Direct Arginine Modification in Native Peptides and Application to Chemical Probe Development

An efficient method for the direct labeling of the Arg guanidinium group in native peptides is reported. This straightforward procedure allows modifying the arginine moiety in peptides with various reporter groups, such as fluorophores, biotin, etc., under mild conditions in an operationally simple procedure. The scope of this method tolerates various functionalized amino acids such as His, Ser, Trp, Tyr, Glu, etc., while the only limitations uncovered so far are restricted to cysteine and free amine residues. The utility of this late-stage diversification method was demonstrated in direct labeling of leuprolide, a clinically used drug, for distribution monitoring in <i>Daphnia</i>, and in labeling of microcystin, a cyanobacterial toxin

Total Synthesis and Structural Revision of Aeruginosin KT608A

The synthesis of the presumed structure of aeruginosin KT608A was accomplished for the first time. The unusual d-<i>diepi</i>-Choi core was prepared from tyrosine via C–H activation and heterogeneous hydrogenation. Due to differences in the spectral data of synthetic and natural samples, a revised structure featuring l-<i>diepi</i>-Choi was proposed, which was synthesized and confirmed to be identical. On the basis of these findings, revised structures for six additional aeruginosins (KT608B, KT650, GH553, DA495A, DA511, and KB676) are presented

Total Synthesis of the Sesquiterpenoid Periconianone A Based on a Postulated Biogenesis

The first enantioselective total synthesis of the complex tricarbocyclic sesquiterpenoid periconianone A based on a postulated biogenesis is reported. Key elements of the synthetic route include the use of an isopropenyl group as a removable directing group for stereoselective synthesis, a sequence featuring a Rh-mediated O–H insertion/[3,3]-sigmatropic rearrangement and subsequent α-ketol rearrangement, and a late stage aldol reaction to furnish the complex cage-like framework

Functionally Optimized Neuritogenic Farinosone C Analogs: SAR-Study and Investigations on Their Mode of Action

Several natural products derived from entomopathogenic fungi have been shown to initiate neuronal differentiation in the rat pheochromocytoma PC12 cell line. After the successful completion of the total synthesis program, the reduction of structural complexity while retaining biological activity was targeted. In this study, farinosone C served as a lead structure and inspired the preparation of small molecules with reduced complexity, of which several were able to induce neurite outgrowth. This allowed for the elaboration of a detailed structure–activity relationship. Investigations on the mode of action utilizing a computational similarity ensemble approach suggested the involvement of the endocannabinoid system as potential target for our analogs and also led to the discovery of four potent new endocannabinoid transport inhibitors

Syntheses of Taiwaniaquinone F and Taiwaniaquinol A via an Unusual Remote C–H Functionalization

A protecting-group-free route to (−)-taiwaniaquinone F based on a ring contraction and subsequent aromatic oxidation of a sugiol derivative is reported. In addition, the first synthesis of (+)-taiwaniaquinol A is reported via short time exposure of (−)-taiwaniaquinone F to sunlight triggering a remote C–H functionalization. The hypothesis that the biogenesis of some methylenedioxy bridged natural products could proceed via similar nonenzymatic mechanisms is presented

Total Synthesis of Tiacumicin A. Total Synthesis, Relay Synthesis, and Degradation Studies of Fidaxomicin (Tiacumicin B, Lipiarmycin A3)

The commercial macrolide antibiotic fidaxomicin was synthesized in a highly convergent manner. Salient features of this synthesis include a β-selective noviosylation, a β-selective rhamnosylation, a ring-closing metathesis, a Suzuki coupling, and a vinylogous Mukaiyama aldol reaction. Careful choice of protecting groups and fine-tuning of the glycosylation reactions led to the first total synthesis of fidaxomicin. In addition, a relay synthesis of fidaxomicin was established, which gives access to a conveniently protected intermediate from the natural material for derivatization. The first total synthesis of a related congener, tiacumicin A, is presented

Investigating Biogenetic Hypotheses of the <i>Securinega</i> Alkaloids: Enantioselective Total Syntheses of Secu’amamine E/<i>ent</i>-Virosine A and Bubbialine

The synthesis of the <i>Securinega</i> alkaloid secu’amamine E (<i>ent</i>-virosine A) has been accomplished for the first time in 12 steps and 8.5% overall yield. In addition, bubbialine has been prepared and characterized. These two alkaloids and bubbialidine, all featuring an azabicyclo­[2.2.2]­octane core, were rearranged to their azabicyclo­[3.2.1]­octane congeners, a framework found in many <i>Securinega</i> alkaloids. These experiments suggest that azabicyclo­[2.2.2]­octane derivatives could serve as intermediates in the biosynthesis of the rearranged azabicyclo­[3.2.1]­octane products

Isolation and Structure Determination of Two Microcystins and Sequence Comparison of the McyABC Adenylation Domains in <i>Planktothrix</i> Species

Microcystins (MCs) are toxic heptapeptides found in cyanobacteria and share the common structure <i>cyclo</i>(-d-Ala¹-l-X²-d-isoMeAsp³-l-Z⁴-Adda⁵-d-isoGlu⁶-Mdha⁷). The letters X and Z in the general formula above represent a wide range of l-amino acids that occupy positions 2 and 4, respectively. In general the variation in structural variants is due to the exchange of amino acids in position 7, 2, and 4. In the present work we report two homotyrosine (Hty)-containing microcystin variants, [d-Asp³,(<i>E</i>)-Dhb⁷]-MC-HtyY (<b>1</b>) and [d-Asp³,(<i>E</i>)-Dhb⁷]-MC-HtyHty (<b>2</b>), which were isolated from strain No80 of <i>Planktothrix rubescens.</i> Their structures were elucidated using amino acid analysis as well as 1D and 2D NMR techniques. The adenylation domains of McyABC involved in amino acid activation in positions 7, 2, and 4 of the microcystin molecule, respectively, were compared with corresponding genes of <i>Planktothrix</i> strain CYA126/8 producing [d-Asp³,Mdha⁷]-MC-RR and [d-Asp³,Mdha⁷]-MC-LR. While the adenylation domain comparison of McyAB between the two <i>Planktothrix</i> strains revealed considerable DNA recombination, the adenylation domain of McyC showed only a single amino acid substitution, which was correlated with the replacement of Arg by Hty in position 4 of the microcystin molecule

Allylic Carbocyclic Inhibitors Covalently Bind Glycoside Hydrolases

Allylic cyclitols were investigated as covalent inhibitors of glycoside hydrolases by chemical, enzymatic, proteomic, and computational methods. This approach was inspired by the C7 cyclitol natural product streptol glucoside, which features a potential carbohydrate leaving group in the 4-position (carbohydrate numbering). To test this hypothesis, carbocyclic inhibitors with leaving groups in the 4- and 6- positions were prepared. The results of enzyme kinetics analyses demonstrated that dinitrophenyl ethers covalently inhibit α-glucosidases of the GH13 family without reactivation. The labeled enzyme was studied by proteomics, and the active site residue Asp214 was identified as modified. Additionally, computational studies, including enzyme homology modeling and density functional theory (DFT) calculations, further delineate the electronic and structural requirements for activity. This study demonstrates that previously unexplored 4- and 6-positions can be exploited for successful inhibitor design