ABSTRACT
Atherosclerosis (AS) is the leading cause of cardiovascular disease. Foam cells, with elevated lipid droplets (LDs) and HClO levels, are the main components of the atherosclerotic plaques that are characteristic of AS. Super-resolution imaging can be used to visualize the distribution of LDs in foam cells at the nanometer level, facilitating the identification of LDs and HClO. In the present study, we report the development of a ratiometric fluorescent probe, SFL-HClO, for super-resolution imaging of LDs and HClO. Super-resolution imaging with this probe revealed the precise structure of LDs at the suborganelle level. Moreover, the fluorescence behavior of SFL-HClO on the surface of LDs verified its excellent performance in detecting HClO in the foam cells. SFL-HClO can sequentially and specifically respond to LDs and HClO via "turn-on" and ratiometric signal output, respectively, thus contributing to precise imaging of foam cells. Importantly, we demonstrate that SFL-HClO can be used to report on upregulated HClO in atherosclerotic plaques in the aorta of AS mice, providing a suitable fluorescent tool for early atherosclerotic disease assessment.
Subject(s)
Atherosclerosis , Fluorescent Dyes , Foam Cells , Hypochlorous Acid , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Foam Cells/pathology , Animals , Atherosclerosis/diagnostic imaging , Atherosclerosis/pathology , Mice , Hypochlorous Acid/analysis , RAW 264.7 Cells , Optical Imaging , Humans , Plaque, Atherosclerotic/diagnostic imaging , Plaque, Atherosclerotic/chemistry , Plaque, Atherosclerotic/pathology , Mice, Inbred C57BL , Lipid Droplets/chemistryABSTRACT
A novel copper-catalyzed cycloaddition of diaryl disulfides to heterobicyclic alkenes has been developed. The C-S and C-C bonds can be formed simultaneously on the CâC bond of the olefins via a single-step cycloaddition to afford a series of 2,3-dihydrobenzo[b]thiophene derivatives. This reaction exhibits excellent diastereoselectivity and relatively broad substrate scope. Various functional groups attached to the substrates are tolerated in this protocol to give the corresponding exo adducts in moderate yields.
ABSTRACT
A novel copper-catalyzed hydrothioetherification of oxa(aza)bicyclic alkenes with potassium thioacetate and aryl or alkyl iodides to synthesize unsymmetrical thioethers has been developed. Notably, the reaction with complete diastereoselectivity went through a syn-selective addition process to give exo-adducts. In addition, this protocol exhibited high efficiency and good functional group tolerance to afford the target thioethers in moderate to good yields. Based on the results of mechanistic investigations, a plausible mechanism was proposed.
ABSTRACT
A cobalt(II)-catalyzed [4+2] annulation of picolinamides with alkynes via C-H bond activation has been developed. The operationally simple annulation reaction allows for the synthesis of acyl-substituted 1H-benzoquinoline bearing multiple aromatic rings (up to 96 % yield) without co-oxidant or other oxidation factors under mild conditions. Several control experiments were carried out. This practical [4+2] annulation provides an efficient route to access highly functionalized compounds.
ABSTRACT
A novel palladium-catalyzed ring-opening reaction of oxabicyclic alkenes with arylsulfonyl hydrazides was first developed. In this work, we provide an efficient one-pot reaction to afford the corresponding cis-2-aryl-1,2-dihydronaphthalen-1-ols and 2-aryl-naphthalenes in moderate to excellent yields (up to 95%) under an open-air condition. Various types of functional groups attached to the substrates were tolerated well in this method. Among them, the cis-1,2-configuration of product 3ag was confirmed by X-ray crystallographic analysis. In addition, a plausible mechanism for ring opening was also proposed.
ABSTRACT
A novel copper-catalyzed complete diastereoselective 1,2-difunctionalization of oxabicyclic alkenes has been developed. Two C-S bonds were constructed simultaneously on the oxabenzonorbornadienes leading to ß-thiocyanato thioethers through the three-component (oxabicyclic alkenes, aryl iodides, and potassium thiocyanate), one-pot reaction. Various functional groups attached to the substrates were tolerated in this protocol to afford the corresponding ß-thiocyanato thioether products in moderate yields.
