Synthesis and antitumor activities of novel rhein α-aminophosphonates conjugates

Several rhein α-aminophosphonates conjugates (5a–5q) were synthesized and evaluated for in vitro cytotoxicity against HepG-2, CNE, Spca-2, Hela and Hct-116 cell lines. Some compounds showed relatively high cytotoxicity. Especially, compound 5i exhibited the strongest cytotoxicity against Hct-116 cells (IC₅₀ was 5.32 μM). All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. The mechanism of compound 5i was preliminarily investigated by Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which indicated that the compound 5i induced apoptosis in Hct-116 cancer cells. Cell cycle analysis showed that these compound 5i mainly arrested Hct-116 cells in G1 stage. The effects of 5i on the activation of caspases expression indicated that 5i might induce apoptosis via the membrane death receptor pathways. In addition, the binding properties of a model analog 5i to DNA were investigated by methods (UV–vis, fluorescence, CD spectroscopy and FRET-melting) in compare with that of rhein. Results indicated that 5i showed moderate ability to interact ct-DNA.     

Synthesis and evaluation of novel α-heteroaryl-phenylpropanoic acid derivatives as PPARα/γ dual agonists

The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the α-position and their evaluation for binding and activation of PPARα and PPARγ are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARα/γ dual agonist (EC₅₀ = 0.013 and 0.061 μM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.     

Synthesis and biological activities of novel indole derivatives as potent and selective PPARγ modulators

Starting from the structure of Telmisartan, a new series of potent and selective PPARγ modulators was identified. The synthesis, in vitro and in vivo evaluation of the most potent compounds are reported and the X-ray structure of compound 7b bound to the PPARγ ligand binding domain is described.     

Synthesis and biological evaluation of novel spin labeled 18β-glycyrrhetinic acid derivatives

Eighteen novel spin-labeled 18β-glycyrrhetinic acid (GA) derivatives were designed, synthesized, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU-145, KB and KBvin). Most of the derivatives showed more significant cytotoxicity than that of the parent compound GA. The best compound, 6j, with a tryptophan amino moiety and piperidine nitroxyl radical showed GI₅₀ values of 13.7–15.0 μM, and was fivefold more potent than GA. In a mechanism of action study, compound 7a was confirmed as a 20S proteasome inhibitor in both in vitro and cell-based assays. These findings support further optimization efforts based on 18β-GA as a lead compound to develop potential anticancer drug candidates.     

Synthesis of novel indenoquinoxaline derivatives as potent α-glucosidase inhibitors

A series of new N-(11H-Indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazide derivatives (3a–3p) were synthesized and evaluated for their α-glucosidase inhibitory activity. The synthesized compounds 3d, 3f, 3g, 3k, 3n, 3p and 4 showed significant α-glucosidase inhibitory activity as compared to acrabose, a standard drug used to treat type II diabetes. Structures of the synthesized compounds were determined by using FT-IR, ¹H NMR, ¹³C NMR, mass spectrometry and elemental analysis techniques.     

Synthesis of novel α-pyranochalcones and pyrazoline derivatives as Plasmodium falciparum growth inhibitors

Both the lack of a credible malaria vaccine and the emergence and spread of parasites resistant to most of the clinically used antimalarial drugs and drug combination have aroused an imperative need to develop new drugs against malaria. In present work, α-pyranochalcones and pyrazoline analogs were synthesized to discover chemically diverse antimalarial leads. Compounds were tested for antimalarial activity by evaluation of the growth of malaria parasite in culture using the microtiter plate based SYBR-Green-I assay. The (E)-3-(3-(2,3,4-trimethoxyphenyl)-acryloyl)-2H-chromen-2-one (Ga6) turned out to be the most potent analog of the series, showing IC₅₀ of 3.1 μg/ml against chloroquine-sensitive (3D7) strain and IC₅₀ of 1.1 μg/ml against chloroquine-resistant field isolate (RKL9) of Plasmodium falciparum. Cytotoxicity study of the most potent compounds was also performed against HeLa cell line using the MTT assay. All the tested compounds showed high therapeutic indices suggesting that they were selective in their action against the malaria parasite. Furthermore, docking of Ga6 into active site of falcipain enzyme revealed its predicted interactions with active site residues. This is the first instance wherein chromeno-pyrazolines have been found to be active antimalarial agents. Further exploration and optimization of this new lead could provide novel, antimalarial molecules which can ward off issues of cross-resistance to drugs like chloroquine.     

