Synthesis and antitumor activity of biotinylated camptothecin derivatives as potent cytotoxic agents

A series of biotinylated camptothecin derivatives were designed and synthesized. The key to the synthesis was achieved by employing an esterification reaction and click chemistry. All of the new derivatives were tested for cytotoxicity against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC₅₀ values ranging from 0.13 to 21.53?μM. Most of the derivatives exhibited potent cytotoxicity, especially compound 17 (IC₅₀?=?0.13–3.31?μM) and compound 18 (IC₅₀?=?0.23–1.48?μM), which exhibited the highest potencies. The structure-activity relationships (SARs) of the biotinylated camptothecin derivatives were discussed for exploring novel anticancer agents.     

Synthesis and antitumor activity of novel ribonucleosides with C-5 OH replaced by a diaminopyrimidinyl group

A series of novel ribonucleosides with C-5 OH replaced by a diaminopyrimidinyl group were synthesized by successively nucleophilic substitutions of 5′-deoxy-5′-amino-ribonucleosides with 2,4-dichloropyrimidine and then with various fatty amines under microwave irradiation. Their anticancer activities in vitro were preliminarily evaluated. Compounds 7a and 8a only exhibited anticancer activity against A549 cell line with the IC₅₀ values of 10.73 and 10.99 μM, respectively. In addition, 7h and 8h showed potent activities against both A549 and Hela cell lines with the IC₅₀ values of 12.71, 8.55 and 8.44, 5.55 μM, respectively.     

Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin scaffolds

In the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC 4.2.1.1) isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2-aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride, followed by conversion to the corresponding phenols via O-demethylation with BBr₃. The novel urea and sulfamide derivatives were tested for inhibition of hCA I, II and AChE enzymes. These derivatives exhibited excellent inhibitory effects, in the low nanomolar range, with K_i values of 2.61–3.69 nM against hCA I, 1.64–2.80 nM against hCA II, and in the range of 0.45–1.74 nM against AChE. In silico techniques such as, atomistic molecular dynamics (MD) and molecular docking simulations, were used to understand the scenario of the inhibition mechanism upon approaching of the ligands into the active site of the target enzymes. In light of the experimental and computational results, crucial amino acids playing a role in the stabilization of the enzyme–inhibitor adducts were identified.     

Design,synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid

A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by ¹H NMR, ¹³C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a–d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC₅₀ values of 0.61 ± 0.07, 0.36 ± 0.05, 12.49 ± 0.08 μM against MDA-MB-231, HeLa and SMMC-7721 cells, respectively, stronger than positive control etoposide. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3b could significantly induce the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The cell cycle analysis also indicated that compound 3b could cause cell cycle arrest of MDA-MB-231 cells at G0/G1 phase.     

Synthesis, structure-activity relationships and preliminary antitumor evaluation of benzothiazole-2-thiol derivatives as novel apoptosis inducers

A series of novel benzothiazole-2-thiol derivatives were synthesized, and their anti-proliferative activities on HepG2 and MCF-7 cells were investigated. Most compounds had inhibitory effects on cell growth, and some of them were more effective than cisplatin. Compounds 6m and 6t displayed good inhibitory activities against a panel of different types of human cancer cell lines, with IC₅₀ values in the low micromolar range. Further biological evaluation indicated that 6m induced apoptosis in HepG2 cancer cells. Structure-activity relationships were also proposed.     

Synthesis and characterization of novel substituted thiophene derivatives and discovery of their carbonic anhydrase and acetylcholinesterase inhibition effects

Novel substituted thiophene derivatives ( 1, 2a‐e, 3, and 4 ) were synthesized and their structures were characterized by infrared radiation, nuclear magnetic resonance, and mass analysis. These novel substituted thiophene derivatives were effective inhibitor compounds of the carbonic anhydrase I and II isozymes (hCA I and II), and acetylcholinesterase (AChE) enzyme with K _i values in the range of 447.28 to 1004.65 nM for hCA I, 309.44 to 935.93 nM for hCA II, and 0.28 to 4.01 nM for AChE, respectively. Novel substituted thiophene derivatives can be good candidate drugs for the treatment of some diseases like neurological disorders, epilepsy, glaucoma, gastric and duodenal ulcers, mountain sickness, or osteoporosis as carbonic anhydrase isozymes inhibitors, and for the treatment of Alzheimer’s and Parkinson’s diseases as acetylcholinesterase inhibitors.     

