rodents. Thus, we successfully developed an ADM analog with long‐term in vivo activity. [ABSTRACT FROM AUTHOR]

Semaphorin‐3A (Sema‐3A) is a chemorepellant protein with various biological functions, including kidney development. It interacts with a protein complex consisting of the receptors neuropilin‐1 (NRP‐1) and plexin‐A1. After acute kidney injury, Sema‐3A is overexpressed and secreted, leading to a loss of kidney function. The development of peptide inhibitors is a promising approach to modulate the interaction of Sema‐3A with its receptor NRP‐1. Few interaction points between these binding partners are known. However, an immunoglobulin‐like domain‐derived peptide of Sema‐3A has shown a positive effect on cell proliferation. To specify these interactions between the peptide inhibitor and the Sema‐3A–NRP‐1 system, the peptides were modified with the photoactivatable amino acids 4‐benzoyl‐l‐phenylalanine or photo‐l‐leucine by solid‐phase peptide synthesis. Activity was tested by an enzyme‐linked immunosorbent‐based binding assay, and crosslinking experiments were analyzed by Western blot and mass spectrometry, demonstrating a specific binding site of the peptide at Sema‐3A. The observed signals for Sema‐3A‐peptide interaction were found in a defined area of the Sema domain, which was also demonstrated to be involved in NRP‐1 binding. The presented data identified the interaction site for further development of therapeutic peptides to treat acute kidney injury by blocking the Sema‐3A–NRP‐1 interaction. [ABSTRACT FROM AUTHOR]

Research describes the isolation and characterization of two quinones with unique terpenoid skeleton, pycnanthuquinones A and B from Pycnanthus angolensis plant. Data suggest that the quinones possess antihyperglycemic activity.

The total synthesis of the sesquiterpene cacalol, together with tangent routes to the tetralin ring system and two methods for the incorporation of the furan moiety, is presented. The straightforward synthetic pathway constructs the 15-carbon furotetralin ring system in 11 steps. Both approaches to the tetralin ring system provide regiochemically pure product free of isolation difficulty. One approach offers the best overall yield of tetralin, while another offers the possibility for an asymmetric synthesis of cacalol via an intermediate.

Main observation and conclusion: The synthesis of an Asp lactam derivative of A‐183, a selective inhibitor of Factor 7a with good anticoagulant and antithrombotic activity, is described. Our synthesis depends on the use of a removable backbone modification (RBM) strategy to prevent aspartimide formation, which thwarted all attempts to synthesize this target using direct solid‐phase peptide synthesis. Validation of the RBM strategy in the synthesis of a second Asp lactam derivative was also accomplished. The RBM strategy is therefore proposed as a general method for the synthesis of Asp lactam cyclic peptides. [ABSTRACT FROM AUTHOR]

The synthesis and characterization of two members of the glycosylated phosphatidylcholine series of antinfungal agent are described. The new compounds are (2)S- and (2R)-beta-D-glucopyranos-1-yl-2-O-palmitoyl-3- O-phosphatidylcholinylglycerol. The in vitro activities of these new agents against the pathogenic fungi Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus were determined.

Dehydrohalogenative photocyclization of pyrazinylimidazoylethylenes provides the key reaction in the regiospecific synthesis of all six polymethyl isomers of 2-aminoimidazoquinoxalines. The intermediates are derived by condensing pyrazinylmethyl anions with methyl imidazolecarboxylates, followed by reduction with sodium borohydride and dehydration with toluene in methanesulfonic acid. Apart from versatility in substitution, the method allows total regioisomeric control of the methylation and, thus, a clear structure-activity analysis of these potent mutagens and carcinogens from overcooked foods.

Disulfide bond‐containing peptides are useful molecular scaffolds with diagnostic and therapeutic applications due to their good biological activity and good target selectivity, but their utility is sometimes limited by the lability of the disulfide moiety under reducing conditions and in the presence of disulfide bond isomerase. The development of disulfide surrogates with improved redox stability has been an area of ongoing research; and one possible strategy is based on a diaminodiacid (DADA) moiety, which can be used to synthesize the disulfide bond replacement peptides with precise structures and enhanced stability through automated solid‐phase peptide synthesis (SPPS). This review summarizes recent developments in the DADA‐based SPPS of peptide disulfide surrogates. Some representative applications and structural studies on the DADA‐based disulfide surrogates are described. [ABSTRACT FROM AUTHOR]

Adrenomedullin (ADM) is a vasoactive peptide hormone of 52 amino acids and belongs to the calcitonin peptide superfamily. Its vasodilative effects are mediated by the interaction with the calcitonin receptor‐like receptor (CLR), a class B G protein‐coupled receptor (GPCR), associated with the receptor activity modifying protein 2 (RAMP2) and functionally described as AM‐1 receptor (AM1R). A disulfide‐bonded ring structure consisting of six amino acids between Cys16 and Cys21 has been shown to be a key motif for receptor activation. However, the specific structural requirements remain to be elucidated. To investigate the influence of ring size and position of additional functional groups that replace the native disulfide bond, we generated ADM analogs containing thioether, thioacetal, alkane, and lactam bonds between amino acids 16 and 21 by Fmoc/t‐Bu solid phase peptide synthesis. Activity studies of the ADM disulfide bond mimetics (DSBM) revealed a strong impact of structural parameters. Interestingly, an increased ring size was tolerated but the activity of lactam‐based mimetics depended on its position within the bridging structure. Furthermore, we found the thioacetal as well as the thioether‐based mimetics to be well accepted with full AM1R activity. While a reduced selectivity over the calcitonin gene‐related peptide receptor (CGRPR) was observed for the thioethers, the thioacetal was able to retain a wild–type‐like selectivity profile. The carbon analog in contrast displayed weak antagonistic properties. These results provide insight into the structural requirements for AM1R activation as well as new possibilities for the development of metabolically stabilized analogs for therapeutic applications of ADM. Replacing the disulfide bond: Adrenomedullin exerts its effects by activating the receptors of the calcitonin receptor‐like receptor/receptor activity‐modifying protein system, in particular the AM1R. Replacement of the functionally important disulfide bond in adrenomedullin with different mimetics led to the identification of two analogs with wild–type‐like AM1R activity as well as a novel antagonist. Our findings provide valuable structure‐activity insights and will be useful for the development of adrenomedullin‐based therapeutics with enhanced metabolic stability. [ABSTRACT FROM AUTHOR]