Synthesis and antitumor activity of three novel ginsenoside M1 derivatives with 3′-ester modifications

Ginsenoside M1 (M1) was considered to be the main antitumor component of ginsenoside metabolites in the body. In order to enhance its potency on antitumor effect, three novel M1 3′–ester derivatives (1c, 2c, 3c) were synthesized and evaluated. The yield of these derivatives was between 41% and 69%. Compared with M1, 2c and 3c can improve the efficacy of the inhibition on breast cancer MCF–7 and MDA–MB–231 cells, especially for MCF–7 (fold: 0.7–4.2, p < 0.0001). Further study suggested that 2c and 3c may cause cell autophagy and promote apoptosis in MCF–7 cells. The results indicated the 3′–ester modified M1 derivatives 2c and 3c possess higher abilities of inhibition growth towards triple–positive breast cancer and provided a new source for synthesis of potential anti-breast cancer drugs.     

Synthesis and biological evaluation of caffeic acid derivatives as potent inhibitors of α-MSH-stimulated melanogenesis

We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of α-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities.     

Synthesis and QSAR study of novel α-methylene-γ-butyrolactone derivatives as antifungal agents

Thirty-six new α-benzylidene-γ-lactone compounds based α-methylene-γ-butyrolactone substructure were prepared and characterized by spectroscopic analysis. All compounds were evaluated for antifungal activities in vitro against six plant pathogenic fungi and the half maximal inhibitory concentration (IC₅₀) against Botrytis cinerea and Colletotrichum lagenarium were investigated. Compounds 5c-3 and 5c-5 with the halogen atom exhibited excellent fungicidal activity against B. cinerea (IC₅₀ = 22.91, 18.89 μM). The structure-activity relationships (SARs) analysis indicated that the derivatives with electron-withdrawing substituents at the meta- or para-positions improves the activity. Via the heuristic method, the generated quantitative structure-activity relationship (QSAR) model (R² = 0.961) revealed a strong correlation of antifungal activity against B. cinerea with molecular structures of these compounds. Meanwhile, the cytotoxicity of 20 representative derivatives was tested in the human tumor cells line (HepG2) and the hepatic L02 cells line, the result indicated that the synthesized compounds showed significant inhibitory activity and limited selectivity. Compound 5c-5 has the highest fungicidal activity with IC₅₀ = 18.89 μM (against B. cinerea.) but low cytotoxicity with IC₅₀ = 35.4 μM (against HepG2 cell line) and IC₅₀ = 68.8 μM (against Hepatic L02 cell line). These encouraging results can be providing an alternative, promising use of α-benzylidene-γ-lactone through the design and exploration of eco-friendly fungicides with low toxicity and high efficiency.     

Synthesis and electrochemical behaviour of β-halodehydroamino acid derivatives

Several new β,β-dihalo and β-halo-β-substituted dehydroalanines and dehydrodipeptides were synthesized by reacting the corresponding dehydroamino acid derivative with a N-halosuccinimide or in the case of β,β-di-iododehydroalanines with iodine. The results obtained confirmed that the stereochemical outcome of the halogenation reaction with β-substituted dehydroamino acids depends on the substrate. Thus, an increase Z-stereoselectivity was found when the β-phenyldehydroalanines were used as substrates and when these compounds were N-protected with 4-tolylsulfonyl or with carbamates. From this study, it is also possible to conclude that when N-iodosuccinimide was used as reagent a much higher Z-stereoselectivity is found. The electrochemical behaviour of the halogenated dehydroamino acids was studied by cyclic voltammetry. The results show a shift in the reduction peak to higher potentials of the β-halogenated dehydroamino acids when compared with the corresponding non-halogenated derivatives. As expected, the β,β-dihalodehydroalanines exhibit higher peak potentials than β-halo-β-substituted dehydroalanines and the bromo derivatives have lower peak potentials when compared with the corresponding iododehydroamino acids. Controlled potential electrolysis of several β-halo-β-substituted dehydroamino acids afforded the corresponding dehalogenated dehydroamino acids as mixtures of their E and Z-isomers. In all cases, the major isomer isolated results from dehalogenation without isomerization. These new results show that electrochemical reduction constitutes a valuable method for the synthesis of the E-isomer of β-substituted dehydroalanines.     