Synthesis, structure-activity relationship and biological evaluation of anticancer activity for novel N-substituted sophoridinic acid derivatives

Sophoridine (1), a natural anticancer drug, has been used in China for decades. A series of novel N-substituted sophoridinic acid derivatives were synthesized and evaluated for their cytotoxicity with 1 as the lead. The structure-activity relationship indicated that introduction of an aliphatic acyl on the nitrogen atom might significantly enhance the anticancer activity. Among the compounds, 6b bearing bromoacetyl side-chain afforded a potential effect against four human tumor cell lines (liver, colon, breast, and lung). The mechanism of action of 6b is to inhibit the activity of DNA topoisomerase I, followed by the S-phase arrest and then cause apoptotic cell death, similar to that of its parent 1. We consider 6b promising for further anticancer investigation.     

Synthesis and insecticidal activity of novel N-oxydihydropyrrole derivatives with a substituted spirocyclohexyl group

A series of 5-spirocyclohexyl-3-(2,6-dimethylphenyl)-1,5-dihydro-2H-pyrrol-2-one derivatives (3) with various substituents on the spirocyclohexyl ring was synthesized and evaluated for its insecticidal activity against the aphid, Myzus persicae. Substituents at the 1- and 4-positions of the dihydropyrrole ring were also varied to optimize the activity. An investigation of the structure-activity relationship revealed that methoxy, alkoxyalkoxy, ethylenedioxy and methoxyimino groups were favorable as substituents at the 4-position of the spirocyclohexyl ring. The activity was optimized by the respective substitution of a methoxy or methoxymethoxy moiety and cyclopropylcarbonyloxy group at the 1- and 4-positions of the dihydropyrrole ring.     

Synthesis and glucose-stimulate insulin secretion (GSIS) evaluation of vindoline derivatives

It is demonstrated that natural product vindoline can enhance the glucose-stimulated insulin secretion (GSIS) in MIN6 cells with the EC₅₀ value of 50.2 μM. In order to improve the activities, a series of vindoline derivatives are synthesized and evaluated in MIN6 cells. Compounds 4, 8, 17 and 24 show about 4.5 times more effective stimulation insulin secretion ability (EC₅₀: 10.4, 14.2, 11.0 and 12.7 μM, respectively) than vindoline.     

Synthesis and in vitro antitubercular evaluation of novel sansanmycin derivatives

Tuberculosis (TB) is a major health problem worldwide. A series of novel sansanmycin derivatives were designed, semi-synthesized and evaluated for their activity against drug-susceptible Mycobacterium tuberculosis strain H(37)Rv with sansanmycin A (SSA) as the lead. Among these analogs tested, compound 1d possessing an isopropyl group at the amino terminal afforded an increased antimycobacterial activity with a MIC value of 8 μg/mL in comparison with SSA. Importantly, it was active for rifampicin- and isoniazid-resistant M. tuberculosis strain isolated from patients in China. These promising results offer an opportunity for further exploration of this novel class of analogs as antitubercular agents.     

Synthesis and anti-proliferative activity of a novel 1,2,3-triazole tethered chalcone acetamide derivatives

A new series of 1,2,3-triazole tethered chalcone acetamide derivatives (7a-c & 8a-r) have been synthesized in excellent yields and their structures were determined by analytical and spectral (FT-IR, ¹H NMR, ¹³C NMR & HRMS) studies. The newly synthesized derivatives were evaluated for their cytotoxic activity against four human cancer cell lines, such as HeLa (Human cervical cancer), A549 (Human alveolar adenocarcinoma), MCF-7 (Human breast adenocarcinoma) and SKNSH (Human brain cancer). Among them, compound 7c exhibited good anti-proliferation activity with HeLa (IC₅₀ 7.41 + 0.8 μM), SKNSH (IC₅₀ 8.68 + 1.1 μM), MCF-7 (IC₅₀ 9.76 + 1.3 μM) and MDA-MB-231, while compounds 7a and 7b showed promising anti-proliferation against above four human cancer cell lines with IC₅₀ 7.95–11.62 μM, respectively, compared with the standard drug Doxorubicin. We explored the probable key active site and binding mode interactions in HDAC8 (PDB ID:3SFH) and EHMT2 (PDB ID:3K5K) proteins. The docking results are complementary to the experimental observations.     

Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M₄ antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M₄ (IC₅₀s < 300 nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K_p,uu = 0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CL_p = 5.37 mL/min/kg). Surprisingly, this series displayed pan-muscarinic antagonist activity across M_1–5, despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan-muscarinic antagonist agents.     

Synthesis and in vitro antibacterial activity of novel fluoroquinolone derivatives containing substituted piperidines

We report herein the synthesis of novel 7-(4-alkoxyimino-3-aminomethyl-3-methylpiperidin-1-yl) fluoroquinolone derivatives. The antibacterial activity of the newly synthesized compounds was evaluated and correlated with their physicochemical properties. Results reveal that all of the target compounds have good potency in inhibiting the growth of Staphylococcus aureus and Staphylococcus epidermidis including MRSE (MIC: 0.125–4 μg/mL). Compounds 12, 13 are more potent than or comparable to levofloxacin against MRSA, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, and Shigella sonnei. Compound 17 is more active than or comparable to levofloxacin against S. aureus including MRSA, S. epidermidis and S. pyogenes.     

Synthesis of novel 1,2,3-triazole/isoxazole functionalized 2H-Chromene derivatives and their cytotoxic activity

A series of novel 2-(1,2,3-triazolylmethoxy) 5a–q and isoxazole tagged 6a–g 2H-Chromene derivatives were prepared starting from salicylaldehyde and ethyl-4,4,4-trifluoroacetoacetate via cyclization to form ethyl 2-hydroxy-2-(trifluoromethyl)-2H-Chromene-3-carboxylate 3. Compound 3 on reaction with propargyl bromide resulted compound 4 and was independently reacted with aryl/alkyl azides and aryl aldoximes obtained 2-(1,2,3-triazolylmethoxy) and isoxazole tagged 2H-Chromene derivatives 5a–q, 6a–i, respectively. Compounds 6 were further hydrolysed to acid derivatives 7a–g. All the products 5a–q, 6a–i, 7a–g were screened for cytotoxic activity against four human cancer cell lines and among all the compounds, 5f, 5g, 5l, 5q showed promising activity at <20 μM concentration.     

Synthesis of novel methyl jasmonate derivatives and evaluation of their biological activity in various cancer cell lines

Warburg hypothesized that the energy consumption of cancer cells is different than the normal cells. When compared to normal conditions, cancer cells do not undergo tricarboxylic acid (TCA) cycle therefore resulting in more lactate in the cells. Glycolysis pathway is a way of cancer cells to provide energy. The first step in glycolysis is the phosphorylation of glucose to glucose-6-phosphate. This reaction is catalyzed by the hexokinase-II enzyme (HK-II) which is known to be overexpressed in tumor cells. The feeding of cancer cells can be prevented by inhibiting the hexokinase-II enzyme in the first step of aerobic glycolysis. In literature, Methyl Jasmonate (MJ) is known as a Hexokinase-II inhibitor since it disposes VDAC and HK-II interaction on mitochondrial membrane. In our study, we aimed to increase the activity by synthesizing the novel MJ analogues with appropriate modifications. Here we report Hexokinase-2 enzyme and cell viability study results in different cancer cells. Based on the three different cancer cell lines we investigated, our novel MJ analogues proved to be more potent than the original molecule. Thus this research may provide more efficacious/novel HK-II inhibitors and may shed light to develop new anti-cancer agents.     

