Human proinsulin VI. Synthesis of protected segment 46-70 of prohormone

The synthesis of the protected pentacosapeptide Trt-Gly-Gly-Pro-Gly-Ala-Gly-Ser-(But)-Leu-Gln-Pro-Leu-Ala-Leu-Glu( OBut)-Gly-Ser (But)-Leu-Gln-Lys(Boc)-Arg-Gly-Ile-Val-Glu-(OBut)-Gln-OH (Pos. 46-70) of human proinsulin is described. This segment was prepared by the mixed anhydride condensation of the trityl-protected peptides (46-64) or (46-59) with the fragments 65-70 and 60-70, respectively. In both the cases the purification was effected by counter current distribution in a yield of 25% and 24%, respectively.     

Synthesis and anti-ulcer activity of 16-phenoxy analogues of (+)-11-deoxyprostaglandin E1

( )-11-Deoxy-16-phenoxy-17,18,19,20-tetranor-prostaglandin E₁ is a highly potent and selective anti-ulcer agent. Analogues of this compound have been synthesized and structure-activity relationships are reported.     

Synthesis of the trypsin fragment 10-25/75-88 of mouse nerve growth factor. I. The protected tetradecapeptide 75-88

Cyanogen bromide cleavage followed by trypsin digestion of mouse nerve growth factor (NGF) allowed the isolation of a double chain unsymmetrical cystine peptide of high neurotrophic activity. The presence of tryptophan residues severely limits the synthetic approaches for selective disulfide bridging. The strategy applied for such a purpose as well as the preparation of the suitably protected tetradecapeptide corresponding to sequence 75-88 as key intermediate for the synthesis of the NGF fragment 10-25/75-88 are described.     

Membrane association and activity of 15/16-membered peptide antibiotics: zervamicin IIB, ampullosporin A and antiamoebin I

Permeabilization of the phospholipid membrane, induced by the antibiotic peptides zervamicin IIB (ZER), ampullosporin A (AMP) and antiamoebin I (ANT) was investigated in a vesicular model system. Membrane-perturbing properties of these 15/16 residue peptides were examined by measuring the K(+) transport across phosphatidyl choline (PC) membrane and by dissipation of the transmembrane potential. The membrane activities are found to decrease in the order ZER>AMP>ANT, which correlates with the sequence of their binding affinities. To follow the insertion of the N-terminal Trp residue of ZER and AMP, the environmental sensitivity of its fluorescence was explored as well as the fluorescence quenching by water-soluble (iodide) and membrane-bound (5- and 16-doxyl stearic acids) quenchers. In contrast to AMP, the binding affinity of ZER as well as the depth of its Trp penetration is strongly influenced by the thickness of the membrane (diC(16:1)PC, diC(18:1)PC, C(16:0)/C(18:1)PC, diC(20:1)PC). In thin membranes, ZER shows a higher tendency to transmembrane alignment. In thick membranes, the in-plane surface association of these peptaibols results in a deeper insertion of the Trp residue of AMP which is in agreement with model calculations on the localization of both peptide molecules at the hydrophilic-hydrophobic interface. The observed differences between the membrane affinities/activities of the studied peptaibols are discussed in relation to their hydrophobic and amphipathic properties.     

Synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate,an analogue of 15R-lipoxin A4

We describe a method for the synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate, a compound that has been described as a metabolically stable analogue of 15R-lipoxin A(4).     

Synthesis, cytostatic, and antiviral activity of novel 6-[2-(dialkylamino)ethyl]-, 6-(2-alkoxyethyl)-, 6-[2-(alkylsulfanyl)ethyl]-, and 6-[2-(dialkylamino)vinyl]purine nucleosides

An efficient and facile synthesis of a large series of diverse 6-[2-(dialkylamino)vinyl]-, 6-[2-(dialkylamino)ethyl]-, 6-(2-alkoxyethyl)-, and 6-[2-(alkylsulfanyl)ethyl]purine nucleosides (35 examples of both ribo- and 2'-deoxyribonucleosides) was developed. The key transformations involved conjugate nucleophilic additions of amines, alcoholates, or thiolates to Tol-protected 6-alkylylpurine or 6-vinylpurine nucleosides. 6-[(2-Dialkylamino)vinyl]- and some 6-[(2-dialkylamino)ethyl]purine ribonucleosides exerted significant cytostatic effects and some anti-HCV activity with low selectivity.     

Conservation of miR-15a/16-1 and miR-15b/16-2 clusters

MiR-15a/16-1 and miR-15b/16-2 clusters have been shown to play very important roles in regulating cell proliferation and apoptosis by targeting cell cycle proteins and the antiapoptotic Bcl-2 gene. However, the physiological implications of those two clusters are largely elusive. By aligning the primary miR-15a/16-1 sequence among 44 vertebrates, we found that there was a gap in the homologous region of the rat genome. To verify that there was a similar miR-15a/16-1 cluster in rats, we amplified this region from rat genomic DNA using PCR and found that a 697-bp sequence was missing in the current rat genome database, which covers the miR-15a/16-1 cluster. Subsequently, we also investigated the expression pattern of individual miRNAs spliced from miR-15a/16-1 and miR-15b/16-2 clusters, including miR-15a, miR-15a*, miR-15b, miR-15b*, miR-16-1/2, and miR-16-1/2* from various rat tissues, and found that all of those miRNAs were expressed in the investigated tissues. MiR-16 was most expressed in the heart, followed by the brain, lung, kidney, and small intestine, which indicates tissue specificity for individual miRNA expression from both clusters. Our results demonstrated that both miR-15a/16-1 and miR-15b/16-2 clusters are highly conserved among mammalian species. The investigation of the biological functions of those two clusters using transgenic or knockout/knockdown models will provide new clues to understanding their implications in human diseases and finding a new approach for miRNA-based therapy.     

