Bis-indole Derivatives Research Articles

Fluorous‐Tagged Indolylboron for the Diversity‐Oriented Synthesis of Biologically‐Attractive Bisindole Derivatives.

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Fluorous-tagged indolylboron for the diversity-oriented synthesis of biologically-attractive bisindole derivatives

The diversity-oriented synthesis of bisindole derivatives to construct concise libraries using consecutive cross-coupling reactions and prepare new sulfonamide type fluorous protecting groups is presented.

An Update on the Other Telomerase Inhibitors: Non-G-Quadruplex Interactive Agent, Non-Antisense, Non-Reverse Transcriptase Telomerase Inhibitors

Human telomeres are several kilobases of repeated (TTAGGG)n sequences at the ends of chromosomes, a short fragment of which is lost with each cell division. This shortening serves as a "mitotic clock", limiting the number of divisions which normal somatic cells can undergo. Cells undergoing continuous division need some method of bypassing this clock. One such method is the expression of telomerase, a ribonucleoprotein that rebuilds the lost portion of telomeres. Between 80-95% of tumors are telomerase-positive, including ovarian and hepatocellular carcinoma, neuroblastoma, leukemia/lymphoma, and cancers of the breast, prostate, lung, kidneys and bladder, and many immortalized cell lines. While absent in most normal tissues, its expressed at higher levels in germline tissues, bone marrow, and lymphocytes. Due to telomerase expression in most tumor cells and its absence in most normal tissues, telomerase inhibitors are being investigated as anticancer agents. This review focuses on non-reverse transcriptase inhibitor, nonoligonucleotide, non-G-quartet interactive agent telomerase inhibitors. These agents include: differentiating agents, kinases and phosphatases, cell cycle and apoptosis regulating agents, immunotherapeutic agents, antibiotics, steroids, bisindole derivatives, and a variety of other compounds, including herbal medical compounds and cyclooxygenase inhibitors. These agents hold great promise for the future treatment of malignancies. Keywords: telomerase inhibitors, cancer treatments, differentiating agents, cell cycle, herbal medicines

Synthesis, Characterization, and Pharmacokinetic Evaluation of a Potential MRI Contrast Agent Containing Two Paramagnetic Centers with Albumin Binding Affinity

A dinuclear gadolinium(III) complex of an amphiphilic chelating ligand, containing two diethylenetriamine-N,N,N',N'',N''-pentaacetate (DTPA) moieties bridged by a bisindole derivative with three methoxy groups, has been synthesized and evaluated as a potential magnetic resonance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37 degrees C the dinuclear gadolinium(III) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s(-1) mmol(-1)). The higher relaxivity of the dinuclear gadolinium(III) complex can be related to its reduced motion and larger rotational correlation time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the noncovalently bound dinuclear complex increases to 15.2 s(-1) per mmol of Gd3+, due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (Ka) was found to be 10(4) M(-1). Because of its interaction with HSA, the dinuclear complex exhibits a longer elimination half-life from the plasma, and a better confinement to the vascular space compared to the commercially available [Gd(DTPA)] contrast agent. Transmetalation of the dinuclear gadolinium(III) complex by zinc(II) has been investigated. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepatobiliary route. In vivo studies indicated that half of the normal dose of the gadolinium(III) complex enhanced the contrast in hepatic tissues around 40 % more effectively than [Gd(DTPA)]. The dinuclear gadolinium(III) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis-targeting properties.

Recent Advances in the Chemistry of 1‐Hydroxyindoles, 1‐Hydroxytryptophans, and 1‐Hydroxytryptamines

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The 'other' telomerase inhibitors: non-G-quadruplex interactive agent, non-antisense, non-reverse transcriptase telomerase inhibitors.

Human telomeres are several kilobases of repeated (TTAGGG)(n) sequences at the ends of chromosomes, a short fragment of which is lost with each cell division. This shortening serves as a "mitotic clock" which limits the number of divisions that a normal somatic cell can undergo. Cells undergoing continuous division need some method of bypassing this clock. One such method is the expression of telomerase. This ribonucleoprotein is an enzyme that rebuilds the lost portion of the telomeres. Between 80-95% of tumors are telomerase-positive, including ovarian carcinoma, hepatocellular carcinoma, neuroblastoma, leukemia/lymphoma, and cancers of the breast, prostate, lung, kidneys and bladder, as well as many immortalized cell lines. While absent in most normal tissues, this enzyme is expressed at higher levels in germline tissues, bone marrow, and lymphocytes. Due to the expression of telomerase in most tumor cells and its absence in most normal tissues, telomerase inhibitors are being investigated as possible anticancer agents. This review focuses on non-reverse transcriptase inhibitor, non-oligonucleotide and non-G-quartet interactive agent telomerase inhibitors. These agents include: differentiating agents, kinases and phosphatases, cell cycle and apoptosis regulating agents, immunotherapeutic agents, antibiotics, steroids, bisindole derivatives, and a variety of other compounds. These agents hold much promise for the future treatment of malignancies.

