Acid-catalyzed synthesis of 10-substituted triazolyl artemisinins and their growth inhibitory activity against various cancer cells

A diastereomeric and regioisomeric library of 10-substituted triazolyl artemisinin compounds (6a–6h, 7a–7h, and 8a–8h) with a potent growth inhibitory activities against various cancer cell lines was established. These compounds were synthesized by a reaction with dihydroartemisinin (2) and various substituted triazoles (5a–5h) in methylene chloride using a BF₃Et₂O catalyst. Most of the compounds exhibited a strong potency in the submicromolar range, and, in particular, 6f, 7f, and 8f, which have a pentylphenyltriazole moiety, proved to be promising candidates for preclinical trials.     

Synthesis of 4-substituted phenyl 3,6-anhydro-1,3-dithio-D-glucofuranosides and -pyranosides as well as 2,6-anhydro-1,2-dithio-alpha-D-altrofuranosides possessing antithrombotic activity

1,2,5-Tri-O-acetyl-3,6-anhydro-3-thio-D-glucofuranose was synthesised starting from D-glucose and was used as a donor for the glycosidation of 4-cyano- and 4-nitrobenzenethiol. In the latter reaction, besides an anomeric mixture of the 4-nitrophenyl 2,5-di-O-acetyl-3,6-anhydro-1,3-dithio-D-glucofuranosides, the corresponding 2,6-anhydro-1,2-dithio-D-altrofuranosides were also obtained, formed via a rearrangement of the sugar moiety. A similar rearrangement could be observed during the hydrolysis of the glycosidic bond of methyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-alpha-D-glucopyranoside with aqueous trifluoroacetic acid, affording after acetylation besides 1-O-acetyl-3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-alpha-D-glucopyranose (32alpha), 1,1,5-tri-O-acetyl-3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-D-glucose, methyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-beta-D-glucopyranoside and 1,5-di-O-acetyl-2,6-anhydro-3-O-(4-nitrobenzoyl)-2-thio-alpha-D-altrofuranose (40). Glycosidation of 4-cyanobenzethiol with 32alpha in the presence of trimethylsilyl triflate as promoter afforded 4-cyanophenyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-1,3-dithio-beta-D-glucopyranoside as a minor component only, besides 4-cyanophenyl 3,6-anhydro-2-S-(4-cyanophenyl)-4-O-(4-nitrobenzoyl)-1,2,3-trithio-beta-D-glucopyranoside. When boron trifluoride etherate was used as promoter in the reaction of 32alpha with 4-cyano- and 4-nitrobenzenethiol, the corresponding beta-thioglycosides were obtained, while 40 gave under identical conditions the alpha anomers exclusively. All thioglycosides obtained after deacylation were submitted to biological evaluation. Among these glycosides, the 4-cyanophenyl 3,6-thioanhydro-1,3-dithio-D-glucofuranoside possessed the strongest oral antithrombotic effect.     

Synthesis and antitumor activity of 10-substituted benzylidene anthrone

Fifteen compounds of 10-substituted benzylidene anthrone were prepared with moderate yield by reaction of anthrone and substituted benzaldehydes under the presence of pyridine and piperidine as catalyst. Their antitumor activities in vitro were evaluated. The results show that the electron-withdrawing substitutes decrease the activities, the electron-donor substitutes increase the activities; the compound with substitute at ortho or para position has stronger activities than that of compound with the same substitute but located at the meta position. There are six compounds which appear as strong effective inhibition for A-549 cancer cell growth. This is a kind of good leading compound which is worth researching further.     

Synthesis of pyrrolizidine alkaloids via 1,3-dipolar cycloaddition involving cyclic nitrones and unsaturated lactones

The 1,3-dipolar cycloaddition of cyclic nitrone derived from tartaric acid and (S)-5-hydroxymethyl-2(5H)-furanone leads to a single adduct which was transformed into 2,6-dihydroxyhastanecine via reaction sequence involving reduction of the lactone moiety, glycolic cleavage of the terminal diol, and the N-O hydrogenolysis followed by the intramolecular alkylation of the nitrogen atom.     

