N-Arylation of Amino Acid Esters via an I2-Mediated Metal-Free Multicomponent Benzannulation Strategy.

Herein, we present a novel method for the N-arylation of amino acid esters using α-bromoacetaldehyde acetal and acetoacetate via an I2-mediated metal-free benzannulation strategy, which disclosed the first synthetic application of N-arylation of amino acids using nonaromatic building blocks. The synthesized N-arylated amino acid derivatives were found to possess promising selective inhibition against human hepatocellular liver carcinoma cells, human melanoma cells, and human normal liver cells, with an IC50 value as low as 16.79 µg·mL-1.

Novel Steroidal[17,16-d]pyrimidines Derived from Epiandrosterone and Androsterone: Synthesis, Characterization and Configuration-Activity Relationships.

Two series of novel steroidal[17,16-d]pyrimidines derived from natural epiandrosterone and androsterone were designed and synthesized, and these compounds were screened for their potential anticancer activities. The preliminary bioassay indicated that some of these prepared compounds exhibited significantly good cytotoxic activities against human gastric cancer (SGC-7901), lung cancer (A549), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), epiandrosterone, and androsterone. Especially the respective pairs from epiandrosterone and androsterone showed significantly different inhibitory activities, and the possible configuration-activity relationships have also been summarized and discussed based on kinase assay and molecular docking, which indicated that the inhibition activities of these steroidal[17,16-d]pyrimidines might obviously be affected by the configuration of the hydroxyl group in the part of the steroidal scaffold.

Diarylamine-Guided Carboxamide Derivatives: Synthesis, Biological Evaluation, and Potential Mechanism of Action.

Diarylamines are a class of important skeleton widely existing in drugs or natural products. To discover novel diarylamine analogues as potential drugs, two series of diamide and carboxamide derivatives containing diarylamine scaffold were designed, synthesized and evaluated for their potential cytotoxic activities. The bioassay results indicated that some of the obtained compounds (C5, C6, C7, C11) exhibited good cytotoxic effect on cancer cell lines (SGC-7901, A875, HepG2), especially, compound C11 present significantly selective proliferation inhibition activity on cancer and normal cell lines (MARC145). In addition, the possible apoptosis induction for highly potential molecules was investigated, which present compound C11 could be used as novel lead compound for discovery of promising anticancer agents.

Design, Synthesis, and Cytotoxic Activity of Novel Natural Arylsulfonamide-Inspired Molecules.

Primary arylsulfonamide functional groups feature prominently in diverse pharmaceuticals. However, natural arylsulfonamides are relatively infrequent. In this work, two novel arylsulfonamide natural products were first synthesized, and then a series of novel molecules derived from natural arylsulfonamides were designed and synthesized, and their in vitro cytotoxic activities against A875, HepG2, and MARC145 cell lines were systematically evaluated. The results indicate that some of these arylsulfonamide derivatives exhibit significantly good cytotoxic activity against the tested cell lines compared with the control 5-fluorouracil (5-FU), such as compounds 10l, 10p, 10q, and 10r. In particular, the potential molecule 10q, containing a carbazole moiety, exhibited the highest inhibitory activity against all tested cell lines, with IC50 values of 4.19 ± 0.78, 3.55 ± 0.63, and 2.95 ± 0.78 µg/mL, respectively. This will offer the potential to discover novel drug-like compounds from the sparsely populated area of natural products that can lead to effective anticancer agents.

Selective and effective anticancer agents: Synthesis, biological evaluation and structure-activity relationships of novel carbazole derivatives.

Carbazole alkaloids is an important class of natural products with diverse biological functions. So, the aim of this article is to explore new chemical entities containing carbazole scaffold as potential novel cytotoxic agents based on our developed three-component indole-to-carbazole reaction. Two series of carbazole derivatives were designed and synthesized, and their in vitro cytotoxic activities against three cell lines (A875, HepG2, and MARC145) were evaluated. The results indicated that some of these carbazole derivatives exhibited significantly good cytotoxic activities against tested cell lines compared with the control 5-fluorouracil (5-FU). Especially, carbazole acylhydrazone compounds 7g and 7p displayed high inhibitory activity on cancer cells, but almost no activity on normal cells. Further analysis of induced apoptosis for potential compounds indicated that the potential antitumor agents induced cell death in A875 cells at least partly (initially) by apoptosis, which might be used as promising lead scaffold for discovery of novel carbazole-type cytotoxic agents.