Thionation of bisindole derivatives with P4S10 or elemental sulfur

Thionation reactions of several bisindole derivatives using elemental sulfur or P4S10 in pyridine have been studied, leading to formation of several novel structures. The reaction of indigo or isatin with P4S10 gave the structurally new salt 10, which could be transformed into the ethyl derivative 11. The first example of a thionated indigo derivative, monothioindigo (6), was isolated in low yield from the thionation of isatin. Treatment of 3,3′-biindolyl with sulfur in hot DMF produced the previously known tetrasulfide 1, which was studied by X-ray crystallography, thus also establishing that 1 is chiral in the crystalline state. The structure of an additional thionation product, the thienoindole derivative 34 was also solved using X-ray crystallography.

A new bis-indole, KARs, induces selective M arrest with specific spindle aberration in neuroblastoma cell line SH-SY5Y.

KARs, new semisynthetic antitumor bis-indole derivatives, were found to be inhibitors of tubulin polymerization with lower toxicity than vinblastine or vincristine, used in chemotherapy. Here, we compare the effect of KARs with those of vinblastine and vincristine on cell viability, cell proliferation, and cell cycle in neuroblastoma cell line (SH-SY5Y). At concentrations of the different compounds equivalent in causing 50% of inhibition of cell growth, KARs induced a complete arrest in the G2/M phase, whereas vinblastine and vincristine induced a partial arrest in both G0/G1 and G2/M. Moreover, a combination of KAR-2 and W13 (an anticalmodulin drug) qualitatively caused a similar arrest in both G0/G1 and G2/M than vinblastine. Levels of cyclin A and B1 were higher in KARs-treated cells than in vinblastine- or vincristine-treated cells. Cdc2 activity was much higher in KAR-2 than in vinblastine-treated cells, indicating a stronger mitotic arrest. The effect of KAR2 and vinblastine on microtubules network was analyzed by immunostaining with anti-tubulin antibody. Results indicated that KAR-2-induces the formation of aberrant mitotic spindles, with not apparent effect on interphase microtubules, whereas vinblastine partially destroyed interphase microtubules coexisting with normal and aberrant mitotic spindles.

Electrochemical oxidation of aspidofractinine-type alkaloids: Formation of kopsine, kopsidine, kopsinitarine and bisindole derivatives

Anodic oxidation of kopsamine on platinum in acetonitrile results in cyanation or cyanomethylation, following ring closure, while oxidation on vitreous carbon in methanol yields a dimerization product with a C2 element of symmetry. This behaviour is reproduced in the aromatic congeners of kopsamine, kopsiflorine and 11-methoxykopsilongine. Oxidation of kopsingine on platinum in CH2Cl2–MeCN leads to a stable conjugated iminium salt which can be trapped by alcohol or water nucleophiles to give kopsidines A, B, and C. Kopsidines A and B can also be obtained directly from electrooxidation in methanol or ethanol. Oxidation of dihydrokopsingine in acetonitrile gives the 17-to-5 and 17-to-3 oxo-bridged compounds directly, while oxidation in methanol yields an additional product which is a caged kopsinitarine derivative. Oxidation of an aspidofractinine derivative without unsaturation in the piperidine ring and with a C(17)-αOH function gives a C2 symmetric dimerization product as well as a caged kopsinitarine-type product. Possible pathways leading to the various products are presented.

Reactions of 1,2-Bis(1 H-indol-2-yl)ethane: Formation of Indolo[2,3- c]carbazole and Cyclohept[1,2- b:5,4- b′]bisindole Derivatives

1,2-Bis(1 H-indol-2-yl)ethane (9) has been prepared and converted into indolo[2,3- c]carbazole (8) using palladium acetate in refluxing acetic acid. Reaction of 9 with CoF 3 in hot TFA led to isolation of cyclohept[1,2- b:5,4- b′]bisindole derivatives 11 and 12, which could be elaborated into further derivatives. Treatment of 9 with orthoesters, aldehydes and ketones under acidic conditions afforded additional bisindoles containing a seven-membered ring.

