Relevance of the C-5 position to schweinfurthin induced cytotoxicity

The schweinfurthins are an intriguing group of anti-proliferative agents that display low nanomolar activities against several cell types, including the human-derived glioblastoma cell line SF-295, but have little impact on other cell lines even at micromolar concentrations. This activity has inspired the synthesis of seven of the natural schweinfurthins, all with the correct absolute stereochemistry, and a variety of analogues designed to probe different facets of the pharmacophore. Reported herein is the synthesis of several new schweinfurthin analogues varied at the C-5 position along with data on their biological activity in the NCI 60 cell-line assay.     

Synthesis and biological activity of a fluorescent schweinfurthin analogue

Most of the natural schweinfurthins are potent and selective inhibitors of cell growth as measured by the National Cancer Institute’s 60-cell line screen. Due to the limited supply of these natural products, we have initiated a program aimed at their synthesis. To date, this effort has led to the preparation of three natural schweinfurthins and more than 40 analogues, and assays on these compounds have afforded some understanding of structure–activity relationships in this family. Further development of schweinfurthins as chemotherapeutic agents would benefit from characterization of their mechanism(s) of action. This perspective led to development of a fluorescent schweinfurthin analogue that retains the differential activity of the natural products, and yet has properties that facilitate its visualization within cells.     

Syntheses and biological activities of bis(3-indolyl)thiazoles, analogues of marine bis(indole)alkaloid nortopsentins

The thiazole analogues of the marine bis(indole)alkaloid nortopsentins, 2,4-bis(3-indolyl)thiazoles, were synthesized using Hantzsch reaction between indole-3-thioamides and 3-(alpha-bromoacetyl)indoles as the key step, and these analogues showed potent cytotoxic activities against a variety of human cancer cell lines in vitro.     

Fluorescent schweinfurthin B and F analogs with anti-proliferative activity

The natural tetracyclic schweinfurthins are potent and selective inhibitors of cell growth in the National Cancer Institute’s 60 cell-line screen. At this time, the mechanism or cellular target that underlies this activity has not yet been identified, and efforts to illuminate the schweinfurthins’ mode of action would benefit from development of potent fluorescent analogs that could be readily visualized within cells. This report describes the synthesis of fluorescent analogs of schweinfurthins B and F, and demonstrates that these compounds retain the potent and differentially toxic activities against select human cancer cells that are characteristic of the natural schweinfurthins. In addition, the synthesis of control compounds that maintain parallel fluorescent properties, but lack the potent activity of the natural schweinfurthin is described. Use of fluorescence microscopy shows differences between the localization of the active and relatively inactive schweinfurthin analogs. The active compounds localize in peripheral puncta which may identify the site(s) of activity.     

Biologically active biotin derivatives of schweinfurthin F

As a prelude to efforts to identify schweinfurthin binding proteins, an ester conjugate and an amide conjugate of schweinfurthin F and biotin have been prepared by chemical synthesis. These compounds maintain activity in SF-295 cells comparable to the parent system, and display the lower potency in A549 cells that is a characteristic of the schweinfurthin pattern of activity.     

InCl3 mediated one-pot multicomponent synthesis,anti-microbial,antioxidant and anticancer evaluation of 3-pyranyl indole derivatives

A simple and convenient method for the one-pot three-component synthesis of 3-pyranyl indoles has been accomplished by tandem Knoevenagel–Michael reaction of 3-cyanoacetyl indole, various aromatic aldehydes and malononitrile catalyzed by InCl₃ in ethanol under reflux conditions. The newly synthesized 3-pyranyl indoles were evaluated for anti-microbial, antioxidant, and anticancer activities. Some of the compounds showed good anticancer activity against MCF-7 breast cancer cell lines on comparison with of standard drug.     