ABSTRACT
An efficient three-component cycloaddition of oxa(aza)bicyclic alkenes/norbornene in the presence of NaN3 and arylsulfonyl chlorides was developed, affording the corresponding aziridine products in good yields (up to 82%) with moderate to good endo/exo selectivities (up to >99:1 endo/exo). Further studies showed that the cycloaddition of oxa(aza)bicyclic alkenes in the presence of NaN3 and chloroalkanes could afford the exo-cycloadduct 1,2,3-triazolines in good to excellent yields (up to 95%). Compared with the existing methodologies, the current protocol demands very simple and mild reaction conditions and is a metal-free catalyzed reaction. In addition, a plausible mechanism for the cycloaddition reaction was also proposed.
ABSTRACT
A novel ICl/AgNO3 co-catalyzed radical oxidation of diaryl- and alkylarylalkynes into 1,2-diketones is reported. The reaction proceeded smoothly under mild conditions and generated 1,2-diketones in moderate to good yields with a good tolerance of functional groups. Furthermore, the obtained C4-(1,2-diketoaryl)isoxazoles could react smoothly with 1,2-diaminobenzene to form C4-(3-arylquinoxalin-2-yl)isoxazoles. At last, a new one-pot strategy for the synthesis of quinoxalines from 1,2-diphenylethynes and 1,2-diaminobenzene is also reported.
ABSTRACT
A Pd-catalyzed Sonogashira cross-coupling reaction for the synthesis of C4-alkynylisoxazoles from 3,5-disubsitituted-4-iodoisoxazoles and terminal alkynes was described, which could afford the corresponding products with high yield (up to 98%). The results indicated that the steric effect from the group at the C3 position of the isoxazole had greater influence on the cross-coupling reaction than that from the group at the C5 position. In addition, the group at the C3 position of the isoxazole showed negligible electronic effects on the cross-coupling reaction. Furthermore, a gram-scale reaction of the Sonogashira coupling reaction was also investigated. Finally, a plausible mechanism for the Sonogashira coupling reaction was proposed.
ABSTRACT
BACKGROUND: The modification of steroidal structure is commonly used to change the biological activity of steroids in medicinal chemistry. Some steroids containing heterocycles exhibit distinct cytotoxicity against various cancer cell lines and have been gotten wide attention over the years by medicinal chemists for drug discovery. METHODS: Using pregnenolone and stigmasterol as starting materials, via different chemical reaction, two series of heterosteroids with side chain of 20- and 22-hydrazone aromatic cycles or heterocycles in their structures were synthesized and characterized by IR, NMR and HRMS. The antiproliferative activity of the compounds in vitro was evaluated against human HT-29, HeLa, Bel 7404 and SGC 7901 cancer cells by MTT assays. RESULTS: The steroidal compounds with side chain of 20-hydrazone aromatic cycles or heterocycles exhibited distinct cytotoxicity. However, analogues with the side chain of 22-hydrazone resulted in a dramatic decrease of the cytotoxicity. The result of Annexin V assay showed that the 20-hydrazone compounds were potent apoptotic inducers against these carcinoma cells. CONCLUSION: Steroidal compounds with the side-chain of 20-hydrazone aromatic heterocycles exhibit distinct antiproliferative activity in vitro. However, the compounds with the side-chain of 22-hydrazone aromatic heterocycle decreased the cytotoxicity of the compounds.
ABSTRACT
Steroidal compounds exhibit particular physiological activities. In this paper, some steroidal thiosemicarbazones platinum (Pt(II)) complexes were synthesized by the condensation of steroidal ketones with thiosemicarbazide using estrone, chenodeoxycholic acid, and 7-deoxycholic acid as starting materials and complexation of steroidal thiosesemicarbazones with Pt(II). The complexes were characterized by IR, NMR, and MS, and their antiproliferative activities were evaluated. The results showed that some steroidal thiosemicarbazones platinum (Pt(II)) complexes displayed moderate cytotoxicity to HeLa and Bel-7404 cells. Thereinto, complex 6 showed an excellent inhibited selectivity to HeLa cells with an IC50 value of 9.2 µM and SI value of 21.7. At the same time, all compounds were almost inactive to HEK293T (normal kidney epithelial cells). The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.
