Efficient synthesis of eudistomin U and evaluation of its cytotoxicity

Eudistomin U is a member of a subclass of naturally occurring indole alkaloids known as β-carbolines. These molecules are reported to have diverse biological activity and high binding affinity to DNA, which make them attractive targets for total synthesis. We describe an efficient, five-step synthesis of eudistomin U by employing two key reactions: a Bischler–Napieralski cyclization and a Suzuki cross coupling. We also describe the cytotoxicity of eudistomin U against various cancer cell lines and human pathogens, in which we observed potent antibacterial activity against Gram-positive bacteria.     

Chemoenzymatic synthesis of diverse thiohydroximates from glucosinolate-utilizing enzymes from Helix pomatia and Caldicellulosiruptor saccharolyticus

Thiohydroximates comprise a diverse class of compounds important in both biological and industrial chemistry. Their syntheses are generally limited to simple alkyl and aryl compounds with few stereocenters and a narrow range of functional groups. We hypothesized that sequential action of two recombinant enzymes, a sulfatase from Helix pomatia and a β-O-glucosidase from Caldicellulosiruptor saccharolyticus, on glucosinolates would allow synthesis of thiohydroximates from a structurally broad array of abundant precursors. We report successful synthesis of thiohydroximates of varied chemical classes, including from homochiral compounds of demonstrated biological activity. The chemoenzymatic synthetic route reported here should allow access to many, if not all, of the thiohydroximate core structures of the ~200 known naturally occurring glucosinolates. The enrichment of this group for compounds with possible pharmacological potential is discussed.     

天然产物黄檀内酯的研究进展

本文概述了目前已发表的天然产物黄檀内酯在植物中分布、生物合成、全合成及生物活性的研究进展。     

Synthesis of fluorine-containing bioisosteres corresponding to phosphoamino acids and dipeptide units

It has been shown that fluorinated analogues of naturally occurring biological active compounds including amino acids often exhibit unique physiological activity. Among wide varieties of fluorine-containing amino acids, nonhydrolyzable phosphoamino acids possessing a substituent of the difluoromethylene (CF(2)) unit for the phosphoryl ester oxygen are of value in the medicinal and biological fields. We have engaged in the synthesis of these classes of nonhydrolyzable phosphoamino acids corresponding to pTyr 3, pSer 4, and pThr 5 with their incorporation into peptides using newly developed deprotecting procedures. In this article, stereoselective synthesis of the CF(2)-substituted pThr mimetics and development of a two-step deprotecting methodology for the nonhydrolyzable analogues are reviewed. In the course of the above synthetic study, we found that gamma,gamma-difluoro-alpha,beta-enoates were reduced to gamma-fluoro-beta,gamma-enoates by organocopper reagents and then applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres, which have served as potential dipeptide mimetics having structural as well as electrostatic similarity to the parent peptide bonds. Furthermore, mechanistic investigation of the organocopper-mediated reduction led us to development of a SmI(2)-mediated approach toward the synthesis of the fluoroalkene isosteres.     

Conjugation of l-NAME to prenyloxycinnamic acids improves its inhibitory effects on nitric oxide production

A series of 10 compounds resulting from the conjugation of O-prenylated naturally occurring benzoic and cinnamic acids to l-NAME were synthesized and tested together with the corresponding unprenylated parent molecule as anti-inflammatory agents for their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophages. Results indicated that the coupling between O-geranyl and O-isopentenylcinnamic acids and l-NAME led to products with an enhanced activity when compared to the parent compounds.     

