Solid-phase synthesis and biological activity of a combinatorial cross-conjugated dienone library

The solid-phase synthesis of a combinatorial cross-conjugated dienone library based on the structure of clavulones and their biological activity are reported. Clavulones are a family of marine prostanoids, and are composed of a cross-conjugated dienone system bearing two alkyl side-chains. The cross-conjugated dienone system irreversibly reacted with two nucleophiles. Our strategy for the solid-phase synthesis of the cross-conjugated dienones involves the Sonogashira-coupling reaction of a solid-supported cyclopentenone 10 bearing an acetylene group, followed by aldol condensation with aldehydes. The diphenyl derivative 7 aA was prepared from the solid-supported cyclopentenone 10 in 56% total yield. Combinatorial synthesis of a small library using twelve halides and eight aldehydes resulted in the production of 74 desired compounds from 98 candidates, and were detected by their mass spectra. Antiproliferative effects of the crude compounds against HeLaS3 cells showed that eleven samples showed strong antitumor activity (IC50<0.05 microM). Further biological examination of four purified compounds by using five tumor cell lines (A549, HeLaS3, MCF7, TMF1, and P388) revealed strong cytotoxicity comparable to that of adriamycin.     

Ketene dithioacetal mediated synthesis of 1,3,4,5-tetrasubstituted pyrazole derivatives and their biological evaluation

Abstract

Ketene dithioacetal mediated chemo- and regioselective synthesis of a series of novel 1,3,4,5-tetrasubstituted pyrazole derivatives (4a-l) integrated with a bioactive indole nucleus was achieved by reacting substituted 2-(1-methyl-1H-indole-3-carbonyl)-3,3-bis-(methylthio)-acrylonitrile (2) and substituted phenyl hydrazine hydrochloride (3) in the presence of a catalytic amount of anhydrous K₂CO₃ under reflux conditions. The structures were ascertained by ¹H NMR, NOESY, ¹³C NMR, FT-IR, and HRMS data. In vitro cytotoxicity evaluation of the synthesized compounds against MCF 7 (breast carcinoma) and normal Vero (monkey kidney) cell lines revealed that the compound 5-(5-Bromo-1-methyl-1H-indol-3-yl)-1-(4-cyano-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carbonitrile (4k) showed significant cytotoxicity against MCF 7 (GI₅₀ = 15.6 µM) with low cytotoxicity against normal Vero cell line. Most of the synthesized compounds were also found to possess excellent anti-inflammatory and antioxidant (DPPH, NO, H₂O₂ and SOR) potential.     

Solid-phase combinatorial synthesis of peptide-biphenyl hybrids as calpain inhibitors

[structure: see text] The combinatorial parallel synthesis of peptide-biphenyl hybrids on solid support using state of the art of peptide synthesis is reported. Key steps were the N to C addition of an amino moiety, hydrolysis of the methyl ester, and the absence of cross-linked compounds when the 2,2'-diamino-1,1'-biphenyl was incorporated. When tested for activity as calpain inhibitors, some of the compounds exhibited IC(50) values in the nanomolar range.     

Solid-phase synthesis of monocyclic beta-lactam derivatives

Liquid-phase studies concerning the solid-phase synthesis of monocyclic beta-lactams via the ester-enolate imine condensation route have been conducted utilizing triazene esters 1 and 2 as model compounds. Esters were attached to benzylamine resin 6 by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates 8 and 10 were reacted with various imines and imine precursors to give polymer-bound beta-lactams 14 and 17 in different substitution patterns. Traceless cleavage from the triazene linker yields the desired beta-lactams 16 and 19.     

Efficient synthesis and biological evaluation of 4-arylcoumarin derivatives

Two bioactive natural 4-arylcoumarins,5,7,4’-trimethoxy-4-phenylcoumarin(1a),5,7-dimethoxy-4-phenylcoumarin(1b) and five closely related derivatives 1c-g were synthesized.In vitro evaluation with a catechol subunit for antioxidant and antimicrobial activity,these compounds using standard methods showed that compounds 1d,1f displayed promise radical scavenging activity and 1f was found to be the most active one against Bacillus dysenteriae.     

Novel synthesis of zerumbone-pendant derivatives and their biological activity

Zerumbone 1, having powerful latent reactivity and containing two conjugated double bonds and a double conjugated carbonyl group is the major component of the essential oil of wild ginger, Zingiber zerumbet Smith. The conjugation system plays an important role in the expression of biological activity. N-Bromosuccinimide (NBS) reaction of 1 gave high reactive intermediate 2 with an exo-methylene group, which was obtained from 1 quantitatively. Treatment of 2 with nucleophiles gave various zerumbone-pendant derivatives, including C–H, C–O, C–N, and C–C bond formation, maintaining the conjugation system through S_N2′-type reaction. Almost all zerumbone-pendant derivatives showed a good value of IC₅₀ against the suppressive effect of NO generation. Among them, amine derivative 5, binding with 2 mol of zerumbone, showed the strongest activity (IC₅₀: 0.24 μM).     