ABSTRACT
Taking orostanal (a compound from a Japanese marine sponge, Stelletta hiwasaensis) as a lead compound, some novel B-norcholesteryl benzimidazole and benzothiazole derivatives were synthesized. The antiproliferative activity of the compounds against human cervical carcinoma (HeLa), human lung carcinoma (A549), human liver carcinoma cells (HEPG2) and normal kidney epithelial cells (HEK293T) was assayed. The results revealed that the benzimidazole group was a better substituent than benzothiazole group for increasing the antiproliferative activity of compounds. 2-(3ß'-Acetoxy-5ß'-hydroxy-6'-B-norcholesteryl)benzimidazole (9b) with the structure of 6-benzimidazole displays the best antiproliferative activity to the cancer cells in all compounds, but is almost inactive to normal kidney epithelial cells (HEK293T). The assay of compound 9b to cancer cell apoptosis by flow cytometry showed that the compound was able to effectively induce cancer cell apoptosis. The research provided a theoretical reference for the exploration of new anti-cancer agents and may be useful for the design of novel chemotherapeutic drugs.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzimidazoles/pharmacology , Benzothiazoles/pharmacology , Drug Design , Neoplasms/drug therapy , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzimidazoles/adverse effects , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Benzothiazoles/adverse effects , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cholesterol/adverse effects , Cholesterol/analogs & derivatives , Cholesterol/chemical synthesis , Cholesterol/chemistry , Cholesterol/pharmacology , Cholesterol Esters/adverse effects , Cholesterol Esters/chemical synthesis , Cholesterol Esters/chemistry , Cholesterol Esters/pharmacology , HEK293 Cells , Humans , Inhibitory Concentration 50 , Japan , Molecular Structure , Neoplasms/pathology , Porifera/chemistry , Porifera/growth & development , Stereoisomerism , Sterols/chemistry , Sterols/pharmacology , Structure-Activity RelationshipABSTRACT
Using 3ß-hydroxy-5-androsten-17-one as a starting material, a series of novel nitrogen-containing B-nor-D-homosteroids were designed and synthesized by the oximation, Beckman rearrangement, ozonation, cyclization and condensation reaction. The structures of all new compounds were determined by analysis of their NMR, MS and IR spectra. The antiproliferative activity of compounds was evaluated against HT-29 (colonic carcinoma), HeLa (human cervical carcinoma) and Bel 7404 (human liver carcinoma) cells.
Subject(s)
Androstenediols/chemistry , Antineoplastic Agents , Cell Proliferation/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , HeLa Cells , HumansABSTRACT
Steroidal thiosemicarbazones, semicarbazones and hydrazones have received extensive attention of scientists recently because they exhibit some biological activities such as antibacterial, antiviral and anticancer. Using different steroids as starting materials, through different chemical methods, 24 steroidal compounds with thiosemicarbazone, semicarbazone or hydrazone groups in their structures, were synthesized, characterized by IR, NMR and MS. The antiproliferative activity of the compounds was evaluated against human gastric cancer (SGC-7901) and human liver cancer (Bel-7404) cells. The structure-activity relationship of these compounds was discussed. The results showed that compound 3 and 12a-12c exhibited significant inhibitory activity to Bel-7404 cells, and IC50 values of them were 4.2, 11.0, 7.4 and 15.0µM respectively (Cisplatin, IC50: 11.6µM).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Hydrazones/chemistry , Steroids/chemical synthesis , Steroids/pharmacology , Thiosemicarbazones/chemistry , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Humans , Steroids/chemistry , Structure-Activity RelationshipABSTRACT