Synthesis of 4-substituted phenyl 2,5-anhydro-1,6-dithio-alpha-D-gluco- and -alpha-L-guloseptanosides possessing antithrombotic activity

Two independent approaches were investigated for the synthesis of 3,4-di-O-acetyl-1,6:2,5-dianhydro-1-thio-D-glucitol (18), a key intermediate in the synthesis of 1,3,4-tri-O-acetyl-2,5-anhydro-6-thio-alpha-D-glucoseptanose (13), needed as glycosyl donor. In the first approach 1,6-dibromo-1,6-dideoxy-D-mannitol was used as starting material and was converted via 2,5-anhydro-1,6-dibromo-1,6-dideoxy-4-O-methanesulfonyl-3-O-tetrahydropy ranyl-D-glucitol into 18. The second approach started from 1,2:5,6-di-O-isopropylidene-D-mannitol and the allyl, 4-methoxybenzyl as well as the methoxyethoxymethyl groups were used, respectively, for the protection of the 3,4-OH groups. The resulting intermediates were converted via their 1,2:5,6-dianhydro derivatives into the corresponding 3,4-O-protected 2,5-anhydro-6-bromo-6-deoxy-D-glucitol derivatives. The 1,6-thioanhydro bridge was introduced into these compounds by exchanging the bromine with thioacetate, activating OH-1 by mesylation and treating these esters with sodium methoxide. Among these approaches, the 4-methoxybenzyl protection proved to be the most suitable for a large scale preparation of 18. Pummerer rearrangement of the sulfoxide, obtained via oxidation of 18 gave a 1:9 mixture of 1,3,4-tri-O-acetyl-2,5-anhydro-6-thio-alpha-L-gulo- (12) and -D-glucoseptanose 13. When 12 or 13 were used as donors and trimethylsilyl triflate as promoter for the glycosylation of 4-cyanobenzenethiol, a mixture of 4-cyanophenyl 3,4-di-O-acetyl-2,5-anhydro-1,6-dithio-alpha-L-gulo- (58) and -alpha-D-glucoseptanoside (61) was formed suggesting an isomerisation of the heteroallylic system of the intermediate. A similar mixture of 58 and 61 resulted when 18 was treated with N-chloro succinimide and the mixture of chlorides was used in the presence of zinc oxide for the condensation with 4-cyanobenzenethiol. When 4-nitrobenzenethiol was applied as aglycon and boron trifluoride etherate as promoter, a mixture of 4-nitrophenyl 3,4-di-O-acetyl-2,5-anhydro-1,6-dithio-alpha-L-gulo- (60) and -alpha-D-glucoseptanoside (62) was obtained. Deacetylation of 58, 61 and 62 according to Zemplen afforded 4-cyanophenyl 2,5-anhydro-1,6-dithio-alpha-L-glucoseptanoside (59), 4-cyanophenyl 2,5-anhydro-1,6-dithio-alpha-D-glucoseptanoside (63) and 4-nitrophenyl 2,5-anhydro-1,6-dithio-alpha-D-glucoseptanoside (66), respectively. The 4-cyano group of 63 was transformed into the 4-aminothiocarbonyl, and the 4-(methylthio)(imino)methyl derivative and the 4-nitro group of 66 into the acetamido derivative. All of these thioglycosides displayed a stronger oral antithrombotic effect in rats compared with beciparcil, used as reference.     

Synthesis and biological evaluation of novel 2,4,5-substituted pyrimidine derivatives for anticancer activity

A series of novel 2,4,5-substituted pyrimidine derivatives were synthesized and evaluated for inhibition against the human hepatocellular carcinoma BEL-7402 cancer cell line. Several compounds showed potent inhibition with an IC₅₀ value less than 0.10 μM. Structure–activity relationships for this class of compounds at the 2- and 5-position of the pyrimidine scaffold have been elucidated. The most active compound 7gc showed good inhibition of several different human cancer cell lines with IC₅₀ values from 0.024 to 0.55 μM.     

Synthesis and antitumor activity of novel 10-substituted camptothecin analogues

In an attempt to improve the antitumor activity and decrease the cytotoxicity of camptothecin, 18 new 10-substituted camptothecin derivatives were prepared. The cytotoxicity in vitro on cancer cell lines and antitumor activity in vivo, and inhibitory properties of topoisomerase I of these derivatives were evaluated. Most of these derivatives possessed lower cytotoxicities than CPT, and the compounds 13, 21, 22, 23, and 24 showed similar topoisomerase I inhibitory activity to CPT. Analogues 13 exhibited the best antitumor activity in vivo among all derivatives we prepared.     