Synthesis and antitumoral evaluation of indole alkaloid analogues containing an hexahydropyrrolo[1',2',3':1,9a,9]imidazo[1,2-a]indole skeleton

The scope of acid-mediated cyclative additions of electrophiles to tryptophan-derived alpha-amino nitriles for the synthesis of 10b-substituted-1,2,4,5,10b,10c-hexahydropyrrolo[1',2',3':1,9a,9]imidazo[1,2-a]indoles analogues of indole alkaloids has been studied. The results demonstrate the high potential of the methodology for the synthesis of 10b-bromo-derivatives, by bromination with NBS, 10b-allyl-derivatives, by bromo-allyl exchange, and 10b-prenyl-derivatives, by reaction with prenyl bromide in the presence of Mg(NO(3))(2).6H(2)0. Some of the new pyrroloimidazoindole derivatives displayed moderate microM cytotoxicities in human cancer cell lines and at 10 microg/mL inhibited more than 50% EGFR or HIF-1alpha.     

Biotinylated indoles as probes for indole-binding proteins

Biotinylated indoles were prepared for application as bifunctional probes for the detection of indole-binding proteins which participate in the life processes of humans, animals, plants, and bacteria. The indole nucleus was functionalized, at ring positions 3, 5, or 6, by attachment of a 2-aminoethyl group, which was then coupled to the carboxyl moiety of biotin, via a spacer composed of 3 or 4 concatenated beta-alanine residues. The constructs thus obtained were able to inhibit tryptophanase activity, similarly to indole in a concentration-dependent manner. They also bound strongly to lysozyme and weakly to bovine and human serum albumins, in accordance with the known affinities of these proteins for indole and 3-(2-aminoethyl)indole (tryptamine). The biotin end of the protein-bound bifunctional probes could then be detected by coupling to (strept)avidin conjugated to alkaline phosphatase or horseradish peroxidase, followed by incubation with substrates which are converted by these enzymes to intensely colored or chemiluminescent products.     

The enzymatic synthesis of L-tryptophan analogues

A convenient method for the synthesis of l-tryptophan analogues is described. The method utilizes E. coli tryptophan synthetase, which catalyses the condensation of indole and l-serine to yield l-tryptophan. It is found that several indole analogues will replace indole as substrate for the enzyme to give the corresponding l-tryptophan analogues in good yield. By using [¹⁴C]serine, analogues can be prepared radioactively labeled in the side-chain carbon atoms.     

Synthesis and evaluation of 1-(1H-indol-3-yl)ethanamine derivatives as new antibacterial agents

A collection of 3-substituted indole derivatives was prepared using nucleophilic addition of indoles to nitrones. The compounds were then tested for their antibacterial activity against almost thirty bacterial strains representative of common human pathogens. Two types of indolic molecules inhibit the growth of Staphylococcus aureus, including MRSA and VISA strains, with MIC values ranging from 8 to 16 mg/L.     

Synthesis and neurite growth evaluation of new analogues of honokiol, a neolignan with potent neurotrophic activity

A versatile synthetic route is reported towards the preparation of new analogues for potent neurotrophic agent biaryl-type lignan honokiol. A focused 24-membered library of derivatives containing five different groups at 5'-position of honokiol has been prepared in fair to good overall yields. Compared to the natural product, or to analogues with a short alkyl chain in this position, these new derivatives have lost most of the neurotrophic activity.     

Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: steric and electronic effects of 4- and 8-halogenated naphthoyl substituents

To develop SAR at both the cannabinoid CB(1) and CB(2) receptors for 3-(1-naphthoyl)indoles bearing moderately electron withdrawing substituents at C-4 of the naphthoyl moiety, 1-propyl and 1-pentyl-3-(4-fluoro, chloro, bromo and iodo-1-naphthoyl) derivatives were prepared. To study the steric and electronic effects of substituents at the 8-position of the naphthoyl group, the 3-(4-chloro, bromo and iodo-1-naphthoyl)indoles were also synthesized. The affinities of both groups of compounds for the CB(1) and CB(2) receptors were determined and several of them were evaluated in vivo in the mouse. The effects of these substituents on receptor affinities and in vivo activity are discussed and structure-activity relationships are presented. Although many of these compounds are selective for the CB(2) receptor, only three JWH-423, 1-propyl-3-(4-iodo-1-naphthoyl)indole, JWH-422, 2-methyl-1-propyl-3-(4-iodo-1-naphthoyl)indole, the 2-methyl analog of JWH-423 and JWH-417, 1-pentyl-3-(8-iodo-1-naphthoyl)indole, possess the desirable combination of low CB(1) affinity and good CB(2) affinity.     