Solid-phase synthesis of indolizidine and quinolizidine derivatives

An efficient method for the construction of simple indolizidine and quinolizidine derivatives on solid support has been developed. An intramolecular tandem Michael reaction initiated by the nucleophilic attack of a suitably placed amino group on the tethered Wittig condensation products between 4- or 5-aminoaldehydes attached to a trityl chloride resin and 4-[(4-methylphenyl)sulfonyl]-1-(triphenylphosphoranylidene)-2-b utanon e is the key step.     

Solid-phase synthesis and modification of Thiazole Orange and its derivatives and their spectral properties

A new solid-phase synthesis is shown to be effective in the preparation of cyanine dye Thiazole Orange (TO) and its derivatives, which can be obtained as a traceless cleavage of the Merrifield resin method. The influence of different solvents, substitutional groups, introduced to benzothiazole such as chlorine, methyl, and nitro was extensively studied. The changes of the special characteristic and fluorescence intensity of the TO derivatives were described. The phenomenon of the synergetic effect was also depicted after modifying the TO molecule with chitosan oligosaccharide (CTS) at the end of the alkyl, which can effectively improve the sensitivity of the fluorescent probe.     

Concise synthesis of 2-benzazepine derivatives and their biological activity

2-Benzazepines, which are potentially good candidates for new drug therapies to treat skin wounds, were readily prepared from substituted cinnamylamide via an intramolecular Friedel-Crafts reaction. With few steps and effective reactions, the procedure enables a rapid derivatization of 2-benzazepines. Moreover, optically active 4-substituted-2-benzazepines were prepared from chiral α-substituted cinnamylamides, which were readily prepared by asymmetric α-alkylation of chiral cinnamyl oxazolidinone amides. We have easily prepared a library of more than 20 derivatives and examined the biological activity of the compounds.     

Design synthesis and biological evaluation of 3-substituted triazole derivatives

Based on the active site of lanosterol 14α-demethylase of azole antifungal agents,sixteen 1-(1H-1,2,4-triazole-1-yl)- 2-(2,4- difluorophenyl)-3-(N-n-butyl-N-1-substitutedbenzyl-4-methylene-1H-1,2,3-triazole)-2-propanols have been designed,synthesized and evaluated as antifungal agents.Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that some of the compounds exhibited excellent activities with broad spectrum.     

Arylpyrazole as selective anti-enterococci; synthesis and biological evaluation of novel derivatives for their antimicrobial efficacy

Exploring the structure–activity relationships (SAR) of a new set of phenylpyrazoles unveiled a potential anti-enterococcus lead compound 12 . The benzofuran moiety linked to the phenylpyrazole 12 was 32 times better than vancomycin against Enterococcus faecalis ATCC 51299. Besides, compound 12 is expected to have an excellent oral bioavailability according to the in silico studies. Of SAR analysis, we found that the benzofuran side chain was essential for the activity. Changing the benzofuran with either benzothiophene, phenyl, pyridinyl, tolyl, or naphthyl reduces/nullifies the pharmacological action. Besides the anti-enterococcal activity, derivatives 4 and 6 can be used to develop new broad-spectrum antibiotics as they exhibited activity against the wild-type highly virulent Escherichia coli isolate. Moreover, compound 13 was proved to show antifungal activity (MIC = 4 μg/ml) against the Candida albicans SS5314 (wild type). Finally, the in silico analysis showed that those compounds have good profiles regarding the absorption, distribution, metabolism, and excretion studies, drug-likeness and pharmacokinetics properties.     

Solid-phase synthesis of N-substituted 3,4-dihydroquinazolinone derivatives

An efficient solid-phase synthetic approach for the synthesis of N-substituted 3, 4-dihydroquinazolinone derivatives has been developed. Four different 2-nitrobenzoic acids and three different 2-phenylacetyl chlorides were employed in the synthesis of this library. After purification, all products were obtained in good yields.     

Solid-phase synthesis of phenolic steroids: from optimization studies to a convenient procedure for combinatorial synthesis of biologically relevant estradiol derivatives

During the course of our studies on therapeutic agents for the treatment of breast cancer, we became interested in the solid-phase combinatorial synthesis of estradiol derivatives that contain a functionalized side chain at either position 16 beta or 7 alpha. Both types of compounds have already demonstrated inhibitory activity toward both biosynthesis and action of estradiol. As a first step, two versatile precursors bearing an azidoalkyl side chain at either position 16 beta or 7 alpha of estradiol were synthesized using standard solution-phase methods. Afterward, the effectiveness of five linkers to attach the phenolic function of these estradiol derivatives to a polystyrene resin was investigated; they were benzylic ether (Merrifield), 4-alkoxy-benzylic ethers (Wang, Sheppard), tetrahydropyranyl ether (Ellman), benzoic ester, and o-nitrobenzyl ether. To test the linker in a synthetic context, a short sequence of reactions, including reduction of the azide and acylation of the corresponding amine, was performed on the polymer-bound estradiol derivative. While all of the tested linkers proved effective in attaching the phenol functionality of the precursor, only the o-nitrobenzyl ether photolabile linker enabled the release of the final products in acceptable purities. Consequently, this linker was used to perform successfully the solid-phase synthesis of four different classes of estradiol derivatives in acceptable yields and excellent purities. This study was preliminary to the combinatorial synthesis of larger libraries of biologically relevant estradiol derivatives.     