Synthesis and in vitro anticancer and antitubercular activity of diarylpyrazole ligated dihydropyrimidines possessing lipophilic carbamoyl group

A series of dihydropyrimidine derivatives were synthesized by utilizing Biginelli reaction and evaluated for their in vitro anticancer activity against MCF-7 human breast cancer (HBC) cell line using sulforhodamine B (SRB) assay and antitubercular activity against Mycobacterium tuberculosis (MTB) H(37)Rv using Microplate Alamar Blue Assay (MABA). Compounds 13p, 13t were exhibited 70.6% and 63.7% of HBC cell growth inhibition at 10 μM concentration. Interestingly compound 13p was also found to be the most potent in the series against MTB H(37)Rv with MIC value of 0.125 μg/mL.     

Efficient synthesis of linear multifunctional poly(ethylene glycol) by copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition

Poly(ethylene glycol) (PEG) is a versatile biocompatible polymer. Improvement of its limited functionality (two chain termini) may significantly expand its current applications. In this communication, a simple and yet highly efficient strategy for the synthesis of linear multifunctional PEGs with "click" chemistry is reported. A short acetylene-terminated PEG was linked by 2,2-bis(azidomethyl)propane-1,3-diol using Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition in water at room temperature. High-molecular-weight PEGs with pendant hydroxyl groups were obtained and characterized by 1H NMR and size-exclusion chromatography. A prototype bone-targeting polymeric drug delivery system was also successfully synthesized based on this new method. It demonstrates strong biomineral-binding ability and the ease of incorporating therapeutic agents into the delivery system. This simple "click" reaction approach provides a useful tool for the development of novel functional polymers and their conjugates for biomedical applications.     

Synthesis of glycoconjugate carbonic anhydrase inhibitors by ruthenium-catalysed azide-alkyne 1,3-dipolar cycloaddition

Carbonic anhydrase IX (CA IX) is a recently validated target for the development of new cancer therapies. In this Letter we describe the synthesis and CA inhibition of a novel series of carbohydrate-based 1,5-disubstituted-1,2,3-triazole benzenesulfonamides. The key step of our synthesis is the regioselective Huisgen's 1,3-dipolar cycloaddition reaction (1,3-DCR) from carbohydrate azide substrates and 4-ethynylbenzenesulfonamide using a ruthenium-catalysed azide-alkyne cycloaddition (RuAAC). Our findings identified a number of triazole inhibitors (compounds 18, 19, 21-23, and 26) that block CA IX activity with inhibition constants less than 10 nM. One inhibitor (compound 17) possessed very good selectivity for CA IX over off-target CAs. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.     

Synthesis and properties of myelopeptides possessing differentiating activity

Bone marrow peptides Phe-Arg-Pro-Arg-Ile-Met-Thr-Pro (MP-4) and Val-Asp-Pro-Pro (MP-6) have been synthesized by the classical and solid-phase methods of peptide chemistry, and their differentiating activity has been studied on leukemia cell lines HL-60 and K-562. It has been shown that both peptides induce the terminal differentiation of leukemic blasts; however, their mechanisms of action are different.     

Synthesis and anticancer activity of thiosemicarbazones

Twenty-six thiosemicarbazones (III-1-III-26) were synthesized via three steps starting from hydrazine hydrate and carbon disulfide. The testing of anticancer activity of these compounds in vitro against P-388, A-549, and SGC-7901 shows that compounds III-15 and III-16 possess a higher inhibitory ability for P-388 and SGC-7901. Further testing shows that the value of IC50 of compound III-16 against SGC-7901 reaches to 0.032 microM.     

Synthesis and anticancer potential of novel xanthone derivatives with 3,6-substituted chains

In an effort to develop new drug candidates with enhanced anticancer activity, our team synthesized and assessed the cytotoxicity of a series of novel xanthone derivatives with two longer 3,6-disubstituted amine carbonyl methoxy side chains on either benzene ring in selected human cancer cell lines. An MTT assay revealed that a set of compounds with lower IC₅₀ values than the positive control, 5-FU, exhibited greater anticancer effects. The most potent derivative (XD8) exhibited anticancer activity in MDA-MB-231, PC-3, A549, AsPC-1, and HCT116 cells lines with IC₅₀ values of 8.06, 6.18, 4.59, 4.76, and 6.09 μM, respectively. Cell cycle analysis and apoptosis activation suggested that the mechanism of action of these derivatives includes cell cycle regulation and apoptosis induction.     

Synthesis of 4'-ethynyl-purine nucleosides possessing anti-HIV activity.

Searching for more effective anti-HIV agents, we have prepared 4'-ethynyl-purine nucleosides. They were derived in several steps from 4-C-triethylsilylethynyl ribose, which was used as an intermediate in the synthesis of pyrimidine nucleosides. The adenine derivative exhibited significant anti-HIV activity and favorable cytotoxicity profile in vitro.     