Synthesis and bioevaluation of novel steroidal isatin conjugates derived from epiandrosterone/androsterone.

Steroids are classes of natural products widely distributed in nature, which have been demonstrated to exhibit broad biological functions, and have also attracted increasing interest from bioorganic and pharmaceutical researches. In order to develop novel chemical entities as potential cytotoxic agents, a series of steroidal isatin conjugations derived from epiandrosterone and androsterone were efficiently prepared and characterized, and all these obtained compounds were screened for their potential cytotoxic activities. The preliminary bioassay indicated that most of the newly synthesized compounds exhibited good cytotoxic activities against human gastric cancer (SGC-7901), melanoma (A875), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), which might be considered as promising scaffold for further development of potential anticancer agents.

An efficient synthesis and bioactivity evaluation of oxazole-containing natural hinduchelins A-D and their derivatives.

Oxazoles are an important class of biologically active metabolites from nature, and exhibit broad biological activities as the lead for drug discovery. Hinduchelins are a class of unusual natural products with an oxazole unit, isolated from Streptoalloteichus hindustanus, and with a potential iron-chelating ability. These compounds are the first identified naturally occurring unusual oxazole derivatives to possess a catechol unit. However, some of these compounds are not abundant in nature, and thus, the efficient syntheses of these compounds are advantageous in exploring their potential applications. This paper reports the efficient synthesis and bio-evaluation of hinduchelins A-D and their derivatives with convenient procedures and high yields.

Synthesis and biological evaluation of marine alkaloid-oriented ß-carboline analogues.

Pityriacitrin is a marine alkaloid with typical ß-carboline scaffold, and which has been proven to exhibit diverse biological functions. During the course of our research for highly active compounds from natural products, the pityriacitrin have also been isolated and identified from a Chinese Burkholderia sp. NBF227. So, in order to explore the potential functional molecules, a series of ß-carboline analogues derived from pityriacitrin were designed and synthesized, and their in vitro cytotoxic activities against SGC-7901, A875, HepG2, and MARC145 cell lines were evaluated. The results demonstrated that some of these ß-carboline derivatives exhibited moderate to good cytotoxic activities, especially, compound 9o with a special sulfonyl group presented the highest inhibitory activities against all tested cell lines with the IC50 values of 6.82 ±â€¯0.98, 8.43 ±â€¯1.93, 7.69 ±â€¯2.17, 7.19 ±â€¯1.43 µM, respectively, which might be used as lead compound for discovery of novel cytotoxic agents.

Cytotoxic and Antibacterial Eremophilane Sesquiterpenes from the Marine-Derived Fungus Cochliobolus lunatus SCSIO41401.

Three new eremophilane sesquiterpenes, dendryphiellins H-J (1-3), and three new phthalide natural products (4-6) were isolated from the marine-derived fungus Cochliobolus lunatus SCSIO41401. Their structures including absolute configurations were determined by spectroscopic and calculated ECD analyses. Dendryphiellin I (2) showed cytotoxic and antibacterial activities against five cancer cell lines (IC50 1.4 to 4.3 µM) and three bacterial species (MIC 1.5 to 13 µg/mL), respectively. Dendryphiellin J (3), a rare naturally occurring aldoxime analogue, displayed cytotoxicities against ACHN and HepG-2 cells with IC50 values of 3.1 and 5.9 µM, respectively. Further studies indicated that 3 induced apoptosis in ACHN cells in a dose- and time-dependent manner.

Four new anthraquinones from a soil actinomycete Streptomyces sp. WS-13394 and their bioactivities.

Further chemical study of secondary metabolites from the soil actinomycete Streptomyces sp. WS-13394 resulted in the isolation of four new alkylated anthraquinone analogues (5-8). Their structures were elucidated on the basis of extensive spectroscopic analysis, including HR-ESI-MS, 1D and 2D NMR. The new compounds, together with analogues obtained before (1-4), were tested for their in vitro cytotoxicity against Huh-7 and SGC-7901.

Nicotinamide-based diamides derivatives as potential cytotoxic agents: synthesis and biological evaluation.

