Cyclization of N[2-(3-indolyl)acetyl]-5-aminovaleraldehydes and N[2-(3-indolyl)ethyl]-5-aminovaleraldehydes

Various model cyclizations related to the organic or biological synthesis of diverse indole alkaloids, are described and discussed, including: 18 → 20, 23 → 25, 28 → 31 and 29 → 35, 37, 38 and 39 (as aldehydes).     

Synthesis of 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine derivatives as CDK inhibitors and cytotoxic agents

We here report the synthesis and biological evaluation of new 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine designed as potential CDK inhibitors. Indole, 5-hydroxyindole, and phenol derivatives were used to generate three substitutions of the pyridine. The resulting skeletons were successively exploited to introduce various dimethylaminoalkyl side chains by Williamson type reactions. The synthesis includes Stille or Suzuki type reactions, which were realized on the 3,5-dibromopyridine. The preparation and the use of stannylindoles in mono or bis cross-coupling reactions were also described and each step was optimized and detailed. Kinase assays were realized and shown that nude compounds 7, 18, and 25 inhibited CDK1 in the 0.3–0.7 micromolar range with a good selectivity over GSK-3. Cytotoxicity against CEM human leukemia cells was evaluated with IC₅₀ values in the 5–15 micromolar range. Precise structure–activity relationships were delineated. Molecular modeling and docking solutions were proposed to complete the studies and to explain the observed SAR in the CDK assays.     

Synthesis and biological evaluation of 2,5-di(7-indolyl)-1,3,4-oxadiazoles,and 2- and 7-indolyl 2-(1,3,4-thiadiazolyl)ketones as antimicrobials

A range of novel hydrazine bridged bis-indoles was prepared from readily available indole-7-glyoxyloylchlorides and 7-trichloroacetylindoles and underwent cyclodehydration to produce 2,5-di(7-indolyl)-1,3,4-oxadiazoles and a 2,2′-bi-1,3,4-oxadiazolyl with phosphoryl chloride in ethyl acetate. This efficient protocol was subsequently used for the synthesis of 2- and 7-indolyl 2-(1,3,4-thiadiazolyl)ketones from related indolyl-hydrazine carbothioamides. The synthesised bis-indoles were evaluated for their antimicrobial properties, particularly the inhibition of protein–protein complex formation between RNA polymerase and σ factor and their bactericidal effect on Gram positive Bacillus subtilis and Gram negative Escherichia coli.     

Enzymatic resolution of 3-(3-indolyl)butyric acid: a key intermediate for indolmycin synthesis

Both enantiomers of 3-(3-indolyl)butyric acid, a key intermediate of indolmycin, were successfully prepared by lipase-catalysed enantioselective hydrolysis. Of the enzymes examined, Pseudomonas fluorescens lipase (lipase AK) showed the best enantioselectivity and highest reactivity for the hydrolysis of (±)-trifluoroethyl 3-(3-indolyl)butyrate. Under optimal conditions, optical resolution was completed in one enzyme-catalysed step, the S-acid and unreacted R-ester being obtained in high optical purity.     

Synthesis and biological evaluation of N-(7-indolyl)-3-pyridinesulfonamide derivatives as potent antitumor agents

We herein report the synthesis and antitumor activity of E7070 analogues containing a 3-pyridinesulfonamide moiety. E7070 was selected from our sulfonamide-based compound collections, currently undergoing Phase II clinical trials because of its tolerable toxicity profile and some antitumor responses in the Phase I setting. Of the analogues examined, ER-35745, a 6-amino-3-pyridinesulfonamide derivative, demonstrated significant oral efficacy against the HCT116 human colon carcinoma xenograft in nude mice.     

Diuretic actions of 1-((tert-butylimino)methyl)-2-(3-indolyl) indoline HCl (MJ 8592-1) in adrenalectomized or ADH-primed rats

MJ 8592-1, an orally active diuretic indolylindoline derivative, effectively reversed the relative oliguria induced by ADH (Pitressin®) in ethanol-saline primed intact rats. It was 5.5, .96 and >18 times as potent, respectively, as furosemide, HCTZ and triamterene in producing a 100% increase in Na excretion in the presence of ADH. Since MJ 8592-1 also elicited a diuretic-saluretic response in ethanolsaline primed rats in the absence of ADH, the antagonism to exogenous vasopressin may be classified as non-specific. In adrenalectomized rats, MJ 8592-1, like triamterene, produced dose-related electrolyte excretion responses in both the presence and absence of exogenous DOCA. Thus, while MJ 8592-1 was effective in counteracting mineralocorticoid-induced Na retention in the distal tubule, it was also capable of increasing Na excretion by a mechanism independent of any direct interactions with adrenal cortical steroids or tubular sites influenced by these hormones.     

Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA-FtsZ interaction

The ZipA-FtsZ protein-protein interaction is a potential target for antibacterial therapy. The design and parallel synthesis of a combinatorial library of small molecules, which target the FtsZ binding area on ZipA are described. Compounds were demonstrated to bind to the FtsZ binding domain of ZipA by HSQC NMR and to inhibit cell division in a cell elongation assay.     

Design, synthesis, and biological evaluation of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibitors

A series of 20 novel 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were designed, synthesized, and screened in vitro for anti-inflammatory activity. These compounds were designed for evaluation as dual inhibitors of cyclooxygenases (COX-1 and COX-2) and lipoxygenases (LOX-5, LOX-12, and LOX-15) that are responsible for inflammation and pain. All pyrazoline molecules prepared are optically active and compounds that are more potent in COX-2 inhibitory activity (5a and 5f) were resolved by chiral column and each enantiomer was tested for cyclooxygenase inhibitory activity. Molecular modeling and comparison of molecular models of 5a enantiomers with that of celecoxib model shows that 5a (enantiomer-1) and 5a (enantiomer-2) have more hydrogen bonding interactions in the catalytic domain of COX-2 enzyme than celecoxib. Compounds 5a, 5e, and 5f showed moderate to good LOX-5 and LOX-15 inhibitory activity and this is comparable to that of celecoxib and more potent than rofecoxib.     

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.     

Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCbeta-selective inhibitors

Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase Cbeta (PKCbeta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKCbeta2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKCbeta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route.     

Synthesis, absolute configuration and biological activity of both enantiomers of 2-(5,6-dichloro-3-indolyl)propionic acid: new dichloroindole auxins

Racemic 2-(5,6-dichloro-3-indolyl)propionic acid (5,6-Cl2-2-IPA) was synthesized from 5,6-dichloroindole-3-acetic acid (5,6-Cl2-IAA) by successive esterification, methoxycarbonylation, methylation, and double hydrolysis. The racemate was converted to the diastereomeric esters of (S)-(-)-1-phenylethyl alcohol. These were separated by HPLC into two optically active diastereomers and then hydrolyzed with p-TsOH to the optically active enantiomers of 5,6-Cl2-2-IPA. The absolute configurations of both the 5,6-Cl2-2-IPA enantiomers were determined by comparing the 1H-NMR spectra of their diastereomeric (S)-(-)-1-phenylethyl esters with those of the diastereomeric (S)-(-)-1-phenylethyl esters of 2-(3-indolyl)propionic acid (2-IPA) whose absolute configurations are already known. There was no essential difference between (S)-(+)- and (R)-(-)-5,6-Cl2-2-IPA in hypocotyl growth-inhibiting activity toward Chinese cabbage, but their inhibitory activities were stronger than that of the potent mother auxin, 5,6-Cl2-IAA. No essential difference in the coleoptile elongating activity of Avena sativa was apparent for the enantiomers, this activity being about one-third that of 5,6-Cl2-IAA.     

Synthesis of 3-(3-pyridyl)- and 3-(3-benzo[b]thienyl)-D-alanine

The DL-arylamino acid ethyl ester derivatives of beta-(3-pyridyl)-DL-alanine, and beta-(3-benzo[b]thienyl)-DL-alanine were synthesized by diethyl acetamidomalonate condensation with the respective arylmethyl halides followed by partial hydrolysis to the monoethyl ester and decarboxylation. Each derivative was enzymatically resolved to a separable mixture of the corresponding N-acetyl-L-amino acid and the unchanged D amino acid derivative. Acidic hydrolysis of the latter gave the corresponding D-amino acid, the optical purity of which was established by HPLC analysis of the 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC) derivative. The free D amino acids were converted to D-BOC derivatives by reaction with di-tert-butyldicarbonate in tert-butyl alcohol, water and sodium hydroxide.     

Preparation of alkyl (R)-(-)-3-hydroxybutyrate by acidic alcoholysis of poly-(R)-(-)-3-hydroxybutyrate

An efficient method for the preparation of optically active alkyl (R)-(-)-3-hydroxybutyrates by chemical depolymerization of biopolymer, poly-(R)-(-)-(3-hydroxybutyrate), was established. This method consists of simple recovery of poly-(R)-(-)-(3-hydroxybutyrate) from bacterial cells followed by acidic alcoholysis. When poly-(R)-(-)-(3-hydroxybutyrate) was purified by a simple digestion method that used 0.2 N sodium hydroxide, alkyl (R)-(-)-hydroxybutyrates were most efficiently produced by alcoholysis with anhydrous hydrochloric acid.     

