Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C

Sphingosine kinases (SphKs) are oncogenic enzymes that regulate the critical balance between ceramide and sphingosine-1-phosphate. Much effort has been dedicated to develop inhibitors against these enzymes. Naturally occurring pachastrissamine (jaspine B) and all its stereoisomers were prepared and evaluated for their inhibitory effects against SphKs. All eight stereoisomers exhibited moderate to potent inhibitory activity against SphK1 and SphK2. Inhibitory effects were profiled against protein kinase C (PKC) isoforms by in vitro experiments. Atypical PKCs (PKCζ and PKCι) were inhibited by several pachastrissamine stereoisomers. The improved activity over N,N-dimethylsphingosine suggests that the cyclic scaffold in pachastrissamines facilitates potential favorable interactions with SphKs and PKCs.     

Synthesis and biological properties of ovine corticotropin-releasing factor (CRF)

The 41-residue sequence of recently identified ovine corticotropin-releasing factor (CRF) was assembled on a benzhydrylamine resin support. Deprotection and cleavage from the resin were accomplished by HF treatment. The crude peptide was purified by gel filtration and reverse-phase, medium pressure, followed by high-performance liquid chromatography (HPLC). In addition to the usual criteria, the homogeneity of the final material, obtained in 7% yield, was assessed by the isolation and examination of cyanogen bromide cleavage and tryptic digestion fragments by HPLC and amino acid analysis. The synthetic 41 amino acid CRF stimulated the release of corticotropin (ACTH) in three in vitro systems: isolated rat pituitary quarters, monolayer cultures of dispersed pituitary cells, and superfused pituitary cells on a column, the responses being related to the log-dose of CRF in the range of 0.05-125 ng/ml. The synthetic peptide also augmented in vivo release of ACTH in rats pretreated with chlorpromazine, morphine, and Nembutal, as assessed by the measurement of serum corticosterone. The data indicates chemical purity and high biological activity of synthetic material.     

Stereoselective synthesis of jaspine B from D-xylose

The natural cytotoxic marine compound, jaspine B, is stereoselectively synthesized from D-xylose in 11 linear steps with a 23.9% overall yield. The key step in the synthesis involves an iodine-induced debenzylation of a primary alcohol and the subsequent 2,5-cyclization to fit the required configuration of jaspine B. A preliminary bioassay shows strong inhibition activities against human MDA231, Hela, and CNE cell lines, indicating potential usage in various cancer treatments.     

Synthesis and biological properties of beta-turned Abeta(31-35) constrained analogues

A series of constrained pentapeptide analogues of the fragment Abeta(31-35) has been prepared using solid phase synthesis protocols. The results of conformational studies and surface plasmon resonance (SPR) experiments seem to indicate that the affinity of these constrained analogues for immobilized Abeta(25-35) peptide could be related to their ability to adopt a Leu34N-Ile31O beta-turn-like folded conformation.     

Synthesis and biological properties of 16(S)-amino-PGF2 alpha methyl ester

A synthesis of 16-amino-derivatives of PGF2 alpha is reported. Introduction of an amino group into position 16 of PGF2 alpha has decreased the sensitivity of the compound to metabolic degradation. 16(S)-amino-PGF2 alpha methyl ester shows high abortifacient activity with reduced diarrhoeic side effect.     

Discovery of novel jaspine B analogues as autophagy inducer

A series of 2-alkylaminomethyl jaspine B analogues were synthesized and evaluated for their cytotoxic effects on human lung adenocarcinoma, breast cancer, and prostate cancer cell lines and a mouse melanoma cell line. Most of the compounds exhibited moderate to good activity against the cancer cell lines. Compound 7f showed the best overall cytotoxicity on PC-3 cells (IC₅₀?=?0.85?μM). Further mechanistic studies revealed that compound 7f induced marked changes in PC-3 cell morphology, disrupted the mitochondrial membrane potential, and increased expression of the autophagy proteins beclin-1, LC3, and P62.     