Determination of the dioxygen quenching constant for protein and model indole triplets

The decay of the indole triplet of single tryptophan-containing proteins and model compounds can be readily determined at room temperature in solution by monitoring the triplet absorption or emission following an exciting laser pulse. The dioxygen triplet quenching constants, can be measured for all these molecules and compared to the analogous singlet values determined by fluorescence methods. The dioxygen triplet quenching constant (tkq) ranged from a high of 5.1.10(9) M-1.s-1 for the exposed indole of corticotropin to a low of 0.1.10(9) M-1.s-1 for the buried indole of asparaginase. The ratio of these values with their respective dioxygen singlet quenching constants (skq), tkq/skq, ranged from 0.3 to 0.6 for aqueous exposed polypeptide indoles. For globular proteins the tkq/skq value is observed to be 0.2 +/- 0.1. This lower value for protein indoles is not attributable to 'bulk' environmental or hydrogen bonding effects, since the magnitude of tkq/skq (= 0.5 +/- 0.1) for model indoles was independent of solvent dielectric constant, polarity, and proticity. Temperature-dependence studies were done to test whether tkq could be used to characterize the nature of the protein matrix. The activation energy (Ea) for tkq was found to be 11 +/- 2 kcal/mol for most proteins. This Ea was independent of whether the indole side-chain was solvent exposed or buried in the non-aqueous protein interior. Large Ea values were also obtained for model indoles, naphthalene and nalidixic acid, dissolved in water, whereas the same compounds dissolved in 95% ethanol exhibited much smaller Ea values. These data, in combination with the observation that the tkq of model indoles is insensitive to changes in solvent viscosity, indicate that dioxygen quenching at the triplet level can not be easily used to characterize the dynamics of proteins.     

Production of indole-3-acetic acid and related indole derivatives from L-tryptophan by <Emphasis Type="Italic">Rubrivivax benzoatilyticus</Emphasis> JA2

Rubrivivax benzoatilyticus JA2 produces indoles with simultaneous utilization of L-tryptophan. Fifteen chromatographically distinct indole derivatives were detected from the L-tryptophan-supplemented cultures of R. benzoatilyticus JA2. Nine of these were identified as, indole 3-acetamide, Methoxyindole-3-aldehyde, indole 3-aldehyde, methoxyindole-3-acetic acid, indole 3-acetic acid, indole-3-carboxylic acid, indole-3-acetonitrile, indole, and trisindoline. Tryptophan stable isotope feeding confirmed the indoles produced are from the supplemented L-tryptophan. Indole 3-acetic acid is one of the major products of L-tryptophan catabolism by R. benzoatilyticus JA2 and its production was influenced by growth conditions. Identification of indole 3-acetamide and tryptophan monooxygenase activity suggests indole 3-acetamide routed IAA biosynthesis in R. benzoatilyticus JA2. The study also indicated the possible multiple pathways of IAA biosynthesis in R. benzoatilyticus JA2.     

Synthesis and biological activity of novel macrocyclic antifungals: acylated conjugates of the ornithine moiety of the lipopeptidolactone FR901469

A series of acylated analogues of the novel macrocyclic lipopeptidolactone FR901469 has been prepared and evaluated for antifungal and hemolytic activity. Several analogues displayed markedly reduced hemolytic potential and comparable protective effects to the natural product in a mouse model of candidiasis.     

The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity

A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki–Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki–Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)₂ and NaBH₄ afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 μg/mL) against the Gram-positive micro-organism Bacillus cereus.     