Using analogues of some marine steroidal oximes as precursors, a series of aza-B-homocholestane derivatives possessing different substituted groups at the 3-position of the steroidal nucleus were synthesized. Their biological activity against cancer cell proliferation was determined with multiple cancer cell lines. Aza-B-homocholestane derivatives possessing 3-hydroxyl, 3-hydroximino and 3-thiosemicarbazone groups displayed remarkable cytotoxicity to cancer cells via apoptosis inducing mechanism. Compounds 5, 10, 12, 15 and 18 exhibited better potency to inhibit cancer cell proliferation. In addition, compound 15 was further evaluated with three dimensional (3D) multicellular spheroids assay to determine its potency against spheroid growth. The structure-activity relationship (SAR) generated in the studies is valuable for the design of novel chemotherapeutic agents.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cholestanes/pharmacology , Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cholestanes/chemical synthesis , Cholestanes/chemistry , Drug Design , Humans , Neoplasms/pathology , Steroids/chemical synthesis , Steroids/chemistry , Steroids/pharmacology , Structure-Activity RelationshipABSTRACT
Some novel B-norcholesterols with different substituted groups were synthesized. The antiproliferative activity of the compounds against cervical carcinoma (HeLa), liver cancer (Bel 7404) and gastric cancer (SGC 7901) cells was assayed. The results revealed that the presence of a 6-alkylthiosemicarbazone or 6-cyano group could enhance the antiproliferative activity of these compounds. The induction of compounds 6 and 9 to cancer cell apoptosis were assayed by flow cytometry, and the results showed that the compounds were able to effectively induce cancer cell apoptosis. The research provided a theoretical reference for the exploration of new anti-cancer drug. The results suggest that compounds 6 and 9 based on its abeo-cholestane may constitute a novel class of antiproliferative agents, which deserve further study.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Cholesterol/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Cholesterol/analogs & derivatives , Cholesterol/chemical synthesis , Drug Screening Assays, Antitumor , Flow Cytometry , HeLa Cells , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Structure-Activity RelationshipABSTRACT
Using cholesterol, stigmasterol and sitosterol as starting materials, some 4,6-diaza-A,B-dihomo-steroid bilactams were synthesized via two different synthetic routes by oxidation, reduction, oximation, Beckman rearrangement, etc. The cytotoxic activity of the synthesized compounds against SGC 7901 (human ventriculi carcinoma), Bel-7404 (human liver carcinoma), HeLa (human cervical carcinoma) and HT-29 (colonic carcinoma) cancer cells were investigated. The results showed that compounds 2 and 7b displayed a good cytotoxic activity to the SGC 7901, Bel 7404 and HeLa tumor cell lines with the IC50 values of 11.6, 16.4, 13.9 and 13.1, 21.8, 13.1 µmol/L, respectively. Their cytotoxic activity is almost same as cisplatin to these cells. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Steroids/chemical synthesis , Steroids/pharmacology , Antineoplastic Agents/chemical synthesis , Azasteroids/chemical synthesis , Azasteroids/chemistry , Azasteroids/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cholesterol/chemistry , Drug Screening Assays, Antitumor , HT29 Cells , HeLa Cells , Homosteroids/chemical synthesis , Homosteroids/chemistry , Homosteroids/pharmacology , Humans , Inhibitory Concentration 50 , Lactams , Models, Chemical , Molecular Structure , Neoplasms/drug therapy , Neoplasms/pathology , Sitosterols/chemistry , Steroids/chemistry , Stigmasterol/chemistryABSTRACT
Using deoxycholic acid as starting materials, a series of 12a-aza-C-homo-12-one 7-deoxycholic acid derivatives were synthesized The antiproliferative activity of the synthesized compounds against some carcinoma cell lines was investigated. The results showed that some 12-oxy-12a-aza-C-homo-7-deoxycholic acid derivatives displayed distinct cytotoxicity to HeLa (human cervical carcinoma) and Tu 686 (laryngocarcinoma) tumor cell lines. In particular, the IC50 values of the compounds 6 and 7 against Tu 686 cells are 16.7 and 19.8 µM/L respectively. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.