Synthesis and biological activity of ribose-5'-carbamate derivatives of vitamin B(12)

Twelve biologically active derivatives of vitamin B(12) (cyanocobalamin) have been synthesized in which spacers were attached to the ribose-5'-hydroxyl group of vitamin B(12). Their potential to act as oral delivery agents for proteins, nanospheres, or immunogens using the vitamin B(12) uptake system was evaluated by determining their affinity for intrinsic factor (IF) and non-IF. The ribose-5'-hydroxyl group of vitamin B(12) was activated through the use of 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonyldi(1,2, 4-triazole) (CDT), or di(1-benzotriazolyl) carbonate (DBTC). Subsequent addition of an aminoalkane, diaminoalkane, or alkane diacid dihydrazide gave rise to vitamin B(12) derivatives suitable for attachment to various proteins, peptides, or nanospheres to enable oral delivery utilizing the vitamin B(12) uptake system. The ribose-5'-carbamate derivatives were found to possess similar affinity for intrinsic factor as that of the e-monocarboxylic acid of vitamin B(12). The affinity for non-IF was similar to cyanocobalamin or even higher for some of the smaller derivatives. Polysciences nanoparticles derivatized with vitamin B(12) 5'-carbamate adipic dihydrazide into CaCo-2 cells showed significantly higher levels of transport of the particles, when compared to unmodified particles.     

Synthesis and biological properties of (Leu-6)-LH-RH and (D-Leu-6,desGly-NH210)-LH-RH ethylamide

[Leu⁶,desGly-NH₂¹⁰]-LH-RH ethylamide and [Leu⁶]-LH-RH, two analogs of LH-RH, were prepared by the solid phase method. LH- and FSH-releasing activity of these peptides was assayed against LH-RH by subcutaneous administration in immature male rats. When the integrated levels of LH and FSH over a 6 hr period after the injection were used as parameter of the LH- and FSH-releasing activities, the [Leu⁶]-LH-RH showed LH-releasing activity of 9 times and FSH-releasing activity of 5 times greater than that of LH-RH. [Leu⁶,desGly-NH₂¹⁰]-LH-RH ethylamide showed LH- and FSH-releasing activities of 53.6 and 14.5 times greater, respectively, than that of LH-RH.     

Synthesis and biological properties of a cyclic analog of ACTH-(5-14)-decapeptide

A cyclic analogue and the corresponding linear segment of the corticotropin molecule, namely ACTH-(5-14)- and [cyclo (Glu gamma-epsilon Lys)]ACTH-(5-14)-decapeptide, both including the specific and unspecific active centers of the ACTH molecule, have been synthesized and studied. The cyclic structure is fixed by amide bond between the glutamic acid and lysine side chains. Condensation of fragments has been realized by azide or DCC/HOBT methods. Cyclization has been achieved using diphenylphosphorylazide. The cyclic analogue has full steroidogenic activity, while its melanotropic activity is 3 orders of magnitude higher than that of the linear decapeptide.     

Synthesis, properties, and biological activity of poly[di(sodium carboxylatoethylphenoxy)phosphazene

A new water-soluble polyphosphazene polyelectrolyte containing carboxylate functionalities, poly[di(sodium carboxylatoethylphenoxy)phosphazene] (PCEP) was synthesized via reaction of macromolecular substitution. The polymer was characterized using (1)H, (31)P NMR, and gel permeation chromatography with multiangle laser light scattering detection. PCEP was shown to undergo hydrolytic degradation in aqueous solutions, as indicated by the decrease in the molecular weight and the release of side groups. A series of incompletely substituted copolymers of PCEP containing varying amounts of residual chlorine atoms was also prepared. The rate of degradation for such copolymers increased with the rise in the content of chlorine atoms. In vivo studies demonstrated high potency of PCEP as a vaccine immunoadjuvant. The new polyphosphazene was also shown to be capable of forming microspheres in aqueous solutions via reactions of ionic complexation with physiologically occurring amines, such as spermine.     

Synthesis, characterization and biological properties of cobalt(II) complexes of 1,10-phenanthroline and maltol

The synthesis and characterization of two cobalt(II) complexes, Co(phen)(ma)Cl 1 and Co(ma)₂(phen) 2, (phen = 1,10-phenanthroline, ma⁻ = maltolate or 2-methyl-4-oxo-4H-pyran-3-olate) are reported herein. The complexes have been characterized by FTIR, CHN analysis, fluorescence spectroscopy, UV-visible spectroscopy, conductivity measurement and X-ray crystallography. The number of chelated maltolate ligands seems to influence their DNA recognition, topoisomerase I inhibition and antiproliferative properties.     