Synthesis and anti-TMV activity of novel β-amino acid ester derivatives containing quinazoline and benzothiazole moieties

Here, a series of β-amino acid ester derivatives containing quinazoline and benzothiazoles was synthesized and evaluated for anti-tobacco mosaic virus (TMV) activity. The compounds 3n, 3o, 3p and 3q showed good antiviral activity against TMV at a concentration of 500 μg/mL, with curative rates of 55.55%, 52.32%, 52.77% and 50.91%, respectively, and protection rates of 52.33%, 55.96%, 54.21% and 50.98%, respectively. These values were close to those of the commercially available antiviral agent ningnanmycin (which has curative and protection rates of 55.27% and 52.16%, respectively). To our knowledge, this is the first report of the anti-TMV activity of β-amino acid ester derivatives containing quinazoline and benzothiazoles moieties; the results indicate that these novel compounds can potentially be used as protective agents against TMV diseases.     

Synthesis,anti-fungal and 1,3-β-d-glucan synthase inhibitory activities of caffeic and quinic acid derivatives

New derivatives of caffeic acid and quinic acid were synthesized and their anti-fungal and inhibitory activities on fungal 1,3-β-glucan synthase were determined in comparison with those of the corresponding chlorogenic acid derivatives. All the chlorogenic, quinic and caffeic acid derivatives that were coupled with an H₂N-orn-4-(octyloxy) aniline group (1, 1b and 1c) displayed potent activities in both anti-fungal and inhibition of 1,3-glucan synthase assays. Compounds 1 and 1c inhibited the fungal membrane enzyme with the potency comparable to that of a known 1,3-β-d-glucan synthase inhibitor, aculeacin A. The results revealed that the anti-fungal activity of the chlorogenic acid derivative with a free amino group was at least partly due to inhibition of the fungal 1,3-β-glucan synthase. These results suggest that further investigation on caffeic acid derivatives may lead to the discovery of novel anti-fungal agents with drug-like properties.     

Synthesis and evaluation of novel photoreactive α-amino acid analog carrying acidic and cleavable functions

A novel photoreactive α-amino acid bearing an acidic residue and a cleavable diazirine was developed. To mimic common acidic α-amino acids, the residue was designed to be N-acylsulfonamide that possesses an acidic proton and is able to dissociate under the physiological conditions. The inhibition assay of its biotin-tagged derivative with glutamyl endopeptidase from Staphylococcus aureus V8 strain revealed a Ki_app value of 162 μM, which is slightly higher than the K_m value of a common substrate. Upon UV irradiation, this derivative specifically photolabeled glutamyl endopeptidase, l-glutamate dehydrogenase, glutamic oxalacetic transaminase, and l-glutamine synthetase, all the enzymes exhibit high affinity toward acidic α-amino acids. In addition, N-acylsulfonamide group functioned as a cleavable linker in mild basic solution after a brief N-alkylation. Either the multifunctional nature or the simple structure of this acidic α-amino acid surrogate would be useful as versatile photoreactive building block.     

Synthesis of novel mono and bis-indole conduritol derivatives and their α/β-glycosidase inhibitory effects

Here we synthesized four novel indole conduritol derivatives 1–4 for the first time in the literature and probed their biological activities with the α and β-glucosidases. The compounds showed quite effective glucosidase inhibitory action. IC₅₀ values of the compounds were compared with the known glucosidase inhibitor acarbose and it was determined that newly synthesized indole conduritols had more powerful effect against β-glucosidase in addition to exhibiting moderate influence against α-glucosidase. Our molecules thus constitute an important starting point for the design and exploitation of novel glucosidase inhibitors since glucosidase inhibitors have widespread applications in the treatment of diabetes, viral infections, lysosomal storage diseases and cancers.     