A series of diamides derivatives containing nicotinamide unit were designed, synthesized and evaluated for their potential cytotoxic activities against human cancer cell lines. All the synthesized compounds were characterized using spectroscopic methods mainly including 1H NMR, 13C NMR and MS. The bio-evaluation results indicated that some of the obtained compounds (such as 4d, 4h, 4i) exhibited good to moderate cytotoxic effects on lung cancer cell lines (NCI-H460, A549, and NCI-H1975), especially, compound 4d exhibited the highly potential inhibitory activities against NCI-H460 cell line with the IC50 values of 4.07 ± 1.30 µg/mL, which might be developed as novel lead compounds for potential cytotoxic agents.

Steroidal[17,16-d]pyrimidines derived from dehydroepiandrosterone: A convenient synthesis, antiproliferation activity, structure-activity relationships, and role of heterocyclic moiety.

A series of steroidal[17,16-d]pyrimidines derived from dehydroepiandrosterone were designed and prepared by a convenient heterocyclization reaction. The in vitro anticancer activities for these obtained compounds were evaluated against human cancer cell lines (HepG2, Huh-7, and SGC-7901), which demonstrated that some of these heterocyclic pyrimidine derivatives exhibited significantly good cytotoxic activities against all tested cell lines compared with 5-fluorouracil (5-FU), especially, compound 3b exhibited high potential growth inhibitory activities against all tested cell lines with the IC50 values of 5.41 ± 1.34, 5.65 ± 1.02 and 10.64 ± 1.49 µM, respectively, which might be used as promising lead scaffold for discovery of novel anticancer agents.

Synthesis, antitumor activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide-hydrazone and carboxamide moiety.

A series of novel 2,4,5-trisubstituted 1,3-thiazole derivatives containing hydrazide-hydrazine, and carboxamide moiety including 46 compounds T were synthesized, and evaluated for their antitumor activity in vitro against a panel of five human cancer cell lines. Eighteen title compounds T displayed higher inhibitory activity than that of 5-Fu against MCF-7, HepG2, BGC-823, Hela, and A549 cell lines. Especially, T1, T26 and T38 exhibit best cytotoxic activity with IC50 values of 2.21µg/mL, 1.67µg/mL and 1.11µg/mL, against MCF-7, BCG-823, and HepG2 cell lines, respectively. These results suggested that the combination of 1,3-thiazole, hydrazide-hydrazone, and carboxamide moiety was much favorable to cytotoxicity activity. Furthermore, the flow cytometry analysis revealed that compounds T1 and T38 could induce apoptosis in HepG2 cells, and it was confirmed T38 led the induction of cell apoptosis by S cell-cycle arrest.

Acylhydrazone derivatives as potential anticancer agents: Synthesis, bio-evaluation and mechanism of action.

A series of novel acylhydrazone derivatives were designed, synthesized and evaluated for their potential cytotoxic effects against human cancer cell lines. The preliminary results indicated that some of the obtained compounds (such as 8b, 13c) exhibited good to moderate cytotoxic activities against human HepG2, Huh-7, and BCG-823 cell lines. Especially, compounds 8c and 8e presented obviously selective cytotoxic activities against Huh-7 in vitro (8c, IC50=7.74±2.18µg/mL; 8e, IC50=4.46±1.05µg/mL) compared to 5-FU (IC50=10.41±3.41µg/mL). The highly potential compounds to induce apoptosis in HepG2 cells were analyzed by flow cytometry, and the apoptotic effects of compounds 8b and 13c were further evaluated using Annexin V-FITC/propidium iodide dual staining assay.

Discovery of novel isatin-dehydroepiandrosterone conjugates as potential anticancer agents.

A series of isatin-dehydroepiandrosterone hybrids were synthesised via a convenient condensation procedure, and which were evaluated for their potential anticancer activities. The preliminary assays indicated that some of the newly obtained compounds exhibited good antitumor activities against human hepatocellular liver carcinoma (HepG2), heptoma (Huh-7), melanoma (A875) and 5-fluorouracil-resistant human hepatocellular carcinoma (BEL-7402/5-FU) cell lines compared with 5-fluorouracil (5-FU), which might be considered as promising lead scaffold for further design and synthesis of highly potential anticancer agents.

Novonestmycins A and B, two new 32-membered bioactive macrolides from Streptomyces phytohabitans HBERC-20821.