Click synthesis of new 7-chloroquinoline derivatives by using ultrasound irradiation and evaluation of their biological activity

This study describes the click synthesis of new 7-chloroquinoline derivatives by using ultrasound irradiation and evaluation of their activity as antimicrobial, antimalarial and the anticancer. All the compounds show moderate antimalarial activity with IC₅₀?<?100?μM, six of them showed high antimalarial activity (2, 3, 4, 6, 8 and 9) with IC₅₀?<?50?μM. The most active 7-chloroquinoline derivative is a compound (9). Also, the newly synthesized compounds were screened for their antitumor activity towards three lines of cancer cells, MCF-7 (human breast cancer), HCT-116 (colon carcinoma) and Hela (Cervical carcinoma) cell lines. Compounds (3) and (9) exerted the highest activity on all cell lines and showed special selectivity toward MCF-7 cells and the antibacterial screening data showed moderate to good inhibition zone (12.5?±?0.63–23.8?±?1.5) towards all the tested compounds. Elucidation of the structures of these new pure compounds was based on, IR, ¹H NMR, ¹³C NMR, MS and their elemental analysis.     

Solid-phase synthesis and biological evaluation of a teleocidin library--discovery of a selective PKCdelta down regulator

Protein kinaseC (PKC) is linked to the signal-induced modulation of a wide variety of cellular processes, such as growth, differentiation, secretion, apoptosis, and tumor development. The design and synthesis of small molecules that regulate these different cellular signaling systems is at the forefront of modern drug design. Herein we report a) an efficient method for the synthesis of indolactamV (6), a PKC activator, and its N13-des(methyl) analogues (19) using a regioselective organometallic transformation, a convenient aminomalonate derivative (10) to introduce the appropriate functionality and an enantiospecific enzymic hydrolysis as key steps; b) the use of this method in the first solid-phase synthesis of a teleocidin library modifying the N-13, C-12 and C-7 alkyl chains, and, therefore, producing a library of potential activators and/or inhibitors of PKC of the general structure (32); c) the activation of PKC by selected members of the library using a MARCKS translocation in vivo assay system; d) the observation that some of these analogues are nearly as effective as the natural PKC activators phorbol dibutyrate and (-)-indolactam V (6), and e) the observation that some of these analogues have different potential to induce down-regulation of members of the PKC gene family after chronic stimulation.     

Solid-phase synthesis of imidazoquinazolinone derivatives with three-point diversity

A novel imidazoquinazolinone-based tricyclic structure with three-point diversity has been synthesized using solid-phase methodology. The compounds were obtained by treating the amino group of polymer-linked amino acids with 2-nitrobenzaldehyde followed by reduction of the nitro group to an amine. Derivatization of amine with isothiocyanates and cyclization of the resulting thioureas with DIC followed by acidolytic cleavage yielded the desired imidazoquinazolinone based compounds in high purity and moderate to high yield.     

A combinatorial access to 1,5-benzodiazepine derivatives and their evaluation for aldose reductase inhibition

Aryldiazepinothiophenones 4 were prepared from the reaction of o-phenylenediamines with acetone in the presence of 2-mercaptocarboxylic acids along with thiazolobenzodiazepines 6, thiazolobenzimidazoles 7 and 1,5-benzodiazepines 5, which were obtained as by-products. The benzodiazepinothiophenones 4a-d and the benzodiazepines 5a-d were also isolated from the reaction of o-phenylenediamines 1a-c with phorone. Structural assignments of the new compounds as well as complete assignment of ¹H and ¹³C NMR signals were based on the analysis of their ¹H and ¹³C NMR (1D and 2D), IR, MS and elemental analysis data. Compounds 4 were evaluated for aldose reductase inhibition and also as antioxidants.     

Practical synthesis of hydroxychromenes and evaluation of their biological activity

A simple and efficient seven steps synthesis of brodifacoum and difethialone from phenylacetyl chloride is described. The key synthetic strategies involve Friedel-Crafts acylation, intramolecular ring cyclization and condensation reaction in the presence of Br?nsted-Lowry acids. It was found that brodifacoum showed favorable inhibiting activities on LPS-stimulated nitrite production in BV-2 microglia cells. Brodifacoum exhibited superior anti-inflammatory effects than difethialone. We expect that an efficient linear synthesis of 4-hydroxycoumarin derivatives and key fragments that are useful agents for the modulation of inflammation as well as inhibition of coagulation will be of practical use.