Synthesis,structure analysis,antitumor evaluation and 3D-QSAR studies of 3,6-disubstituted-dihydro-1,2,4,5-tetrazine derivatives

3,6-Diaryl-dihydro-1,2,4,5-tetrazine derivatives were synthesized and their structures were confirmed by single-crystal X-ray diffraction. Monosubstituted dihydrotetrazines are the 1,4-dihydro structure, but disubstituted dihydrotetrazines are the 1,2-dihydro structure. The results of further research indicated there may be a rearrangement during the synthesis process of disubstituted dihydrotetrazines. Their antitumor activities were evaluated against A-549 and P388 cells in vitro. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. Two compounds were highly effective against A-549 cell and IC₅₀ values were 0.575 and 2.08 μM, respectively. Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 37 1,2,4,5-tetrazine derivatives with antitumor activity against A-549 cell. Models with good predictive abilities were generated with the cross validated q² values for CoMFA and CoMSIA being 0.744 and 0.757, respectively. Conventional r² values were 0.978 and 0.988, respectively, the predicted R² values were 0.916 and 0.898, respectively. The results provide the tool for guiding the design and synthesis of novel and more potent tetrazine derivatives.     

Synthesis, X-ray crystallographic analysis, and antitumor activity of 1-acyl-3,6-disubstituted phenyl-1,4-dihydro-1,2,4,5-tetrazines

Eleven compounds of 1-acyl-3,6-disubstituted phenyl-1,4-dihydro-1,2,4,5-tetrazines were prepared from 3,6-disubstituted phenyl-1,2-dihydro-1,2,4,5-tetrazines and anhydrides or acyl chlorines, and their structures were confirmed by single-crystal X-ray diffraction and the semi-empirical calculation of PM3 method. This reaction yields the 1,4-dihydro derivatives rather than the 1,2-dihydro derivatives. The central six-membered ring of these compounds has an obvious boat conformation and therefore is not homoaromatic. Their antitumor activities were evaluated in vitro by the SRB method for A-549 cell and the MTT method for P-388 cells. The results show that there is one compound which is highly effective against A-549 cells and two compounds which are highly effective against P-388 cells. Thus, this compound possesses potential antitumor activities and is worth researching further.     

Synthesis of novel 2,3-dihydro-1,4-dioxino[2,3-g]quinoline derivatives as potential antitumor agents

New dioxinoquinolines (1-8) have been synthesized and their antiproliferative properties have been tested against several cell lines. The treatment of the 6-acetamido-2,3-dihydro-1,4-benzodioxine (10) with phosphorous oxychloride in the presence of DMF leads to a mixture of linear and angular tricyclic compounds. The key intermediates were modified and cyclized giving the corresponding dioxinoquinolines. In general, these compounds have a moderate citotoxycity.     

Synthesis and antitumor activity of s-tetrazine derivatives

Fifty-five compounds of s-tetrazine derivative including hexahydro-, 1,6-dihydro, 1,4-dihydro-, 1,2-dihydro- and aromatic s-tetrazine were prepared. Their antitumor activities were evaluated in vitro by MTT method for P-388 cell and SRB method for A-549 cell. The results show that there are 9 compounds which in 10(-6) microM have more than 50% inhibition rate to A-549 cancer cell growth, and 7 compounds in 10(-6) microM have more than 50% inhibition rate to P-388 cancer cell growth. The IC(50) of compound 3q for P-388, Bel-7402, MCF-7 and A-549 are 0.6 microM, 0.6 microM, 0.5 microM and 0.7 microM, respectively. So s-tetrazine derivative is a kind of compound which possesses potential antitumor activities and is worth to research further.     

Synthesis and antitumor activity of 4-hydroxycoumarin derivatives

A series of 4-hydroxycoumarin derivatives was prepared and evaluated for antitumor activity. The key fragments were 2a-c, 5c, 12b, 13b, 17, and 18 which were prepared via dianion ring cyclization, Friedel-Crafts acylation, and Reformatsky reaction. Compound 20b showed the most potent antitumor activity among the total 12 derivatives and compounds 19a and 19b exhibited efficacy comparable to etoposide in vitro antitumor activity.     