Synthesis,characterization, in vitro cytotoxicity and antimicrobial investigation and evaluation of physicochemical properties of novel 4-(2-methylacetamide)benzenesulfonamide derivatives

In this study, several sulfonamide derivatives, 4-(2-methylacetylamino)benzenesulfonamides were synthesized. Chemical structures of the derivatives were characterized by ¹H NMR, ¹³C NMR, LC–MS–MS, UV–Vis, FTIR, photoluminescence and elemental analysis. Sulfanilamide was reacted with 2-bromopropionyl bromide, in the presence of pyridine, to form bromo-substituted sulfonamide key intermediates, which were subsequently treated with secondary amines to obtain novel sulfonamide derivatives. All the synthesized compounds were evaluated for in vitro antimicrobial activities and cytotoxicity. Increases in ring size, and rings bearing a nitrogen heteroatom led to improvements in antimicrobial activities. As the presence of CA IX and CA XII enzymes have been implicated in some cancerous tumors, the studies presented herein focuses on targeting these enzymes. It was found that the synthesized derivatives had in vitro anti-cancer properties, where compounds (3–6) were found to be active against all cancerous cells, and no cytotoxic effects on normal cells were observed.     

Synthesis,antitumor activity evaluation and mechanistic study of novel hederacolchiside A1 derivatives bearing an aryl triazole moiety

In an attempt to arrive at a more potent antitumor agent than the parent natural saponin hederacolchiside A₁, 23 hederacolchiside A₁ derivatives (4a-4w) were synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and screened in vitro for cytotoxicity against six human cancer cell lines. The structure-activity relationship of these compounds was elucidated, and the biological screening results showed that most of the compounds exhibited moderate to high levels of antitumor activities against the tested cell lines and some of them displayed more potent inhibitory activities compared with hederacolchiside A₁. Compound 4f showed a 2- to 7-fold more potent activity than hederacolchiside A₁. The mechanistic study of 4f revealed that this compound can induce cell apoptosis in HepG2 cells via mitochondrial-mediated intrinsic pathways.     

Prenylflavone derivatives from Broussonetia papyrifera,inhibit the growth of breast cancer cells in vitro and in vivo

Two new prenylflavones 5,7,3′,4′-tetrahydroxy-3-methoxy-8-geranylflavone (1) and 5,7,3′,4′-tetrahydroxy-3-methoxy-8,5′-diprenylflavone (2), as well as four known ones, uralenol (3), papyriflavonol A (4), broussoflavonol B (5) and broussochalcone A (6) were isolated and purified from an ethyl acetate-soluble extract of the barks of Broussonetia papyrifera. Their structures were determined with the spectroscopic methods including HR-EI-MS, 1D and 2D NMR. We found that compounds 2–6 showed potent anti-proliferation effects on ER-positive breast cancer MCF-7 cells in vitro. The IC₅₀ values of compounds 2 and 5 were 4.41 and 4.19 μM respectively after the treatment of 72 h. We also found that compounds 2 and 5 strongly down-regulated expression concentrations of estrogen receptor-α (ER-α) and were able to inhibit tumor growth in a xenograft model of the human breast cancer line BCAP-37 in vivo. Our results demonstrated that prenylflavones from B. Papyrifera exhibit potent anti-tumor activity.     

Synthesis and in vitro growth inhibitory activity of novel silyl- and trityl-modified nucleosides

Seventeen silyl- and trityl-modified (5′-O- and 3′,5′-di-O-) nucleosides were synthesized with the aim of investigating the in vitro antiproliferative activities of these nucleoside derivatives. A subset of the compounds was evaluated at a fixed concentration of 100 μM against a small panel of tumor cell lines (HL-60, K-562, Jurkat, Caco-2 and HT-29). The entire set was also tested at varying concentrations against two human glioma lines (U373 and Hs683) to obtain GI₅₀ values, with the best results being values of ∼25 μM.     

Synthesis and cytotoxic evaluation of a series of resveratrol derivatives

A total of 17 resveratrol (=(E)-5-[2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol) derivatives were synthesized from resveratrol (RES) through a facile approach. Among them, 13 compounds, 2 and 6-17, were reported for the first time, while 1 and 3-5 had already been reported several years ago. The cytotoxic activities of these compounds were evaluated against human nasopharyngeal epidermoid tumor cell line KB, and compounds 1 and 8-11 showed strong anticancer activities in vitro, comparable with that of 5-fluorouracil, an anticancer drug. On the basis of the experimental data obtained, structure-activity relationships are discussed.