The Hydrogenobyric Acid Structure Reveals the Corrin Ligand as an Entatic State Module Empowering B12 Cofactors for Catalysis.

The B12 cofactors instill a natural curiosity regarding the primordial selection and evolution of their corrin ligand. Surprisingly, this important natural macrocycle has evaded molecular scrutiny, and its specific role in predisposing the incarcerated cobalt ion for organometallic catalysis has remained obscure. Herein, we report the biosynthesis of the cobalt-free B12 corrin moiety, hydrogenobyric acid (Hby), a compound crafted through pathway redesign. Detailed insights from single-crystal X-ray and solution structures of Hby have revealed a distorted helical cavity, redefining the pattern for binding cobalt ions. Consequently, the corrin ligand coordinates cobalt ions in desymmetrized "entatic" states, thereby promoting the activation of B12 -cofactors for their challenging chemical transitions. The availability of Hby also provides a route to the synthesis of transition metal analogues of B12 .

Phenylbenzenesulfonates and -sulfonamides as 17ß-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis.

17ß-Hydroxysteroid dehydrogenase type 2 (17ß-HSD2) converts the potent estrogen estradiol into the weakly active keto form estrone. Because of its expression in bone, inhibition of 17ß-HSD2 provides an attractive strategy for the treatment of osteoporosis, a condition that is often caused by a decrease of the active sex steroids. Currently, there are no drugs on the market targeting 17ß-HSD2, but in multiple studies, synthesis and biological evaluation of promising 17ß-HSD2 inhibitors have been reported. Our previous work led to the identification of phenylbenzenesulfonamides and -sulfonates as new 17ß-HSD2 inhibitors by ligand-based pharmacophore modeling and virtual screening. In this study, new molecules representing this scaffold were synthesized and tested in vitro for their 17ß-HSD2 activity to derive more profound structure-activity relationship rules.

Chlorophyll Catabolites in Fall Leaves of the Wych Elm Tree Present a Novel Glycosylation Motif.

Fall leaves of the common wych elm tree (Ulmus glabra) were studied with respect to chlorophyll catabolites. Over a dozen colorless, non-fluorescent chlorophyll catabolites (NCCs) and several yellow chlorophyll catabolites (YCCs) were identified tentatively. Three NCC fractions were isolated and their structures were characterized by spectroscopic means. Two of these, Ug-NCC-27 and Ug-NCC-43, carried a glucopyranosyl appendage. Ug-NCC-53, the least polar of these NCCs, was identified as the formal product of an intramolecular esterification of the propionate and primary glucopyranosyl hydroxyl groups of Ug-NCC-43. Thus, the glucopyranose moiety and three of the pyrrole units of Ug-NCC-53 span a 20-membered ring, installing a bicyclo[17.3.1]glycoside moiety. This structural motif is unprecedented in heterocyclic natural products, according to a thorough literature search. The remarkable, three-dimensional bicyclo[17.3.1]glycoside architecture reduces the flexibility of the linear tetrapyrrole. This feature of Ug-NCC-53 is intriguing, considering the diverse biological effects of known bicyclo[n.3.1]glycosidic natural products.

Hydroxymethylated Dioxobilins in Senescent Arabidopsis thaliana Leaves: Sign of a Puzzling Biosynthetic Intermezzo of Chlorophyll Breakdown.

1-Formyl-19-oxobilin-type tetrapyrroles are characteristic, abundant products of chlorophyll breakdown in senescent leaves. However, in some leaves, 1,19-dioxobilin-type chlorophyll catabolites (DCCs) lacking the formyl group accumulate instead. A P450 enzyme was identified in in vitro studies that removed the formyl group of a primary fluorescent chlorophyll catabolite (pFCC) and generated fluorescent DCCs. These DCCs are precursors of isomeric nonfluorescent DCCs (NDCCs). Here, we report a structural investigation of the NDCCs in senescent leaves of wild-type Arabidopsis thaliana. Four new NDCCs were characterized, two of which carried a stereoselectively added hydroxymethyl group. Such formal DCC hydroxymethylations were previously found in DCCs in leaves of a mutant of A. thaliana. They are now indicated to be a feature of chlorophyll breakdown in A. thaliana, associated with the specific in vivo deformylation of pFCC en route to NDCCs.