Synthesis, absolute configuration and biological activities of both enantiomers of 2-(5,7-Dichloro-3-indolyl)propionic acid: a novel dichloroindole auxin and antiauxin

Racemic 2-(5,7-dichloro-3-indolyl)propionic acid (5,7-Cl(2)-2-IPA) was synthesized from 5,7-dichloroindole-3-acetic acid by successive esterification, methoxycarbonylation, methylation, and double hydrolysis. The racemate was converted to diastereomeric esters of l-menthol; these were separated by recycling HPLC into two optically active diastereomers that were then hydrolyzed with p-TsOH to two optically active enantiomers of 5,7-Cl(2)-2-IPA. The absolute configurations of both these enantiomers were determined by comparing the (1)H-NMR spectra of their diastereomeric l-menthyl esters with those of the diastereomeric l-menthyl esters of 2-(3-indolyl)propionic acid (2-IPA) of known absolute configurations.An assay by the coleoptile elongation of Avena sativa showed the (S)-(+)-enantiomer of 5,7-Cl(2)-2-IPA to have weak auxin activity, whereas the (R)-(-)-antipode had no auxin activity at any concentration tested. Interestingly, the (R)-(-)-enantiomer had antiauxin activity very close to that of 2-(5,7-dichloro-3-indolyl)isobutyric acid (5,7-Cl(2)-IIBA), a strong antiauxin. These data indicate that, of the two methyl groups in its molecule, the antiauxin activity of 5,7-Cl(2)-IIBA was due only to the (R)-methyl group.     

Novel substituted (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(+/-)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol derivatives as potent thermal sensitizing agents

Use of ionizing radiation is essential for the management of many human cancers, and therapeutic hyperthermia has been identified as a potent radiosensitizer. Radiation therapy combined with adjuvant hyperthermia represents a potential tool to provide outstanding local-regional control for refractory disease. (Z)-(±)-2-(N-Benzylindol-3-ylmethylene)quinuclidin-3-ol (2) and (Z)-(±)-2-(N-benzenesulfonylindol-3-ylmethylene)quinuclidin-3-ol (4) were initially identified as potent thermal sensitizers that could lower the threshold needed for thermal sensitivity to radiation treatment. To define the structural requirements of the molecule that are essential for thermal sensitization, we have synthesized and evaluated a series of (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one (9), and (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol (10) analogs that incorporate a variety of substituents in both the indole and N-benzyl moieties. These systematic structure–activity relationship (SAR) studies were designed to further the development and optimization of potential clinically useful thermal sensitizing agents. The most potent analog was compound 10 (R¹ = H, R² = 4-Cl), which potently inhibited (93% inhibition at 50 μM) the growth of HT-29 cells after a 41 °C/2 h exposure.     

Production of poly-D(-)-3-hydroxybutyrate and poly-D(-)-3-hydroxyvalerate by strains ofAlcaligenes latus

Alcaligenes latus strains can accumulate poly-D(-)-3-hydroxybutyrate (PHB) up to about 85% of cell dry weight. The abilities to store poly-D(-)-3-hydroxyvalerate (PHV) of three strains ofA. latus were investigated. With Na-propionate as PHV precursor, strainA. latusDSM 1122 had better PHV accumulation ability than strainsA. latusDSM 1123 and 1124. StrainA. latus DSM 1123 could store PHV when Na-valerate but not Na-propionate served as the PHV precursor. PHB and PHV accumulation byA. latus DSM 1124 rapidly increased when propionic acid and acetic acid were together added to the fermentor. This increase was not obtained in the culture shaker flask and fermentor growing the same strain when Na-propionate alone served as a PHV precursor.     

Identification of trans-4-[1-[[7-fluoro-2-(1-methyl-3-indolyl)-6-benzoxazolyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid as a potent, orally active VLA-4 antagonist

For the purpose of obtaining orally potent VLA-4 inhibitors, we have carried out structural modification of the (N'-phenylureido)phenyl group in compound 1, where the group was found to be attributed to poor pharmacokinetic profile in our previous research. Through modification, we have identified several compounds with both potent in vitro activity and improved oral exposure. In particular, compound 7e with 7-fluoro-2-(1-methyl-1H-indol-3-yl)-1,3-benzoxazolyl group as a novel replacement of the (N'-phenylureido)phenyl group significantly inhibited eosinophil infiltration into bronchoalveolar lavage fluid at 15mg/kg in an Ascaris-antigen-induced murine bronchial inflammatory model, and its efficacy was comparable to that of the anti-mouse α(4) antibody (R1-2).