Chemoenzymatic approach to enantiopure streptogramin B variants: characterization of stereoselective pristinamycin I cyclase from Streptomyces pristinaespiralis

Streptogramin B antibiotics are cyclic peptide natural products produced by Streptomyces species.In combination with the synergistic group A component, they are "last line of defense" antimicrobial agents against multiresistant cocci. The racemization sensitivity of the phenylglycine (Phg(7)) ester is a complex challenge in total chemical synthesis of streptogramin B molecules. To provide fast and easy access to novel streptogramin antibiotics, we introduce a novel chemoenzymatic strategy in which diversity is generated by standard solid phase protocols and stereoselectivity by subsequent enzymatic cyclization. For this approach, we cloned, overproduced, and biochemically characterized the recombinant thioesterase domain SnbDE TE of the pristinamycin I nonribosomal peptide synthetase from Streptomyces pristinaespiralis. SnbDE TE catalyzes regioselective ring closure of linear peptide thioester analogues of pristinamycin I as well as stereoselective cyclization out of complex in situ racemizing substrate mixtures, enabling synthesis of Streptogramin B variants via a dynamic kinetic resolution assay. A remarkable substrate tolerance was detected for the enzymatic cyclization including all the seven positions of the peptide backbone. Interestingly, SnbDE TE was observed to be the first cyclase from a macrolactone forming NRPS which is additionally able to catalyze macrolactamization of peptide thioester substrates. An N-methylated peptide bond between positions 4 and 5 is mandatory for a high substrate turnover. The presented strategy is potent to screen for analogues with improved activity and guides our understanding of structure--activity relationships in the important class of streptogramin antibiotics.     

Synthesis and Structural Characterization of [Mn(ethyl isonicotinate)(2)(N(3))(2)](n)(), a Two-Dimensional Alternating Ferromagnetic-Antiferromagnetic Compound. Magnetostructural Correlations for the End-to-End Pseudohalide-Manganese System

Three compounds with formula [Mn(L)(2)(N(3))(2)](n)(), in which L is 4-acpy = 4-acetylpyridine (1), Etinc = ethyl isonicotinate (2), and py = pyridine (3), have been studied from the magnetic point of view. The new compound [Mn(L)(2)(N(3))(2)](n)() (2) crystallizes in the monoclinic system, space group P2(1)/a (No. 14), formula [C(16)H(18)MnN(8)O(4)], with a = 15.176(5) ?, b = 9.060(3) ?, c = 15.760(6) ?, beta = 111.62(3) degrees, and Z = 4. Compounds 1 and 2 are two-dimensional systems, whereas 3 is a 3-D compound. Compound 2 shows ferromagnetic Mn(2)(N(3))(2) dimeric entities linked antiferromagnetically to the four neighboring dimeric entities by four end-to-end azido bridges, leading to an alternate ferromagnetic-antiferromagnetic two-dimensional compound. MO calculations have been performed to study the superexchange pathway for the manganese 1,3-azido system.     

New pyranosyl cembranoid diterpenes from Sarcophyton trocheliophorum

During our continual searching programme for novel bioactive metabolites from Sarcophyton trocheliophorum, collected from Red Sea, we describe herein the isolation and structural elucidation of further two new pyrane-based cembranoid diterpenes: 9-hydroxy-7,8-dehydro-sarcotrocheliol (1) and 8,9-expoy-sarcotrocheliol acetate (2), along with the well-known sarcotrocheliol acetate (3), (+)-sarcophine (4), (+)-sarcophytoxide (5) and (-)-sarcophytoxide (6). The chemical structures of compounds 1 and 2 were determined on the basis of 1D and 2D NMR (¹H, ¹³C, ¹H–¹H COSY, HMQC, HMBC and NOE), mass spectra (ESI and HR-ESIMS) and by comparison with related structures. The antimicrobial activities of the reported compounds 1–6 were investigated. According to the molecular docking study of compounds 1–6 using 3D structure of α,β tubulin in complex with taxol (PDB code 1JFF) and epothilone A (PDB code 1TVK), sarcophine (4) displayed the highest affinity towards both crystal structures, followed by 5 and 6, meanwhile pyrane-based cembranoid diterpenes (1–3) showed less affinity.     

Optical emission spectroscopy as a real time diagnostic tool for plasma-assisted deposition of TiN

Real-time optical emission spectroscopy (OES) was used to monitor the deposition of TiN both from mixtures of tetrakis(dimethylamino)titanium (TDMATi)-N₂ and TiCl₄-H₂-N₂ in an electron cyclotron resonance chemical vapor deposition system. The accurate control of the ratio of the emission intensities of ionized nitrogen at 391.4 nm and molecular nitrogen at 357.7 nm (N ₂ ⁺ /N₂) led to low temperature deposition of stoichiometric TiN (Ti/N ≈ 1) and very low resistivity in both cases. It was found that high ion density plasmas are crucial for a considerable reduction of the deposition temperature while maintaining good film quality. OES shows that the abundance of certain excited plasma species is not only dependent on the gas mixture and the deposition parameters, such as total pressure and microwave power, but also is strongly affected by the magnetic field configuration. The deposition rate and the film resistivity can be related to the emission intensity ratio, I(N ₂ ⁺ )/I(N₂). Finally, the two processes are compared in terms of the quality of as-deposited and heat-treated films. The comparison shows that the films obtained with TDMATi exhibit lower resistivity and are thermally more stable than with TiCl₄.     