Synthesis,single crystal and antitumor activities of benzimidazole–quinazoline hybrids

A series of novel regioisomeric hybrids of quinazoline/benzimidazole viz. (3-allyl-2-methyl-3H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine and (1-allyl-2-methyl-1H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine of biological interest were synthesized. All the synthesized compounds were well characterized by ¹H and ¹³C NMR as well as mass spectroscopy. The newly synthesized compounds were screened for in vitro antitumor activities against 60 tumor cell lines panel assay. A significant inhibition for cancer cells were observed with compound 9 and also more active against known drug 5-fluorouracil (5-FU) in some tumor cell lines. Compound 9 displayed appreciable anticancer activity against leukemia, colon, melanoma, renal and breast cancer cell lines.     

Synthesis of thiobarbituric acid derivatives: In vitro α-glucosidase inhibition and molecular docking studies

Synthesis, structure, and evaluation of in vitro α-glucosidase enzyme inhibition of a new class of diethylammonium salts of aryl substituted thiobarbituric acid is described. This protocol is straight, environmentally benign and efficient, involving Aldol-Michael addition reaction in one pot fashion. The 3D chemical structures of the synthesized compounds were assigned based on spectroscopic methods and X-ray single crystal diffraction analyses. All synthesized compounds 3a-3n were evaluated for their in vitro α-glucosidase enzyme inhibitory activity, whereas acarbose was used as the standard drug (IC₅₀ = 840 ± 1.73 µM). All tested compounds were found to possess varying degree of α-glucosidase enzyme inhibition activity with (IC₅₀ = 19.46 ± 1.84–415.8 ± 4.0 µM). Compound 3i (IC₅₀ = 19.4 ± 1.84 µM) exhibited the highest activity. To the best of knowledge this is the first report of the in vitro α-glucosidase enzyme inhibition by the diethylamonium salts of aryl substituted thiobarbituric acid. Furthermore, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites.     

Synthesis of 4″-O-desosaminyl clarithromycin derivatives and their anti-bacterial activities

A series of new 4″-O-desosaminyl clarithromycin derivatives were designed and synthesized. The efficient synthesis routes of 6-deoxy-desosamine donors 8 and 11 were developed and the methodology of glycosylation of clarithromycin 4″-OH with desosamine was studied. The activities of the target compounds were tested against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed activities against macrolide sensitive pathogens, and compounds 19 and 22 displayed significant improvement of activities against sensitive pathogens and two strains of MRSE, which verified the importance of desosamine in the interaction of macrolide and its receptor, and offered valuable information of the SAR of macrolide 4″-OH derivatives.     

Synthesis of long-chain fatty acid derivatives as a novel anti-Alzheimer’s agent

In order to develop new drugs for Alzheimer’s disease, we prepared 17 fatty acid derivatives with different chain lengths and different numbers and positions of double bonds by using Wittig reaction and stereospecific hydrogenation of triple bonds as key reactions. Among them, (4Z,15Z)-octadecadienoic acid (10) and (23Z,34Z)-heptatriacontadienoic acid (16) showed the most potent neurite outgrowth activities on Aβ(25–35)-treated rat cortical neurons, which activities were comparable to that of a positive control, NGF. Both fatty acids 10 and 16 possess two (Z)-double bonds at the n-3 and n-14 positions, which might be important for the neurite outgrowth activity.     

Design, synthesis and cytotoxic activities of novel β-amino alcohol derivatives

Three series of novel β-amino alcohols possessing an N-anthranyl group have been obtained using tryptophan as the major starting material. These compounds were screened for cytotoxic activity against five human cancer cell lines in vitro by MTT assay, and some of them exhibited potential ability to be anticancer agents. Structure-activity relationship was carefully investigated. Only the compounds possessing small substituents (H or CH₃) at C-6 position showed the same activity as cisplatin (DDP) did.