Synthesis of multivalent lactose derivatives by 1,3-dipolar cycloadditions: selective galectin-1 inhibition

Acetylene derivatives of phenylalanine, phenethylamine and the multifunctional unnatural amino acids, phenyl-bis-alanine and phenyl-tris-alanine, were synthesized and functionalized with 2-azidoethyl beta-D-galactopyranosyl-(1-->4)-beta-D-glucopyranoside via regioselective copper(I)-mediated 1,3-dipolar cycloaddition to give a panel of mono-, di- and trivalent lactoside derivatives. Evaluation of the compounds as inhibitors against the tumour- and inflammation-related galectin-1, -3, -4N, -4C, -4, -7, -8N and -9N revealed a divalent compound with a Kd value as low as 3.2 microM for galectin-1, which corresponded to a relative potency of 30 per lactose unit as compared to the natural disaccharide ligand lactose. This divalent compound had at least one order of magnitude higher affinity for galectin-1 than for any of the other galectins investigated.     

Synthesis and anticancer activity of open-resorcinarene conjugates

The first example of conjugation of open-resorcinarenes with chlorambucil, ibuprofen, naproxen and indomethacin are presented. The cytotoxic properties of the obtained conjugates were tested against the cancer cell lines U-251, PC-3, K-562, HCT-15, MCF-7 and SKLU-1. It was found that the conjugate with chlorambucil, naproxen or indomethacin (having 8 moieties) was toxic towards cancer cell lines U-251 and K-562, with no activity against non-cancerous COS-7 cells. The conjugates with naproxen and indomethacin showed high selectivity towards U-251 tumor cells.     

Synthesis and anticancer activity of sclerophytin-inspired hydroisobenzofurans

Three structurally related sets of hydroisobenzofuran analogs of sclerophytin A were prepared in three or four steps from (S)-(+)-carvone via an aldol-cycloaldol sequence. The most potent members of each set of analogs exhibited IC₅₀’s of 1–3 μM in growth inhibitory assays against KB3 cells. The NCI 60-cell line 5-dose assay for analog 6h revealed a GI₅₀ = 0.148 μM and LC₅₀ = 9.36 μM for the RPMI-8226 leukemia cell line, and a GI₅₀ = 0.552 μM and LC₅₀ = 26.8 μM for the HOP-92 non-small cell lung cancer cell line.     

Synthesis and antibacterial activity of 5-substituted oxazolidinones

A series of 5-substituted oxazolidinones with varying substitution at the 5-position of the oxazolidinone ring were synthesized and their in vitro antibacterial activity was evaluated. The compounds demonstrated potent to weak antibacterial activity. A novel compound (PH-027) demonstrated potent antibacterial activity, which is comparable to or better than those of linezolid and vancomycin against antibiotic-susceptible standard and clinically isolated resistant strains of gram-positive bacteria. Although the presence of the C-5-acetamidomethyl functionality at the C-5 position of the oxazolidinones has been widely claimed and reported as a structural requirement for optimal antimicrobial activity in the oxazolidinone class of compounds, our results from this work identified the C-5 triazole substitution as a new structural alternative for potent antibacterial activity in the oxazolidinone class.     

Synthesis and anticancer activity studies of cyclopamine derivatives

A diversity-oriented synthesis has been developed for facile construction of a library of carbohydrate-cyclopamine conjugates. The synthetic protocol is suitable for generating cyclopamine derivatives with various structural motifs for exploring the desired activity. From this initial library, we have observed one derivative that exhibits improved activity against lung cancer cell as compared to cyclopamine.     

Synthesis and anticancer activity studies of indolylisoxazoline analogues

A new library of thirteen indolylisoxazolines 6a–m has been synthesized by the treatment of indolylchalcones with hydroxylamine hydrochloride. Evaluation of anticancer activity of indolylisoxazolines 6a–m led to the identification of potent compounds 6c–d, 6i and 6l, with IC₅₀ ranging 2.5–5.0?µM against the tested cancer cell lines. Using a number of complementary techniques such as acridine orange/ethidium bromide staining, PARP1 cleavage and DNA strand breaks assay, we show that the compounds 6c and 6i induce apoptosis in highly aggressive C4-2 cells. Our data further revealed that 6c and 6i inhibited C4-2 cells proliferation without inducing reactive oxygen species (ROS). Finally, we show that compounds 6c and 6i also potently inhibit cell migration, indicating these compounds have the potential to serve as effective anti-cancer agents.