Closely-spaced chelating centers: synthesis of novel spiro-bridged bis-phenanthrolines and bis-indole derivatives

The syntheses of novel soluble ditopic 1,10-phenanthroline ligands bearing a central spiro-[5.5]undecane or a spiro-[5.5]bifluorylidene fragment are reported. The synthetic approach is based on a Friedländer condensation between 8-amino-7-quinolinecarbaldehyde and either 3,9-diketospiro-[5.5]undecane or 2,2′-diacetyl-spiro[5.5]bifluorylidene derivatives. Reaction of the latter with phenylhydrazine and subsequent cyclization afforded 2,2′-di-(2″-indolyl)-[5.5]spirobifluorylidene. The photophysical properties of the new compounds are briefly discussed and Ru(II) and Cu(I) complexes were prepared.

Simultaneous binding of drugs with different chemical structures to Ca2+-calmodulin: crystallographic and spectroscopic studies.

The modulatory action of Ca2+-calmodulin on multiple targets is inhibited by trifluoperazine, which competes with target proteins for calmodulin binding. The structure of calmodulin crystallized with two trifluoperazine molecules is determined by X-ray crystallography at 2.74 A resolution. The X-ray data together with the characteristic and distinct signals obtained by circular dichroism in solution allowed us to identify the binding domains as well as the order of the binding of two trifluoperazine molecules to calmodulin. Accordingly, the binding of trifluperazine to the C-terminal hydrophobic pocket is followed by the interaction of the second drug molecule with an interdomain site. Recently, we demonstrated that the two bisindole derivatives, vinblastine and KAR-2 [3"-(beta-chloroethyl)-2",4"-dioxo-3, 5"-spirooxazolidino-4-deacetoxyvinblastine], interact with calmodulin with comparable affinity; however, they display different functional effects [Orosz et al. (1997) British J. Pharmacol. 121, 955-962]. The structural basis responsible for these effects were investigated by circular dichroism and fluorescence spectroscopy. The data provide evidence that calmodulin can simultaneously accommodate trifluoperazine and KAR-2 as well as vinblastine and KAR-2, but not trifluoperazine and vinblastine. The combination of the binding and structural data suggests that distinct binding sites exist on calmodulin for vinblastine and KAR-2 which correspond, at least partly, to that of trifluoperazine at the C-terminal hydrophobic pocket and at an interdomain site, respectively. This structural arrangement can explain why these drugs display different anticalmodulin activities. Calmodulin complexed with melittin is also able to bind two trifluoperazine molecules, the binding of which appears to be cooperative. Results obtained with intact and proteolytically cleaved calmodulin reveal that the central linker region of the protein is indispensable for simultanous interactions with two molecules of either identical or different ligands.

Structure of a novel bisindole derivative

(3aR-[3a alpha,4 beta,5a beta,9[1R,3R(2S),5R,7aS,-12aS],10bR,13a alpha])-Methyl-4-(acetyloxy)-3a-ethyl-3a,4,5,5a,6,11,12,13a-oct ahy dro-9- [1,2,3,4,6,7,7a,- 12-octahydro-3-(2-hydroxy-2-hydroxymethylbutyl)- 1-(methoxycarbonyl)indolizino[1,2-b]indol-7a-yl]-5- hydroxy-8-methoxy-6-methyl-1H-indolizino[8,1-c,d]- carbazole-5-carboxylate methanol hydrate solvate, C46H60N4O10.CH3OH.H2O, Mr = 879 x 06, monoclinic, P2(1), a = 8 x 2878 (8), b = 31 x 018 (4), c = 9 x 2267 (7) A, beta = 105 x 211 (7) degrees, V = 2288 x 8 (4) A3, Z = 2, Dx = 1 x 28 g cm-3, mu = 0 x 8580 cm-1, Mo K alpha radiation, lambda = 0 x 7107 A, F(000) = 944, T = 198 K, R = 0 x 0382 for 2931 reflections [Fo greater than or equal to 4 sigma(Fo)]. A very short intramolecular hydrogen-bonding interaction is observed between the hydroxyl group and N9 of the vindoline portion of the molecule. The relevant parameters are: O3--H3O...N9, O...N 2 x 598 (4), H...N 1 x 68 (5) A, O--H...N 164 (5) degrees. Molecules related by the 2(1) screw operation are hydrogen bonded into columns parallel to b.(ABSTRACT TRUNCATED AT 250 WORDS)