Photooxidation of thiosaccharides mediated by sensitizers in aerobic and environmentally friendly conditions

A series of β-d-glucopyranosyl derivates have been synthesized and evaluated in photooxidation reactions promoted by visible light and mediated by organic dyes under aerobic conditions. Among the different photocatalysts employed, tetra-O-acetyl riboflavin afforded chemoselectively the respective sulfoxides, without over-oxidation to sulfones, in good to excellent yields and short reaction times. This new methodology for the preparation of synthetically useful glycosyl sulfoxides constitutes a catalytic, efficient, economical, and environmentally friendly oxidation process not reported so far for carbohydrates.

An environmentally friendly and simple sensitized photooxidation methodology to obtain glycosyl sulfoxides with outstanding chemoselectivity in aerobic conditions is described.     

Design,synthesis and pharmacological evaluation of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives as antitumor agents: in vitro and in vivo antitumor activity,cell cycle arrest and apoptotic response

A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives (3a₁−3d₆) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activities against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicities against HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results showed that the representative compound 3a₁ exhibited effective inhibition on tumor growth in the HepG2 xenograft mouse model. Mechanistic studies suggested that 3a₁ may exert antitumor activity by the up-regulation of Bax, intracellular Ca²⁺ release, ROS generation, p21, p27 and p53, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, and inhibition of CDK activity.

A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives were designed and synthesized as antitumor agents under the combination principle. The antitumor activity and mechanisms were then evaluated.     

Synthesis of benzo[b]furans from alkynyl sulfoxides and phenols by the interrupted Pummerer reaction

The interrupted Pummerer reaction of alkynyl sulfoxides with phenols is disclosed. A wide range of benzo[b]furans were efficiently synthesized through unexplored electrophilic activation of the electron-deficient alkynyl sulfinyl group. Based on the good availability of alkynyl sulfoxides, we successfully prepared various functionalized benzo[b]furans from readily available alkynes, thiosulfonates, and phenols.

The interrupted Pummerer reaction of alkynyl sulfoxides with phenols is disclosed. The good availability of alkynyl sulfoxides and phenols enabled us to prepare various functionalized benzo[b]furans.     

Synthesis and biological evaluation of 3-nitro-4-chromanone derivatives as potential antiproliferative agents for castration-resistant prostate cancer

A series of novel 3-nitro-4-chromanones were synthesized and their in vitro cytotoxicity was evaluated on castration-resistant prostate cancer cell (CRPC) lines using the sulforhodamine B (SRB) assay. The amide derivatives showed more potent antitumor activity than their corresponding ester derivatives. Most of the tested compounds showed less toxicity towards human fibroblasts (HAF) compared with the tumor cell lines. The optimal compound 36 possessed much more potent antiproliferative activity than the positive compound cisplatin. The colony formation, cell cycle distribution, apoptosis, transwell migration and wound healing assays of 36 were performed on CRPC cell lines.

A series of novel 3-nitro-4-chromanones were synthesized and their in vitro cytotoxicity was evaluated on castration-resistant prostate cancer cell lines.     

Electrochemical sulfonylation of alkenes with sulfonyl hydrazides: a metal- and oxidant-free protocol for the synthesis of (E)-vinyl sulfones in water

An efficient electrochemical transformation of a variety of alkenes and sulfonyl hydrazides into vinyl sulfones with a catalytic amount of tetrabutylammonium iodide in water is reported. The reaction proceeds smoothly to afford vinyl sulfones with good selectivities and yields at room temperature under air in an undivided cell. Cyclic voltammograms and control experiments have been performed to provide preliminary insight into the reaction mechanism. The key features of this reaction include using pure water as solvent, transition metal- and oxidant-free conditions, and being easily scaled up to gram-scale synthesis.

An electrochemical sulfonylation of alkenes with sulfonyl hydrazides for the synthesis of (E)-vinyl sulfones in water is reported.     

Highly efficient synthesis of 3,4-diarylbutadiene sulfones using Heck–Matsuda reaction

For the first time we describe a general method for the synthesis of previously not synthesized unsymmetrical 3,4-diarylbutadiene sulfones which can be stable convenient precursors for 2,3-diaryl-1,3-butadienes. Our method for arylation of butadiene sulfones via Heck–Matsuda reaction allows to obtain unsymmetrical 3,4-diarylbutadiene sulfones with a variety of alkyl, alkoxy, nitro, ethoxycarbonyl, perfluoroalkyl and halogen substituents (30 examples) in very good yields using readily available reagents and catalysts.