Synthesis and antitumor activity of 10-arylcamptothecin derivatives

A series of 10-arylcamptothecin derivatives was designed and synthesized. The key step of the synthesis was achieved by employing Suzuki cross-coupling chemistry. All of the new derivatives were tested for cytotoxicity against three human tumor cell lines, BEL-7402, A549, and HL-60; most of the derivatives exhibited potent cytotoxicity. The stability study showed that compound 30 was more stable than its lead compound 10-hydroxycamptothecin under the physiological condition. Mechanistic study demonstrated that compound 30 and its hydrochloride 31 had a pharmacological profile similar with camptothecin.     

Synthesis,in silico and in vitro studies of new 1,4-dihydropiridine derivatives for antitumor and P-glycoprotein inhibitory activity

P-glycoprotein (P-gp) is one of the cell membrane pumps which mediate the efflux of molecules such as anticancer drugs to the extracellular matrix of tumor cells. P_gp is a member of the ATP-binding cassette (ABC) transporter family that is implicated in cancer multidrug resistance (MDR). Since MDR is a contributor to cancer chemotherapy failure, modulation of efflux pumps is a viable therapeutic strategy. In this study, new synthetic 1,4 dihydropiridine (DHP) derivatives containing thiophenyl substitution were tested as inhibitors of P-gp. Efflux assay was conducted to evaluate the intracellular accumulation of Rhodamine123 (Rh123) as a pump substrate. MTT assay, cell cycle analysis and in silico methods were also examined. Flow cytometric analysis revealed that synthetic DHP derivatives (15 µM) increased intracellular concentration of the substrate by 2–3 folds compared with verapamil as a standard P-gp inhibitor. MTT assay on EPG85-257P and its drug-resistant EPG85-257RDB cell line revealed antitumor effects (30–45%) for new DHP derivatives at 15 µM following 72 h incubation. However, MTT test on normal cell line showed negligible toxic effects. Finally combination of synthetic derivatives with doxorubicin showed that these compounds decrease IC50 of doxorubicin in resistant cell lines from 9 to 1.5 µM. Sub-G1 peak-related apoptotic cells showed a stronger effect of synthetic compounds at 5 µM compared with verapamil. Molecular dynamic results showed a high binding affinity between DHP derivative and protein at drug binding site. Findings of these biological tests indicated the antitumor activity and P-gp inhibitory effects of new 1,4-DHP derivatives.     

Synthesis and antitumor activity of feruloyl and caffeoyl derivatives

We developed two efficient protocols for the synthesis of feruloyl and caffeoyl derivatives from commercial vanillin and veratraldehyde. Pharmacological activities were assessed against a panel of human cancer cell lines in vitro. Most synthesized compounds demonstrated attractive cytotoxicity. Several new compounds demonstrated significant antiproliferative and cytotoxic activities against HeLa and Bewo tumor cell lines. In particular, 5-nitro caffeic adamantyl ester showed broad spectrum of tumor inhibition in 10 cell lines, and reduced tumor weight by 36.7% in vivo when administered at a dose of 40 mg kg⁻¹.     

Synthesis and antitumor activity of betulin, erythrodiol and uvaol aminopropoxy derivatives

The synthesis of aminopropoxy derivatives of betulin, erythrodiol, uvaol and oleantriol via cyanoethylation of triterpenoids hydroxyl groups and subsequent reduction of cyanoethyl fragments is described. High and specific in vitro antitumor activity (cytotoxicity) of 3beta,28-di-O-[3-(aminopropoxy)]lupa-20(29)-ene and 3beta-O-hydroxy-28-O-[3-(aminopropoxy)]olean-12-ene towards a wide range of human tumor cell lines is discovered. The aminopropoxy group is shown to be a new perspective pharmacophor group for design of anticancer agents on the basis of triterpenoids.     

