An Enantioselective Total Synthesis and Stereochemical Revision of (+)-Citrinadin B

This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed an anomaly in the original structural assignment that has led to the proposal of a stereochemical revision. This revision is consistent with the structures previously reported for a closely related family of alkaloids, PF1270A–C. The synthesis is convergent and employs a stereoselective intermolecular nitrone cyloaddition reaction as a key step

An Enantioselective Total Synthesis and Stereochemical Revision of (+)-Citrinadin B

This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed an anomaly in the original structural assignment that has led to the proposal of a stereochemical revision. This revision is consistent with the structures previously reported for a closely related family of alkaloids, PF1270A–C. The synthesis is convergent and employs a stereoselective intermolecular nitrone cyloaddition reaction as a key step

An Enantioselective Total Synthesis and Stereochemical Revision of (+)-Citrinadin B

This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed an anomaly in the original structural assignment that has led to the proposal of a stereochemical revision. This revision is consistent with the structures previously reported for a closely related family of alkaloids, PF1270A–C. The synthesis is convergent and employs a stereoselective intermolecular nitrone cyloaddition reaction as a key step

An Enantioselective Total Synthesis and Stereochemical Revision of (+)-Citrinadin B

This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed an anomaly in the original structural assignment that has led to the proposal of a stereochemical revision. This revision is consistent with the structures previously reported for a closely related family of alkaloids, PF1270A–C. The synthesis is convergent and employs a stereoselective intermolecular nitrone cyloaddition reaction as a key step

Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors

The synthesis of 4′,6′-dihydrospiro­[piperidine-4,5′-pyrazolo­[3,4-<i>c</i>]­pyridin]-7′(2′<i>H</i>)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 <i>tert</i>-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1<i>H</i>-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 <i>tert</i>-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues

Glycomimetic Ligands for the Human Asialoglycoprotein Receptor

The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent <i>N</i>-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR

Spirolactam-Based Acetyl-CoA Carboxylase Inhibitors: Toward Improved Metabolic Stability of a Chromanone Lead Structure

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in <i>de novo</i> lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide <b>21</b>, which was advanced to preclinical development

Germ cell apoptosis induced by artificial cryptorchidism.

Abstrakt. Studovali jsme vliv experimentalniho unilateralniho kryptorchismu na morfologicke a histologicke ukazatele ve tkanich varlat a nadvarlat skupiny samců potkana Wistar. Doba trvani experimentu byla 7 dnů, přičemž byla do kryptorchickych varlat injikovana latka MDOCTM. Pro histologicke hodnoceni kratšich časovych intervalů jsme použili take material z jinych srovnatelnych pokusů, ale bez MDOCTM. Delka a hmotnost kryptorchickych varlat byly vyznamně sniženy v porovnani s kontrolami (22,4% a 52,6%). Degenerativni změny byly patrne již v intervalu jedne hodiny (desintegrace zarodečneho epitelu). Nezrale zarodečne buňky včetně apoptotickych jsme nalezli v lumen kanalku nadvarlete. 6. den jsme v zarodečnem epitelu objevili take mnohojaderne buňky a jeho vakuolizaci. Po sedmi dnech s aplikaci MDOCTM jsme našli vyznamnou degeneraci zarodečneho epitelu zahrnujici mnoho znaků od vakuolizace epitelu po značne množstvi apoptotickych buněk. Take jsme nalezli velke množstvi infiltrovanych makrofagů. Nezazmamenali jsme žadne degenerativni znaky u kontralateralnich kontrol, ani u kontroly, kde jsme opět vratili varle do skrota (shame operated).Abstract. We had studied morfological and histological changes of Wistar rat germinal epithelium after experimentally induced cryptorchidism. Our experiment had lasted seven days. Cryptorchic testes was injected by solution of MDOCTM. We used also tissues which was taken from other comparable studies but without MDOCTM for histological evaluation of shorter time intervals. Both size and weight was significantly reduced in cryptorchid testes compared to contralateral and control testes (22.4% and 52.6% respectively). We recorded degenerative changes of germinal epithelium including epithelial desintegration and release of immature and apoptotic cells, which was found in epydidimal tubules, even in one hour interval. Six days after operation, multinucleated cells and vacuolization of epithlelium also appeared. Seven days after operation (and aplication MDOCTM) we found a significant degeneration of germinal epithelium comprising features from vacuoles to apoptotic cells. A large number of macrophages also appeared in this interval. We didn't record any degenerative features in contralateral and control testes.Katedra biologických a lékařských vědDepartment of Biological and Medical SciencesFaculty of Pharmacy in Hradec KrálovéFarmaceutická fakulta v Hradci Králov

Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor

A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo. Assessment of the biodistribution in rodents of a prototypical Alexa647-labeled trivalent conjugate showed selective hepatocyte targeting with no detectable distribution in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed hepatocellular uptake and prolonged retention compared to a similar GalNAc derived trimer conjugate. Selective release in the liver of a passively permeable small-molecule cargo was achieved by retro-Diels–Alder cleavage of an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, the multicomponent construct described here represents a highly efficient delivery vehicle to hepatocytes

Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor

A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo. Assessment of the biodistribution in rodents of a prototypical Alexa647-labeled trivalent conjugate showed selective hepatocyte targeting with no detectable distribution in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed hepatocellular uptake and prolonged retention compared to a similar GalNAc derived trimer conjugate. Selective release in the liver of a passively permeable small-molecule cargo was achieved by retro-Diels–Alder cleavage of an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, the multicomponent construct described here represents a highly efficient delivery vehicle to hepatocytes