An efficient and facile Pd-catalyzed synthesis of 3,4-diarylbutadiene sulfones with high regioselectivity from aryldiazonium salts and butadiene sulfone was developed.     

Palladium-catalyzed regioselective hydrosulfonylation of allenes with sulfinic acids

An atom-economic method of preparing allylic sulfones via hydrosulfonylation of allenes with sulfinic acids under Pd(0)-catalysis was reported. This process has a high degree of regio- and stereoselectivity, and provides the target product with a moderate to excellent yield. A wide range of nitrogen- or oxygen-containing linear E-allylic sulfones have been synthesized. With the support of experimental research, a possible mechanism was proposed.

A simple palladium-based catalytic system for hydrosulfonylation of allenamides was established. Various nitrogen-containing linear allylic sulfones can be generated in moderate to excellent yield with E-selectivity and 100% atom utilization.     

Visible-light-induced one-pot synthesis of sulfonic esters via multicomponent reaction of arylazo sulfones and alcohols

Sulfonic ester is a chemical structure common to many organic molecules, including biologically active compounds. Herein, a visible-light-induced synthetic method to prepare aryl sulfonic ester from arylazo sulfones was developed. In the present study, a one-pot reaction was carried out using arylazo sulfones, DABSO (DABCO·(SO₂)₂), and alcohols in the presence of CuI as a coupling catalyst and HCl as an additive to yield sulfonic esters via multicomponent reaction. This synthetic method afforded a wide range of sulfonic esters with high yields under mild conditions.

Facile and efficient one-pot synthesis of sulfonic esters has been achieved via visible-light-induced multicomponent reaction of arylazo sulfones, and alcohols in the presence of DABSO, CuI, and HCI.     

Synthesis of new N,N′-Pd(Pt) complexes based on sulfanyl pyrazoles,and investigation of their in vitro anticancer activity

The synthesis of new N,N′-mononuclear bi-ligand Pd(ii) and tri-ligand Pt(ii)complexes bearing sulfanyl(phenyl, benzyl, cyclohexyl, 4-hydroxyphenyl)3,5-dimethyl-1H-pyrazole ligands has been carried out. The obtained compounds were studied for apoptosis-inducing activity and effect on the cell cycle for Jurkat, K562, and U937 neoplastic cell cultures and conditionally normal human embryonic kidney HEK293 cells. The cells showed the highest sensitivity to platinum and palladium complexes in comparison with ligands and cisplatin. The cytotoxic properties are enhanced for compounds with cyclohexyl substituents at the S-atom in sulfanyl pyrazoles and complexes.

Efficient cytostatics against Jurkat, K562 and U937 neoplastic cell lines were found among the synthesized new Pd(ii) and Pt(ii)complexes (six examples) with sulfanyl-1H-pyrazole ligands using in vitro assay.     

Synthesis and biological evaluation of dehydroabietic acid-pyrimidine hybrids as antitumor agents

A series of novel dehydroabietic acid derivatives containing pyrimidine moieties were designed and synthesized to explore more efficacious and less toxic antitumor agents according to the principle of combination and hybridization. The cytotoxicity against human liver cancer (HepG2) cells, human breast cancer (MCF-7) cells, human colon cancer (HCT-116) cells, human lung cancer (A549) cells, and human normal liver cells (LO2) was estimated by MTT assay in vitro. Cytotoxic activity screening revealed that most of the compounds showed moderate to high levels of cytotoxicity against these four cancer cell lines and that some displayed more potent inhibitory activities compared with 5-FU. In particular, compound 3b exhibited promising cytotoxicity with IC₅₀ values ranging from 7.00 to 11.93 μM against all the tested cell lines and displayed weak cytotoxicity towards normal cells. Besides, cell cycle analysis indicated that compound 3b mainly arrested MCF-7 cells at the S stage and induced cell apoptosis.

A series of novel dehydroabietic acid derivatives containing pyrimidine moieties were designed and synthesized. Some of them displayed more potent inhibitory activities compared with 5-FU.     