Synthesis and antihepatotoxic activity of 5-(2,3-dihydro-1,4-benzodioxane-6-yl)-3-substituted-phenyl-4,5-dihydro-1H-pyrazole derivatives

In continuance of our search for newer antihepatotoxic agents some novel pyrazoline derivatives containing 1,4-dioxane ring system were synthesized starting from 3-(2,3-dihydro-1,4-benzodioxane-6-yl)-1-substituted-phenylprop-2-en-1-one. Some of the synthesized compounds were evaluated for antihepatotoxic activity against CCl(4)-induced hepatotoxicity in rats. Among them some compounds have shown significant antihepatotoxic activity comparable to standard drug silymarin.     

Synthesis and antitumor activity of the hexacyclic camptothecin derivatives

A series of hexacyclic camptothecin derivatives were synthesized to test for antitumor activity as topoisomerase I inhibitor. The strategy of synthesis was used for the formation of additional furan and dihydrofuran rings fused with 9- and 10-positions of camptothecin. All of the hexacyclic camptothecins were assayed for cytotoxicity against four human tumor cell lines, HL60, BEL-7402, HCT-116, and HeLa, and showed very impressive cytotoxicity activity in vitro. Enzyme activity of the hexacyclic camptothecins was evaluated, being equal or superior to that of SN-38. The stability of four compounds was assessed in human plasma. Two of these compounds were chosen to test for antitumor activity in vivo against Sarcoma-180. The results suggested that additional furan and dihydrofuran rings could improve the antitumor activity in vitro and vivo, though the stability of the lactone ring did not increase.     

Synthesis and antitumor activity of aminopropoxy derivatives of betulin,erythrodiol, and uvaol

Aminopropoxy derivatives of betulin, erythrodiol, uvaol, and oleantriol have been synthesized by the cyanoethylation of the hydroxyl groups of triterpenoids with the subsequent reduction of cyanoethyl fragments. It has been found that 3β,28-di-O-[3-(aminopropoxy)]lupa-20(29)-ene and 3β-O-hydroxy-28-O-[3-(aminopropoxy)]olean-12-ene possess high in vitro antitumor activity toward a wide range of human tumor cell lines. It has been shown that the aminopropoxy fragment is a novel promising pharmacophore group in the synthesis of anticancer agents based on triterpenoids.     

Synthesis and biological activity of 1,4:3,6-dianhydro-2,5-diazido-2,5-dideoxyhexitols

Reaction of 1,4:3,6-dianhydro-2,5-di-O-mesyl- and -tosyl-d-mannitol with sodium azide afforded the 2,5-diazido-l-iditol derivative. The analogous d-glucitol isomer was obtained in a similar reaction starting from the corresponding d-glucitol derivatives, and showed significant, hypnotic activity. For establishing the structure-activity relationship, 1,4:3,6-dianhydro-2,5-diazido-2,5-dideoxy-l-mannitol (19), as well as its antipode 27, was synthesized, starting from dmannitol. Compound 19 was as effective as Doriden® (3-ethyl-3-phenylglutarimide), a well known, hypnotic drug. The antipode 27 and the bioisosteric 1(4),3(6)-dithio derivative were, however, inactive.     

Synthesis and antitumor activity of N-sulfonyl derivatives of nucleobases and sulfonamido nucleoside derivatives

The introduction of sulfonamido group on the C-2 position of pyrimidine nucleosides was achieved by ring opening of 2,2'- and 2,3'-anhydronucleosides. N-sulfonyl derivatives of nucleobases and sulfonamido derivatives of nucleosides were assayed for in vitro antitumor activity.     