Two new 32-membered macrolide compounds, named Novonestmycins A (1) and B (2), were isolated from the soil strain Streptomyces phytohabitans HBERC-20821. Their structures were elucidated by using spectroscopic methods, including 1D, 2D-NMR and MS spectrometry. The two compounds showed strong activities against the phytophathogenic fungi Corynespora cassiicola, Rhizoctonia solani and Septoria nodorum, with MIC values of 0.78, 0.39 and 0.78 µg ml(-1), respectively. In addition, the two compounds exhibited potent inhibitory activities against four different human tumor cell lines as well as one 5-FU-resistant human hepatocellular carcinoma cell line, with IC50 of 0.15-0.48 µg ml(-1) and 0.24-1.34 µg ml(-1), respectively.

Antiviral effects against EV71 of pimprinine and its derivatives isolated from Streptomyces sp.

BACKGROUND: The pimprinine family of compounds represent very important and promising microbial metabolites for drug discovery. However, their ability in inhibiting viral infections has not yet been tested. METHODS: The antiviral activity of the pimprinine family of compounds was evaluated by determining the cytopathic effect (CPE), cell viability or plaque-forming unit (PFU), and virus yield. The mechanism of action against EV71 was determined from the virucidal activity, and effective stage and time-of-addition assays. The effects on EV71 replication were evaluated further by determining viral RNA synthesis, protein expression and cells apoptosis using the SYBR Green assays, immunofluorescence assays and flow cytometric assays, respectively. RESULTS: Pimprinethine, WS-30581 A and WS-30581 B inhibited EV71-induced CPE, reduced progeny EV71 yields, as well as prevented EV71-induced apoptosis in human rhabdomyosarcoma (RD) cells. These compounds were found to target the early stages of the EV71 replication in cells including viral RNA replication and protein synthesis. They also showed antiviral activity against ADV-7, and were slightly active against CVB3, HSV-1 and H1N1 with a few exceptions. Pimprinine was slightly active or inactive against all the viruses tested. The mechanisms by which these compounds act against the viruses tested may be similar to that demonstrated for EV71. CONCLUSION: The data described herein demonstrate that the pimprinine family of compounds are inhibitors effective against the replication of EV71 and ADV-7, so they might be feasible therapeutic agents for the treatment of viral infections.

Multisubstituted indole-acrylonitrile hybrids as potential cytotoxic agents.

A series of multisubstituted indole-acrylonitrile hybrids were designed, synthesized and evaluated for their potential cytotoxic activities. The bio-evaluation results indicated that some of the target compounds (such as 3a, 3f, 3k, 3n) exhibited good to moderate cytotoxic effect on HepG2, BCG-823, BEL-7402, and HL-7702 cell lines. Especially, the compounds 3a and 3k also exhibited high cytotoxic activities (3a, 19.38±3.38 µM; 3k, 15.43±3.54 µM) against the BEL-7402 cell line resistant to Taxol (>25µM) and 5-FU (>500 µM), which might be developed as novel lead scaffold for potential anticancer agents.

New cytotoxic alkylated anthraquinone analogues from a soil actinomycete Streptomyces sp. WS-13394.

Four new alkylated anthraquinone analogues (1-4) were isolated from a soil actimomycete Streptomyces sp. WS-13394. The structures of compounds 1-4 were elucidated to be 1,4,6-trihydroxy-8-alkylanthraquinones by means of spectroscopic methods, including UV, one dimensional (1D), 2D-NMR and MS spectrometry. All compounds showed activities against BGC-823 and MCF-7 with IC50 from 0.99 to 3.54 µg/mL, while 2 exhibited cytotoxicity against HepG2, A875, BGC-823 and MCF-7 with IC50 2.29, 4.90, 0.99, and 1.66 µg/mL, respectively.

Synthesis of novel steroid derivatives derived from dehydroepiandrosterone as potential anticancer agents.

A series of dehydroepiandrosterone derivatives containing dihydrazone unit was synthesized via a convenient condensation procedure, and which were evaluated for their potential anticancer activities. The preliminary assays indicated that some of the newly synthesized compounds exhibited good antitumor activities against human hepatocellular liver carcinoma (HepG2), heptoma (Huh-7), gastric cancer (BGC-823) and breast adenocarcinoma (MCF-7) cell lines compared with 5-fluorouracil (5-FU), which might be considered as promising lead scaffold for further design and synthesis of potential anticancer agents.