Nonenzymatic Stereoselective S-Glycosylation of Polypeptides and Proteins.

Here we report a nonenzymatic glycosylation reaction that builds axial S-glycosidic bonds under biorelevant conditions. This strategy is enabled by the design and use of allyl glycosyl sulfones as precursors to glycosyl radicals and exploits the exceptional functional group tolerance of radical processes. Our method introduces a variety of unprotected glycosyl units to the cysteine residues of peptides in a highly selective fashion. Through developing the second-generation protocol, we applied our method in the direct glycosylation of complex polypeptides and proteins. Computational studies were performed to elucidate the reaction mechanism.

Aromatic Ring Substituted Aaptamine Analogues as Potential Cytotoxic Agents against Extranodal Natural Killer/T-Cell Lymphoma.

A chemical modification study was conducted on the marine natural product aaptamine (1), isolated from the marine sponge Aaptos aaptos. Thirty new derivatives substituted by various aromatic rings at the 3- and 7-positions of aaptamine were prepared by bromination, followed by the Suzuki coupling reaction. Sixteen compounds displayed cytotoxicities to four cancer cell lines (IC50 < 10 µM). In particular, compound 5i demonstrated a significant antiproliferative effect on the extranodal natural killer/T-cell lymphoma (ENKT) cell line SNK-6 with an IC50 value of 0.6 µM. Additionally, compound 5i showed cytotoxicities to multiple lymphoma cell lines, including Ramos, Raji, WSU-DLCL2, and SU-DHL-4 cells.

Amentotaxins C-V, Structurally Diverse Diterpenoids from the Leaves and Twigs of the Vulnerable Conifer Amentotaxus argotaenia and Their Cytotoxic Effects.

A phytochemical investigation of the MeOH extract of the leaves and twigs of Amentotaxus argotaenia, a relict vulnerable coniferous species endemic to China, led to the isolation and characterization of 35 diterpenoids/norditerpenoids. Twenty of these are new, including 11 ent-kaurane-type (amentotaxins C-M, 1-11, respectively), three icetexane-type [= 9(10→20)abeo-abietane-type (amentotaxins N-P, 12-14, respectively)], four ent-labdane-type (amentotaxins Q-T, 15-18, respectively), and two isopimarane-type [amentotaxins U (19) and V (20)] compounds. Their structures were elucidated on the basis of spectroscopic data, single-crystal X-ray diffraction, the modified Mosher's method, and electronic circular dichroism data analyses. Compounds 1-9 are rare 18-nor-ent-kaurane-type diterpenoids featuring a 4ß,19-epoxy ring. All the isolates were evaluated for their cytotoxic effects against a small panel of cultured human cancer cell lines (HeLa, A-549, MDA-MB-231, SKOV3, Huh-7, and HCT-116), and some of them exhibited cytotoxicities with IC50 values ranging from 1.5 to 10.0 µM.

Sungeidines from a Non-canonical Enediyne Biosynthetic Pathway.

We report the genome-guided discovery of sungeidines, a class of microbial secondary metabolites with unique structural features. Despite evolutionary relationships with dynemicin-type enediynes, the sungeidines are produced by a biosynthetic gene cluster (BGC) that exhibits distinct differences from known enediyne BGCs. Our studies suggest that the sungeidines are assembled from two octaketide chains that are processed differently than those of the dynemicin-type enediynes. The biosynthesis also involves a unique activating sulfotransferase that promotes a dehydration reaction. The loss of genes, including a putative epoxidase gene, is likely to be the main cause of the divergence of the sungeidine pathway from other canonical enediyne pathways. The findings disclose the surprising evolvability of enediyne pathways and set the stage for characterizing the intriguing enzymatic steps in sungeidine biosynthesis.

Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska's Deep Ocean.

We report here the orchestration of molecular ion networking and a set of computationally assisted structural elucidation approaches in the discovery of a new class of pyrroloiminoquinone alkaloids that possess selective bioactivity against pancreatic cancer cell lines. Aleutianamine represents the first in a new class of pyrroloiminoquinone alkaloids possessing a highly strained multibridged ring system, discovered from Latrunculia ( Latrunculia) austini Samaai, Kelly & Gibbons, 2006 (class Demospongiae, order Poecilosclerida, family Latrunculiidae) recovered during a NOAA deep-water exploration of the Aleutian Islands. The molecule was identified with the guidance of mass spectrometry, nuclear magnetic resonance, and molecular ion networking (MoIN) analysis. The structure of aleutianamine was determined using extensive spectroscopic analysis in conjunction with computationally assisted quantifiable structure elucidation tools. Aleutianamine exhibited potent and selective cytotoxicity toward solid tumor cell lines including pancreatic cancer (PANC-1) with an IC50 of 25 nM and colon cancer (HCT-116) with an IC50 of 1 µM, and represents a potent and selective candidate for advanced preclinical studies.

Relative and absolute stereochemistry of diacarperoxides: antimalarial norditerpene endoperoxides from marine sponge Diacarnus megaspinorhabdosa.

Five new norditerpene endoperoxides, named diacarperoxides H-L (1-5), and a new norditerpene diol, called diacardiol B (6), were isolated from the South China Sea sponge, Diacarnus megaspinorhabdosa. Their structures, including conformations and absolute configurations, were determined by using spectroscopic analyses, computational approaches and chemical degradation. Diacarperoxides H-J (1-3) showed some interesting stereochemical issues, as well as antimalarial activity.

Eucalyptals D and E, new cytotoxic phloroglucinols from the fruits of Eucalyptus globulus and assignment of absolute configuration.

Two new phloroglucinols, named eucalyptals D (1) and E (2), along with a related known compound (euglobal-In-3, 3) were isolated from the fruits of Eucalyptus globulus. Their structures were established on the basis of extensive spectroscopic studies, revealing that they share a common 3,5-diformyl-isopentyl phloroglucinol unit, but each is instead coupled to a different sesquiterpenoid skeleton (aromadendrene in 1, cadinene in 2, and a spirosesquiterpene in 3). Compound 1 possessed an unusual seven-membered D ring with an ether bridge between C-2 of the aromadendrene moiety and C-2' of the aromatic unit. The absolute configuration of the isolates was defined by the comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1-3 exhibited significant in vitro cytotoxicities against a few human cancer cell lines (Huh-7, Jurkat, BGC-823, and KE-97) using the CellTiter-Glo™ luminescent cell viability assay method.