Chemoselective thioacetalization and transthioacetalization of carbonyl compounds catalyzed by immobilized scandium(III) triflate in ionic liquids

Immobilized scandium triflate [Sc(OTf)₃] in ionic liquids has been found to be an extremely efficient and recyclable catalyst for the thioacetalization and transthioacetalization of both aromatic and aliphatic aldehydes. Significant rate acceleration and chemoselectivity was achieved by employing this catalytic system.     

Synthesis and spectroscopic studies of methoxy-substituted phenylthienylnicotinamidines

Abstract

Five thienylnicotinamidine derivatives 5a–e were prepared from their corresponding nicotinonitriles 3a–e on treatment with lithium trimethylsilylamide [LiN(TMS)₂] followed by hydrolysis using ethanolic/HCl (gas). The nicotinonitriles 3a–e were prepared via Suzuki coupling reaction of bromothienyl derivative 1 with the appropriate phenylboronic acids 2a–e. The DFT calculation was used to optimize the geometric structure of the newly synthesized nicotinamidines. The comparison of DFT/B3LYP calculated spectral data (¹H-NMR and ¹³C-NMR) with the experimental data showed acceptable agreement. Mass fragmentation patterns of 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, and 3,4,5-trimethoxyphenyl thienylnicotinamidine derivatives were investigated.     

Synthesis and derivatization of daptomycin: a chemoenzymatic route to acidic lipopeptide antibiotics

Daptomycin is a branched cyclic nonribosomally assembled acidic lipopeptide, which is the first clinically approved antibiotic of this class. Here we show that the recombinant cyclization domain of the Streptomyces coelicolor calcium-dependent antibiotic (CDA) nonribosomal peptide synthetase (NRPS) is a versatile tool for the chemoenzymatic generation of daptomycin derivatives. Linear CDA undecapeptide thioesters with single exchanges at six daptomycin-specific residues were successfully cyclized by CDA cyclase. Simultaneous incorporation of all six of these residues into the peptide backbone and elongation of the N-terminus of CDA by two residues yielded a daptomycin derivative that lacked only the beta-methyl group of l-3-methylglutamate. Bioactivity studies with several substrate analogues revealed a significant role of nonproteinogenic constituents for antibacterial potency. In accordance with acidic lipopeptides, the bioactivity of the chemoenzymatic assembled daptomycin analogue is dependent on the concentration of calcium ions. Single deletions of the four acidic residues in the peptide backbone suggest that only two aspartic acid residues are essential for antimicrobial potency. These two residues are strictly conserved among other nonribosomal acidic lipopeptides and the EF-motif of ribosomally assembled calmodulin. Based on these findings CDA cyclase is a versatile catalyst that can be used to generate novel daptomycin derivatives that are otherwise difficult to obtain by chemical modification of the parental tridecapeptide to improve further its therapeutic activity.     

A novel and expeditious approach to unusual spirolactam building blocks

A rapid access to 7-azaspiro[4.5]decan-6-ones 1 involving three regio- and chemoselective reactions starting from tetrabromonorbornyl derivatives is described. The alkaline H(2)O(2) cleavage reaction of monosubstituted alpha-diketones 9 furnished the potential bridged bicyclic lactones 10in a highly regio- and stereoselective manner. The radical-mediated, intermolecular bridgehead C-C bond formation of the versatile bridged lactones 10 with acrylonitrile followed by LAH reduction of the adduct 13 intriguingly leads to the formation of novel spirolactam building blocks 1.     

Synthesis and Reactions of 5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-phenyl-7 H -thiazolo[3,2- a ]pyrimidine-6-carbonitrile

5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile was synthesized via the reaction of 4-(2-aminothiazol-4-yl)-3-methyl-1-phenyl-2-pyrazolin-5-one with benzylidene malononitrile and was then transformed to related fused heterocyclic systems. The antifungal and antibacterial studies revealed in some cases excellent biocidal properties.     

Organophosphorus chemistry,XII. Reaction of furil with alkyl phosphites and ylide-phosphoranes

Summary The reaction of furil (1) with trialkyl phosphites2 yielded caged phosphorane derivatives of types3a-c. Dry hydrogen chloride gas converted3a-c into the respectivea-hydroxyvinyl-phosphates8a-c which are equally produced by reacting furil with the appropriate dialkyl phosphite7. The reaction of furil with ylide-phosphoranes10 proceeded according to the Wittig reaction mechanism to give the respective ethylenes11a-c. The new compounds have been characterized by their spectroscopic data (IR, PMR,³¹P-NMR, MS) and elementary analyses.Dedicated to Prof. M. Sidky on the occasion of his 60th birthday