Sweet antibiotics - the role of glycosidic residues in antibiotic and antitumor activity and their randomization

A large number of antibiotics are glycosides. In numerous cases the glycosidic residues are crucial to their activity; sometimes, glycosylation only improves their pharmacokinetic parameters. Recent developments in molecular glycobiology have improved our understanding of aglycone vs. glycoside activities and made it possible to develop new, more active or more effective glycodrugs based on these findings – a very illustrative recent example is vancomycin. The majority of attention has been devoted to glycosidic antibiotics including their past, present, and probably future position in antimicrobial therapy. The role of the glycosidic residue in the biological activity of glycosidic antibiotics, and the attendant targeting and antibiotic selectivity mediated by glycone and aglycone in antibiotics some antitumor agents is discussed here in detail. Chemical and enzymatic modifications of aglycones in antibiotics, including their synthesis, are demonstrated on various examples, with particular emphasis on the role of specific and mutant glycosyltransferases and glycorandomization in the preparation of these compounds. The last section of this review describes and explains the interactions of the glycone moiety of the antibiotics with DNA and especially the design and structure–activity relationship of glycosidic antibiotics, including their classification based on their aglycone and glycosidic moiety. The new enzymatic methodology 'glycorandomization' enabled the preparation of glycoside libraries and opened up new ways to prepare optimized or entirely novel glycoside antibiotics.     

Synthesis and antitumor activity of C-9 epimers of the tetrahydrofuran containing acetogenin 4-deoxyannoreticuin

A highly convergent synthesis of mono-tetrahydrofuran (THF) containing acetogenins, that is based on the cross-metathesis of THF and butenolide alkene precursors, was developed. This methodology was applied to the epimers of the C-9 alcohol of 4-deoxyannoreticuin, in an attempt to assign the configuration at this position in the naturally occurring material. Unfortunately, identification of one or the other epimeric structures with the natural product was not possible because of the closeness of the physical data for all three compounds. Both C-9 epimeric analogues showed similar cytotoxicity in the low micromolar range, against two human tumor cell lines PC-3 (prostate) and Jurkat (T-cell leukemia). This result contrasts to previous studies on closely related THF acetogenins, wherein configurational variation at analogous carbinol centers resulted in a significant effect on antitumor activity.     

Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity

The consumption of food products containing high amounts of flavonoids has been reported to lower the risk of various cancers. The mechanisms underlying the cancer-protective effects of these naturally occurring polyphenolic compounds, however, remain elusive. Based on our previous finding that the cytotoxic effect of the flavanol epigallocatechin-3-gallate on prostate cancer cells correlates with its ability to inhibit fatty acid synthase (FAS, a key lipogenic enzyme overexpressed in many human cancers), we examined the anti-lipogenic effects of a panel of 18 naturally occurring polyphenolic compounds. In addition to epigallocatechin-3-gallate, five other flavonoids, more particularly luteolin, quercetin, kaempferol, apigenin, and taxifolin, also markedly inhibited cancer cell lipogenesis. Interestingly, in both prostate and breast cancer cells, a remarkable dose-response parallelism was observed between flavonoid-induced inhibition of fatty acid synthesis, inhibition of cell growth, and induction of apoptosis. In support for a role of fatty acid synthesis in these effects, the addition of exogenous palmitate, the end product of FAS, markedly suppressed the cytotoxic effects of flavonoids. Taken together, these findings indicate that the potential of flavonoids to induce apoptosis in cancer cells is strongly associated with their FAS inhibitory properties, thereby providing a new mechanism by which polyphenolic compounds may exert their cancer-preventive and antineoplastic effects.     

Synthesis and biological activities of substance P iodinated derivatives

The synthesis of four substance P (SP) derivatives obtained by coupling the monoiodo and diiodo Bolton and Hunter reagents with synthetic SP is described. These compounds were proved to be good ligands for SP antibodies. As seen for SP, they exhibit a high biological activity in the guinea pig ileum bioassay.     

Digging Deep into Peptidomics Applied to Body Fluids

Peptidomics techniques have allowed the identification of thousands of peptides that are derived from proteins in body fluids, despite the considerable challenges behind sample handling, MS‐based identification, data analysis, and integration with bioinformatics tools. Body fluids’ naturally occurring peptides are known to perform a variety of local and systemic functions; however, its knowledge is limited. Even so, the biological meaning that can be retrieved from peptidomics applied to the identification of disease markers and to the development of therapies using peptides has driven the progresses made in this field. In this review, a comparative analysis of body fluids’ peptidome data retrieved from databases and from scientific papers is performed to identify the biological processes modulated by naturally occurring peptides. This integrative analysis highlights several interesting facts, such as the small overlap between blood‐derived serum and plasma, which illustrates the impact of sample handling on these fluids peptidome. Urine is the body fluid with more naturally occurring peptides identified so far, most of which are derived from collagens. In saliva, the majority of peptides are originated from extracellular matrix proteins. Cerebrospinal fluid presents a high number of peptides derived from distinct proteins, mostly involved in the regulation of nervous system homeostasis. The lowest number of endogenous peptides was found in tears, most of which present antimicrobial activity. Collectively, data analysis highlights a peptidome signature for each body fluid, which comprehension will certainly help to improve disease management.     