Synthesis and structure-activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein

Tryprostatin A is an inhibitor of breast cancer resistance protein, consequently a series of structure-activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These analogues were assayed for their growth inhibition properties and their ability to perturb the cell cycle in tsFT210 cells. SAR studies resulted in the identification of the essential structural features required for cytotoxic activity. The absolute configuration L-Tyr-L-pro in the diketopiperazine ring along with the presence of the 6-methoxy substituent on the indole moiety of 1 was shown to be essential for dual inhibition of topoisomerase II and tubulin polymerization. Biological evaluation also indicated the presence of the 2-isoprenyl moiety on the indole scaffold of 1 was essential for potent inhibition of cell proliferation. Substitution of the indole N(a)-H in 1 with various alkyl or aryl groups, incorporation of various L-amino acids into the diketopiperazine ring in place of L-proline, and substitution of the 6-methoxy group in 1 with other functionality provided active analogues. The nature of the substituents present on the indole N(a)-H or the indole C-2 position influenced the mechanism of action of these analogues. Analogues 68 (IC(50)=10 microM) and 67 (IC(50)=19 microM) were 7-fold and 3.5-fold more potent, respectively, than 1 (IC(50)=68 microM) in the inhibition of the growth of tsFT210 cells. Diastereomer-2 of tryprostatin B 8 was a potent inhibitor of the growth of three human carcinoma cell lines: H520 (IC(50)=11.9 microM), MCF-7 (IC(50)=17.0 microM) and PC-3 (IC(50)=11.1 microM) and was equipotent with etoposide, a clinically used anticancer agent. Isothiocyanate analogue 71 and 6-azido analogue 72 were as potent as 1 in the tsFT210 cell proliferation and may be useful tools in labeling BCRP.     

WITHDRAWN: Heme oxygenase-1 mediates the anti-inflammatory effect of propyl gallate in LPS-stimulated macrophages

Tryptophans in membrane proteins display strong preference for the lipid membrane interface and are important for anchoring proteins at the proper longitudinal level. Linear dichroism spectroscopy on indoles in shear-deformed liposomes has been used to show that this positioning is accompanied by an intrinsically adopted orientation, also observed for tryptophans in membrane-bound peptides. Similarities in orientation of different indoles suggest that tryptophan will adopt this orientation independent of the protein it is part of. From the orientation of indole electronic transition moments L(a), L(b) and B(b), a binding model is proposed where the indole long axis is approximately 60-65 degrees from the membrane normal and the indole plane is at an oblique angle. We propose that dipole-dipole interactions and steric constraints in the membrane hydrocarbon region determine positioning and orientation of tryptophans whereas hydrogen bonding and cation-pi interactions with lipid head-groups, though contributing to the membrane affinity of indoles, are less important.     

Synthesis of methoxylated goniothalamin, aza-goniothalamin and γ-pyrones and their in vitro evaluation against human cancer cells

The present work describes the preparation of three novel series of compounds based on the structure of goniothalamin, a natural styryl lactone which has been found to display cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 29 novel goniothalamin analogues was prepared and evaluated against seven human cancer cell lines. While the γ-pyrones and the aza-goniothalamin analogues were less potent than the lead compound, 2,4-dimethoxy analogue 88 has shown to be more potent in vitro than goniothalamin against all cancer cell lines evaluated. Furthermore, it was more potent than doxorubicin against NCI-ADR/RES, OVCAR-03 and HT-29 while being less toxic to human keratinocytes (HaCat). The 3,5-dimethoxy analogue 90 and 2,4,5-trimethoxy analogue 92 also displayed promising antiproliferative activity when compared to goniothalamin (1). These results provide new elements for the design and synthesis of novel representatives of this family of natural compounds.     

Synthesis of new bioisosteric hemiasterlin analogues with extremely high cytotoxicity

In this Letter, the synthesis and the evaluation of the cytotoxicity of new hemiasterlin analogues were reported. The indole moiety was replaced respectively by benzofurane, naphthalene and 4-bromobenzene groups. Most of these derivatives possess strong cytotoxic activity on two human tumour cell lines (KB and Hep-G₂), and some analogues showed comparable cytotoxic activity to that observed for paclitaxel and ellipticine, against KB and Hep-G₂ cancer cell lines.