Synthesis and antitumor activity of new D-galactose-containing derivatives of doxorubicin

A general scheme of synthesis of antibiotic doxorubicin derivatives is based on the 13-dimethyl ketal of 14-bromodaunorubicin (4). The interaction of 4 with melibiose (5), lactose (6), 3-methoxy-4-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-4-oxybenzaldehyde (12) or 4-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-4-oxybenzaldehyde (13) by reductive alkylation followed by hydrolysis of the corresponding intermediate bromoketals produced 3'-N-[alpha-D-galactopyranosyl-(1-->6)-O-1-deoxy-D-glucit-1-yl]doxorubicin (7), 3'-N-[beta-D-galactopyranosyl-(1-->4)-O-1-deoxy-D-glucit-1-yl]doxorubicin (8), 3'-N-[3"-methoxy-4"-O-(beta-D-galactopyranosyl)-4"-oxybenzyl]doxorubicin (16), and 3'-N-[4"-O-(beta-D-galactopyranosyl)-4"-oxybenzyl]doxorubicin (17). Cytotoxic and antitumor activity of the synthesized drug candidates compared to the parent doxorubicin was studied using various experimental models, in particular, on mice bearing lymphocyte leukemia P-388 at single and multiple i.v. injection regimens.     

Synthesis and in vitro antitumor activity of novel scopoletin derivatives

Twenty scopoletin derivatives were developed by a systematic combinatorial chemical approach and their chemical structures were confirmed by MS, IR, (1)H NMR spectra and elemental analysis. Primary screening against mammary (MCF-7 and MDA-MB 231) and colon (HT-29) carcinoma cells indicated that five compounds (8d, 8g, 8j, 11b and 11g) displayed high antitumor potencies with IC(50) values below 20 μM whereas scopoletin showed IC(50) values above 100 μM. Moreover, the most promising compound 11g was more active than 5-fluorouracil. These results clearly indicated that the modification of the scopoletin structure could greatly increase its antitumor activity in vitro.     

Synthesis and antitumor activity of tetrahydrocarbazole hybridized with dithioate derivatives

Abstract

The present study reported the synthesis of tetrahydrocarbazoles hybridized with dithioate derivatives. Three series were synthesized namely alkyl dithiocarbonates (4a–d), heterocyclic dithiocarbamates (6a–g) and dialkyl dithiocarbamate (7). The synthesized compounds were tested in vitro on human breast adenocarcinoma cell line (MCF7) and the human colon tumor cell line (HCT116). Most of the synthesized compounds exploited potent antitumor activity, especially compound 6f [4-chlorophenylpiperazine derivative], which showed cytotoxic activity against MCF7 superior to doxorubicin with IC₅₀ value of 7.24?nM/mL.     

Synthesis of new 2,5-disubstituted-1,3,4-thiadiazole derivatives and their in vivo anticonvulsant activity

A series of 2,5-disubstituted-1,3,4-thiadiazole derivatives were synthesized by the reaction of 3-(2-cyanopropan-2-yl)-N-(5-(piperazine-1-yl)-1,3,4-thiadiazol-2-yl)benzamide with various sulfonyl chlorides and evaluated for their anticonvulsant activity in MES test. Rotorod method was employed to determine the neurotoxicity. The purity of the compounds is confirmed on the basis of their elemental analysis. The structures of all the new compounds are established on the basis of ¹H NMR and mass spectral data. Out of fifteen compounds, three were found to be potent anticolvunstants. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg).     

Synthesis of beta-C-glycopyranosyl-1,4-naphthoquinone derivatives and their cytotoxic activity

Beta-C-Glucosyl and beta-C-galactosyl-1,4-dimethoxynaphthalenes have been synthesized using a F3CCO2Ag/SnCl4 promoted Friedel-Crafts electrophilic substitution reaction. Both glycosyl acetates and methyl glycosides can be used as glycosyl donors. Further oxidation afforded the corresponding beta-C-glycosyl-1,4-naphthoquinones. The in vitro cytotoxic activity of these compounds was evaluated against the A375 cell line.