Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Synthesis of a hexasaccharide partial sequence of hyaluronan for click chemistry and more

In the present work, the synthesis of a hexasaccharide partial sequence of hyaluronan equipped with a terminal azido moiety is reported. This hexasaccharide can be used for the attachment on surfaces by means of click chemistry and after suitable deprotection for biophysical studies

C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

The chemical synthesis of carbacyclopamine analog 2, a cyclopamine analog with an all-carbon E-ring, is reported. The use of C–H-functionalization logic and further metal-catalyzed transformations allows for a concise entry to this new class of acid-stable cyclopamine analogs

Backbone and side chain NMR assignments of the H-NOX domain from Nostoc sp. in complex with BAY58-2667 (cinaciguat)

Soluble guanylate cyclase (sGC) enzyme is activated by the gaseous signaling agent nitric oxide (NO) and triggers the conversion of GTP (guanosine 5′-triphosphate) to cGMP (cyclic guanylyl monophosphate). It contains the heme binding H-NOX (heme- nitric oxide/oxygen binding) domain which serves as the sensor of NO and it is highly conserved across eukaryotes and bacteria as well. Many research studies focus on the synthesis of chemical compounds bearing possible therapeutic action, which mimic the heme moiety and activate the sGC enzyme. In this study, we report a preliminary solution NMR (Nuclear Magnetic Resonance) study of the H-NOX domain from Nostoc sp. cyanobacterium in complex with the chemical sGC activator cinaciguat (BAY58-2667). An almost complete sequence-specific assignment of its 1H, 15N and 13C resonances was obtained and its secondary structure predicted by TALOS+

Insights into Soluble Guanylyl Cyclase Activation Derived from Improved Heme-Mimetics

Recently, the structure of BAY 58-2667 bound to the Nostoc sp. H-NOX domain was published. On the basis of this structural information, we designed BAY 58-2667 derivatives and tested their effects on soluble guanylyl cyclase (sGC) activity. Derivative 20 activated sGC 4.8-fold more than BAY 58-2667. Co-crystallization of 20 with the Ns H-NOX domain revealed that the increased conformational distortion at the C-terminal region of alpha F helix containing 110-114 residues contributes to the higher activation triggered by 20

A Fast Entry to Furanoditerpenoid-Based Hedgehog Signaling Inhibitors: Identifying Essential Structural Features

New, small molecule Hedgehog (Hh) pathway inhibitors, such as the furanoditerpenoid taepeenin D, are of high medicinal importance. To establish key structure–activity relationships (SARs) for this lead, a synthetic sequence has been developed for the expedient preparation of several derivatives and their evaluation as Hh inhibitors exploiting its structural similarity to abietic acid. While C(14) substitution is not essential for biological activity, the presence of a hydrogen bond acceptor at C(6) and an intact benzofuran moiety are

Insights into Soluble Guanylyl Cyclase Activation Derived from Improved Heme-Mimetics

Recently, the structure of BAY 58-2667 bound to the Nostoc sp. H-NOX domain was published. On the basis of this structural information, we designed BAY 58-2667 derivatives and tested their effects on soluble guanylyl cyclase (sGC) activity. Derivative <b>20</b> activated sGC 4.8-fold more than BAY 58-2667. Co-crystallization of <b>20</b> with the <i>Ns</i> H-NOX domain revealed that the increased conformational distortion at the C-terminal region of αF helix containing 110–114 residues contributes to the higher activation triggered by <b>20</b>