Flavonoid function and activity to plants and other organisms.

Flavonoid compounds distribute widely in vascular plants and Bryophytes, and ca. 5,000 kinds have been reported as naturally occurring substances. Many biological activities of the flavonoids were found until now. They include pollinator attractants, oviposition stimulants, feeding attractants and deterrents, allelopathy and phytoalexins. This paper reviews function and activity of flavonoids against plants and other organisms.     

Ether lipids

The naturally occurring 1-O-alkyl-sn-glycerols and their methoxylated congeners, 1-O-(2′-methoxyalkyl)-sn-glycerols, are biologically active compounds, ubiquitously found in nature as diacyl glyceryl ether lipids and phosphoether lipids. The chief objective of this article is to provide a comprehensive and up to date review on such ether lipids. The occurrence and distribution of these compounds in nature are extensively reviewed, their chemical structure and molecular variety, their biosynthesis and chemical synthesis and, finally, their various biological effects are described and discussed. An unprecedented biosynthesis of the 2′-methoxylated alkylglycerols is proposed. The first synthesis of enantiopure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol, the most prevalent 2′-methoxylated type alkylglycerol present in cartilaginous fish, is described. It was accomplished by a highly convergent five step process.     

Structural and Biological Diversity of Cyclic Octadecanoids,Jasmonates, and Mimetics

The jasmonate family of plant signaling compounds comprises biologically highly active cyclopentenones (for example, 12-oxo-phytodienoic acid) (12-OPDA) and cyclopentanones (for example, jasmonic acid) (JA) of related origin via the octadecanoid pathway, and structure. Among others, their biological activities include a broad range of defense-related reactions. Several lines of evidence indicate both common and different biological responses mediated by 12-OPDA and/or JA, suggesting the existence of at least two separate structure-activity groups. Based on the structure of a bacterial phytotoxin, coronatine, with similar biological activities compared with jasmonates, indanoyl isoleucine conjugates have been designed as functional synthetic mimics of octadecanoid-derived signals. The structural diversity of naturally occurring jasmonate-related compounds and synthetic mimics is discussed with respect to their corresponding biological activities. Novel strategies for the synthesis of various indanoyl isoleucine conjugates will be presented.     

1-Azaaurones derived from the naturally occurring aurones as potential antimalarial drugs

We report the synthesis and in vitro antiplasmodial activity of 35 compounds, designed as analogues of the naturally occurring aurones. Several of these analogues showed submicromolar antimalarial activity against a chloroquine-resistant strain of Plasmodium falciparum (FcB1-Columbia strain) cultured on human erythrocytes. Substitution of the intracyclic oxygen in aurones by a nitrogen atom and systematic variation of the substituent at the B-ring revealed promising leads showing good activity on the CQ-resistant strain. In particular, 4,6-dimethoxy-4′-ethylazaaurone 22 showed antiplasmodial potency without noticeable toxicity. The easy synthesis of this family of compounds and the relevant antiplasmodial activity are in favor of promising candidates for further development.     

Synthesis of enantiopure 2-carba-cyclic phosphatidic acid and effects of its chirality on biological functions

Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator, which has a quite unique cyclic phosphate ring at sn-2 and sn-3 positions of the glycerol backbone. We have designed and chemically synthesized several metabolically stabilized derivatives of cPA. 2-Carba-cPA (2ccPA) is one of the synthesized compounds in which the phosphate oxygen was replaced with a methylene group at the sn-2 position, and it showed much more potent biological activities than natural cPA. Here, we developed a new method of 2ccPA enantiomeric synthesis. And we examined the effects of 2ccPA enantiomers on autotaxin (ATX) activity, cancer cell invasion and nociceptive reflex. As well as racemic-2ccPA, both enantiomers showed inhibitory effects on ATX activity, cancer cell invasion and nociceptive reflex. As their effects were not significantly different from each other, the chirality of 2ccPA may not be critical for these biological functions of 2ccPA.     