Synthesis of 2-methoxybenzamide derivatives and evaluation of their hedgehog signaling pathway inhibition

Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened (Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway to target the Smo receptor is a practical approach for development of anticancer agents. We report herein the design and synthesis of a series of 2-methoxybenzamide derivatives as Hh signaling pathway inhibitors. The pharmacological data demonstrated that compound 21 possessed potent Hh pathway inhibition with a nanomolar IC₅₀ value, and it prevented Shh-induced Smo from entering the primary cilium. Furthermore, mutant Smo was effectively suppressed via compound 21. The in vitro antiproliferative activity of compound 21 against a drug-resistant cell line gave encouraging results.

Benzamide analog (21) was identified as a potent hedgehog signaling pathway inhibitor that targeted the Smo receptor and blocked Daoy cell proliferation.     

Visible light-induced photoredox catalyzed C–N coupling of amides with alcohols

A visible-light-mediated method for the construction of N-monoalkylated products from easily available benzamides and benzyl alcohol in the presence of eosin Y has been developed. The reaction proceeded smoothly, for a wide range of derivatives of benzamides and benzyl alcohols, to give the desired products in good to excellent yields. Biological studies, such as those on drug-likeness and molecular docking, are carried out on the molecules.

A visible-light-mediated method for the construction of N-monoalkylated products from easily available benzamides and benzyl alcohol in the presence of eosin Y has been developed.     

Photo-induced synthesis,structure and in vitro bioactivity of a natural cyclic peptide Yunnanin A analog

A cyclic analog of natural peptide Yunnanin A was synthesized via photoinduced single electron transfer reaction (SET) in the paper. The resulting compound exhibited potent bioactivity (with IC₅₀ values 29.25 μg mL⁻¹ against HepG-2 cell lines and 65.01 μg mL⁻¹ against HeLa cell lines), but almost have no toxicity to normal cells (with IC₅₀ values 203.25 μg mL⁻¹ against L929 cell lines), which may be served as a potential antitumor drug for medical treatment. The spatial structure was examined by experimental electronic circular dichroism (ECD) and quantum chemistry calculations. Moreover, the theoretical study suggested that special intramolecular hydrogen bonds and γ, β-turn secondary structures may be possible sources affecting cyclic peptide''s bioactivity.

The photo-induced synthesis, structure and in vitro bioactivity study of a Yunnanin A cyclopeptide analog was presented.     

Synthesis of novel 10,11-methylenedioxy-camptothecin glycoside derivatives and investigation of their anti-tumor effects in vivo

10,11-Methylenedioxy-camptothecin (FL118) is a novel camptothecin analogue that possesses exceptional antitumor efficacy in human tumor xenograft models. The aim of the current study was to develop novel 20-substituted FL118 derivatives coupled with glycosyl-succinic acid esters with improved antitumor efficacy. These FL118 glycoside derivatives were designed, synthesized and their cytotoxicity evaluated in three tumor cell lines (A-549, MDA-MB-231 and RM-1). All of the derivatives showed superior in vitro cytotoxic activity and were more potent than irinotecan in A549 and MDA-MB-231 cells. In mouse prostate cancer cells RM-1, 10,11-methylenedioxy-camptothecin rhamnoside 11b displayed significant activities with IC₅₀ of 48.27 nM. Western blot analysis demonstrated that 11b inhibited survivin expression and induced cancer cells apoptosis. Further cell cycle analyses clearly showed 11b induced G2/M phase cell cycle arrest. Molecule docking studies suggested that the binding mode of 11b was different from that of the crystal complex of ligand topotecan in Top1/DNA. Importantly, 11b showed high in vivo antitumor efficacy in the RM-1 mouse model with transplantation of prostate cancer (TGI = 44.9%) at dose of 9 mg kg⁻¹ without apparent toxicity.

In a RM-1 xenograft model, 11b had superior in vivo antitumor efficacy (TGI = 44.9%) at a dose of 9 mg kg⁻¹.     

Benzyl thioether formation merging copper catalysis

A novel copper-catalyzed thioetherification reaction has been developed to afford benzyl thioethers in moderate to excellent yields. Under the mild and easy-to-operate conditions, a variety of thioethers are efficiently prepared from readily available benzyl alcohols (primary, secondary, and tertiary) and thiols in the presence of Cu(OTf)₂ as the Lewis acid catalysis. This C–S bond formation protocol furnishes exceptional chemoselectivity, and the preliminary mechanism studies show that the reaction should proceed through a Lewis-acid-mediated S_N1-type nucleophilic attack of the carbocations formed in situ.