Synthesis of the fully protected phosphoramidite of the benzene-DNA adduct, N2-(4-Hydroxyphenyl)-2'-deoxyguanosine and incorporation of the later into DNA oligomers

N(2)- (4-Hydroxyphenyl)-2'-deoxyguanosine-5'-O-DMT-3'-phosphoramidite has been synthesized and used to incorporate the N(2)-(4-hydroxyphenyl)-2'-dG (N(2)-4-HOPh-dG) into DNA, using solid-state synthesis technology. The key step to obtaining the xenonucleoside is a palladium (Xantphos-chelated) catalyzed N(2)-arylation (Buchwald-Hartwig reaction) of a fully protected 2'-deoxyguanosine derivative by 4-isobutyryloxybromobenzene. The reaction proceeded in good yield and the adduct was converted to the required 5'-O-DMT-3'-O-phosphoramidite by standard methods. The latter was used to synthesize oligodeoxynucleotides in which the N(2)-4-HOPh-dG adduct was incorporated site-specifically. The oligomers were purified by reverse-phase HPLC. Enzymatic hydrolysis and HPLC analysis confirmed the presence of this adduct in the oligomers.     

Effect of gemini surfactant (16-6-16) on the synthesis of silver nanoparticles: A facile approach for antibacterial application

In this report, we describe the effect of Gemini surfactants1, 6-Bis (N, N-hexadecyldimethylammonium) adipate (16-6-16) on synthesis, stability and antibacterial activity of silver nanoparticles (AgNPs). The stabilizing effect of Gemini surfactant and aggregation behavior of AgNPs was evaluated by plasmonic property and morphology of the AgNPs were characterized by UV–vis spectroscopy, Dynamic Light Scattering (DLS), X-ray diffraction (XRD), High resolution transmission electron microscopy (HRTEM) and Energy dispersive X-ray analysis (EDX) techniques. Interestingly, the formation of quite mono-dispersed spherical particles was found. Apart from the stabilizing role, the Gemini surfactant has promoted the agglomeration of individual AgNPs in small assemblies whose Plasmon band features differed from those of the individual nanoparticles. The antibacterial activity of the synthesized AgNPs on Gram-negative and Gram-positive bacterium viz., E. coli and S. aureus was carried out by plate count, growth kinetics and cell viability assay. Furthermore, the mechanism of antibacterial activity of AgNPs was tested by Zeta potential and DLS analysis, to conclude that surface charge of AgNPs disrupts the cells causing cell death.     

The first total synthesis of the peptaibol hypomurocin A1 and its conformation analysis: an application of the 'azirine/oxazolone method'

The first total synthesis of Hypomurocin A1 (HM A1) in solution phase is described. As members of the peptaibol family, hypomurocins are constituted by two groups of peptides: six undecapeptides (undecamers) in the HM A group and six octadecapeptides (18-mers) in the HM B group. The synthesis presented has been successfully achieved by the 'azirine/oxazolone method' to introduce the two Aib-Pro sequences included in this undecapeptaibol in one step with methyl 2,2-dimethyl-2H-azirine-3-prolinate as the building block. The coupling reactions of the Z-protected amino acids or peptide acids involved the use of N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt), and led to the peptides in good-to-very-good yields. The peptides were purified by reverse-phase HPLC and characterized by NMR spectroscopy (1H, 13C, COSY, TOCSY, HSQC, HMBC, ROESY), ESI-MS, IR, elemental analysis, optical rotation, and X-ray crystallography. An NMR analysis of HM A1 was also carried out in deuterated micelles to perform a structural comparison of the helix in solution and in membranes.     

Synthesis of the sultam analog of 11-deoxy PGE2.

As an extension of our work on the series of N-alkylmethanesulfonamidoheptanoic acids, we have prepared the cyclic-sulfonamide (sultam) analog of 11-deoxy PGE2. Although numerous publications have described the introduction of heteroatoms into the 5-membered ring of the prostaglandins, the cyclic-sulfonamides have remained a heretofore unexplored class. The synthetic scheme for the preparation of this unique PG analog is presented in this paper.     

Stereoselective total synthesis of a potent natural antifungal compound (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one

A practical stereoselective synthesis of (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one (1), a potent natural antifungal compound, is described. The sequence involves diastereoselective iodine-induced electrophilic cyclization, epoxide ring opening with a vinyl Grignard reagent and ring closing metathesis (RCM) as the key steps.     

Synthesis and bioactivity of novel methyl 6-deoxy-6-(N'-alkyl/aryl-N'-benzothiazol-2-yl)guanidino-alpha-D-glucopyranosides

A series of new methyl 6-deoxy-6-[N′-alkyl/aryl-N″-(benzothiazol-2-yl)]guanidino-α-d-glucopyranosides were obtained from the reaction of an alkyl/aryl amine in the presence of HgCl₂ and sugar-thiourea derivatives, followed by the removal of protecting groups. The sugar-thiourea derivatives were obtained from the treatment of 2-aminobenzothiazole derivatives with methyl 2,3,4-tri-O-acetyl-6-deoxy-6-isothiocyanato-α-d-glucopyranoside in dry pyridine. Some of the synthesized guanidines displayed anti-influenza activity.