Synthesis of novel 2-cyano substituted glycyrrhetinic acid derivatives as inhibitors of cancer cells growth and NO production in LPS-activated J-774 cells

Here we report the synthesis and biological activity of new semi-synthetic derivatives of naturally occurring glycyrrhetinic acid bearing a 2-cyano-3-oxo-1-en moiety in the A-ring and double bonds and carbonyl groups in the C, D and E rings. Bioassays using murine macrophage-like and tumor cells show that compound 4, which differs from Soloxolone methyl by the absence of a 9(11)-double bond in the C-ring, displays anti-inflammatory and inhibitory activities with respect to tumor cells with a high selectivity index value.     

Dirigent proteins: molecular characteristics and potential biotechnological applications

Dirigent proteins (DIRs) are thought to play important roles in plant secondary metabolism. They lack catalytic activity but direct the outcome of bimolecular coupling reactions toward regio- and stereospecific product formation. Functionally described DIRs confer specificity to the oxidative coupling of coniferyl alcohol resulting in the preferred production of either (+)- or (?)-pinoresinol, which are the first intermediates in the enantiocomplementary pathways for lignan biosynthesis. DIRs are extracellular glycoproteins with high β-strand content and have been found in all land plants investigated so far. Their ability to capture and orientate radicals represents a unique naturally evolved concept for the control of radical dimerization reactions. Although oxidative coupling is commonly used in biological systems, its wider application in chemical synthesis is often limited by insufficient selectivity. This minireview gives an overview of functionally described DIRs and their molecular characteristics and wants to inspire further research for their use in biotechnological applications.     

Integrated process for the enzymatic synthesis of the octapeptide PhAcCCK-8

A process for the enzymatic synthesis of PhAcCCK-8 is presented. The CCK-8 (CCK(26-33)) peptide fragment is the minimum sequence with biological activity of the cholecystokinin hormone. A synthetic convergent strategy has been developed starting from amino acid derivatives as raw materials, employing proteases as biocatalysts for each peptide coupling. The enzymes have been immobilized by deposition onto solid supports in order to be employed in organic media at low water activity. N-terminal protecting groups such as PhAc, which can be introduced and removed enzymatically, have been employed. The synthesis process has been set up at preparative level with focus in the integration of reaction and separation steps with an overall yield of 15%.     

Increasing the amphiphilicity of an estradiol based steroid structure by Barbier-allylation--ring-closing metathesis--dihydroxylation sequence

Polyhydroxylated steroids, such as brassinosteroids, phytoecdysteroids and steroid saponins, are structurally attractive compounds possessing a number of interesting biological properties. Accordingly, development of synthetic procedures to build steroid based structures mimicking the naturally occurring hydrophilic steroids is of topical interest. In the present work, a D-secoestrone derivative was modified further by Barbier-allylation - ring-closing metathesis - dihydroxylation sequence with the aim to prepare steroid based structures with limited hydrophilicity. A straightforward synthesis route was developed with the isolated yield for each step ranging from good to excellent. All compounds prepared were fully characterized by NMR spectroscopic techniques and completely assigned (1)H and (13)C spectra are reported herein. Finally, the effects of the synthesized amphiphilic steroid derivatives on the proliferation of cancer cells are reported and discussed.     

Cytotoxic and aromatic constituents from Salvia miltiorrhiza

As part of an ongoing study of traditional Chinese medicinal plants, the root tissue of Salvia miltiorrhiza was further investigated for its chemical constituents. Five naturally occurring products along with 13 known constituents were isolated from an ethyl acetate-soluble portion of its ethanol extract. Their structures were elucidated by means of spectroscopic methods. Some selected compounds were also evaluated for biological activity.