A novel copper-catalyzed thioetherification reaction has been developed to afford benzyl thioethers in moderate to excellent yields.     

Pyrazole-based lamellarin O analogues: synthesis,biological evaluation and structure–activity relationships

A library of pyrazole-based lamellarin O analogues was synthesized from easily accessible 3(5)-aryl-1H-pyrazole-5(3)-carboxylates which were subsequently modified by bromination, N-alkylation and Pd-catalysed Suzuki cross-coupling reactions. Synthesized ethyl and methyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylates were evaluated for their physicochemical property profiles and in vitro cytotoxicity against three human colorectal cancer cell lines HCT116, HT29, and SW480. The most active compounds inhibited cell proliferation in a low micromolar range. Selected ethyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylates were further investigated for their mode of action. Results of combined viability staining via Calcein AM/Hoechst/PI and fluorescence-activated cell sorting data indicated that cell death was triggered in a non-necrotic manner mediated by mainly G2/M-phase arrest.

Isosteric pyrrole–pyrazole exchange in the natural alkaloid lamellarin O resulted in 18 fully characterized derivatives. Obtained compounds were investigated as potent agents against human colon cancer cell lines HCT116, HT29 and SW480.     

Substrate switchable Suzuki–Miyaura coupling for benzyl ester vs. benzyl halide

Two reaction conditions were developed to accomplish the substrate switchable Suzuki–Miyaura coupling of benzyl derivatives and arylboronic acid derivatives. Under conditions for esters, benzyl esters such as carbonates and acetates reacted with arylboronic acids to afford the corresponding diarylmethanes. However, the benzyl halides did not react under the same conditions. On the other hand, benzyl halides such as bromides and chlorides furnished diarylmethanes under conditions for halides, under which benzyl ester substrates did not react, in which water was found to play an important role. This switching system was tested using the intermolecular/intramolecular competitive reactions, during which the desired products could be synthesized by selecting the appropriate reaction conditions.

Two reaction conditions were developed to accomplish the substrate switchable (benzyl esters vs. benzyl halides) Suzuki–Miyaura coupling.     

Highly reactive 2-deoxy-2-iodo-d-allo and d-gulo pyranosyl sulfoxide donors ensure β-stereoselective glycosylations with steroidal aglycones

The preparation of well-defined d-xylo and d-ribo glycosides represents a synthetic challenge due to the limited configurational availability of starting materials and the laborious synthesis of homogeneous 2-deoxy-β-glycosidic linkages, in particular that of the sugar-steroid motif, which represents the “stereoselective determining step” of the overall synthesis. Herein we describe the use of 2-deoxy-2-iodo-glycopyranosyl sulfoxides accessible from widely available d-xylose and d-ribose monosaccharides as privileged glycosyl donors that permit activation at very low temperature. This ensures a precise kinetic control for a complete 1,2-trans stereoselective glycosylation of particularly challenging steroidal aglycones.

Highly stereoselective synthesis of challenging steroidal 2-deoxy-β-glycosides with d-xylo and d-ribo configurations enabled by low temperature activation of 2-deoxy-2-iodoglycopyranosyl sulfoxides.     

Synthesis and in vitro anti-proliferative evaluation of naphthalimide–chalcone/pyrazoline conjugates as potential SERMs with computational validation

A series of naphthalimide-chalcone/pyrazoline conjugates was prepared and evaluated for their anti-breast cancer potential against estrogen responsive, i.e. MCF-7 (ER+), and triple-negative, i.e. MDA-MB-231 (ER−), cell lines. The structure-activity-relationship (SAR) was deduced based on the influence of linker length, substituents on the phenyl ring and the generated functionalities, on anti-proliferative activities. Docking simulations further delineate the type of interactions of the designed molecules with the selected targets. This report discloses the scope of triazole tethered naphthalimide-chalcone/pyrazoline conjugates as anti breast cancer agents.

Design, synthesis and anti-proliferative evaluation of naphthalimide–chalcone/pyrazoline conjugates.