Characterization of biological properties of synthetic and biological leukotriene B3

Leukotriene B3 was chemically synthesized and its ability to aggregate rat polymorphonuclear leukocytes (PMN) and to enhance chemokinesis of human leukocytes demonstrated. In both these assays the potency of synthetic leukotriene B3 was marginally less than that of leukotriene B4. Rat PMN incubated with leukotriene A3 were very inefficient in the enzymatic conversion of this epoxide to leukotriene B3. However, the leukotriene B3 produced was able to aggregate rat PMN. These results suggest that unlike leukotriene B5, the proinflammatory properties of leukotriene B3 are similar to those of leukotriene B4. However, since the enzymatic conversion of leukotriene A3 to leukotriene B3 is extremely poor it seems unlikely that leukotriene B3 itself has any major role in vivo.     

Synthesis and biological properties of novel sphingosine derivatives

Sphingosine-1-phosphate (S-1P) derivatives such as threo-(2S,3S)-analogues, which are C-3 stereoisomers of natural erythro-(2S,3R)-S-1P, have been synthesized starting from l-serine or (1S,2S)-2-amino-1-aryl-1,3-propanediols (6). threo-(1S,2R)-2-Amino-1-aryl-3-bromopropanols (HBr salt) have also been prepared from 6. The threo-S-1Ps and the threo-amino-bromide derivatives have shown potent inhibitory activity against Ca(2+) ion mobilization in HL60 cells induced by erythro-S-1P, suggesting that these compounds would compete with cell surface EDG/S1P receptors.     

Synthesis of benzo-annulated tryptanthrins and their biological properties

A series of benzo-annulated derivatives of tryptanthrin were prepared and their optical and redox properties were studied. Tryptanthrin and its benzo-annulated derivatives showed selective inhibitory activity on topo I with an increase of activity on topo II by benzo-annulation on quinazolin-4(3H)-one moiety. Although the benzo-annulation on quinazolin-4(3H)-one ring did not affect significantly on the inhibitory activities against topo I and II, the benzoannulation on indolin-3-one ring affected the inhibitory activity very much especially by linear annulation. Cytotoxicities were not significantly changed upon benzoannulation, which were not directly related either to the inhibitory activities against topo I and II or to the reduction potentials.     

Synthesis and biological properties of galactofuranosyl-containing fluorescent dyes

Two fluorescent galactofuranosides were synthesized and their biological activities evaluated on non-infected and Leishmania infected macrophages. Both tagged scaffolds were able to penetrate macrophages. Compared to the activity of the parent octyl galactofuranoside used as a reference, the fluorescein-conjugate showed altered biological properties while the rhodamine 6G one synergistically acted with the lipid chain to significantly increase antiparasitic activity.     

Synthesis and biological properties of aryl methyl sulfones

A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC₅₀ COX-1?=?0.04 and COX-2?=?0.10?μM, and naproxen: IC₅₀ COX-1?=?11.3 and COX-2?=?3.36?μM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies.The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.     

Synthesis and biological activities of (Z) and (E) alpha-ethenyl acyclonucleosides

Synthesis of Z and E ethenyl acyclonucleosides (6a-e and 7a-e) via Michael addition of nucleobases with the diethyl acetylenedicarboxylate is described. The structures of compounds have been confirmed by spectral data. New compounds were found to be inactive against DNA and RNA viruses.     

Variation of diastereoisomeric pyrrolizidine alkaloids in Pleurothallis (Orchidaceae)

The alkaloids of leaves and flowers of 18 populations of four Pleurothallis (Orchidaceae) species were characterized. Both leaves and flowers of individuals from all populations have two diasteroisomers of 1-hydroxymethylpyrrolizidine (RI=1290 and 1311). The 1290 isomer was the most abundant in all populations of P. johannensis (74-93%) and P. fabiobarrosii (63-93%), two morphologically closed species. On the other hand, in almost all populations of P. teres the 1311 isomer is the more abundant (61-95%), except in one population occurring disjunct from the core area distribution of the species. These results support the recent taxonomic revision for these three species. Almost all P. ochreata populations also have the 1290 as the most abundant isomer, except in one morphologically differentiated population situated at the southern extreme of the distribution of this species.     

Synthesis and biological evaluation of (-)-laulimalide analogues

Analogues of the marine natural product (-)-laulimalide were prepared by total synthesis and evaluated in vitro for anticancer activity.