Synthesis of new water-soluble phosphonate calixazacrowns and their use as drug solubilizing agents

This study presents the selective chloromethylation of calix[4](aza)crown ethers 2a–c, using chloromethyl n-octyl ether and SnCl₄ in chloroform at room temperature in good yield for the first time. Chloromethylated products 2a–c are used as key intermediates to synthesize new water-soluble p-phosphonato calix[4](aza)crown ethers 5a–c. Liquid–liquid phase extraction and phase solubility studies with poor water soluble drug molecules such as nifedipine, niclosamide and furosemide are performed to evaluate their binding properties. Among the studied drugs, furosemide was the most effectively dissolved drug by p-phosphonato calix[4](aza)crown ethers 5a–c in water.     

Synthesis and biological evaluation of glyco-GA compounds as anticancer agents

A series of novel glyco-gambogic acid（GA） compounds were synthesized and evaluated for their in vitro anti-proliferative activity against human hepatocellular carcinoma（HCC） cells.All compounds showed much better aqueous solubility（0.92- 1.89 mg/mL） than GA（0.013 mg/mL）,and displayed potent inhibition on HCC cells(IC₅₀:0.21-12.23μmol/L) and little affects on non-tumor liver cells(IC₅₀:42.56-86.43μmol/L),suggesting that glyco-GA compounds selectively inhibit HCC proliferation,and may be promising candidates for further intensive study.     

新型萘酰亚胺衍生物的合成及抗肿瘤活性评价

本文合成了三种新的萘酰亚胺衍生物,并对其体外抗肿瘤活性进行了评价.初步实验结果表明,以芳基修饰氨萘菲特芳环上氨基所得化合物体外活性不如阳性对照氨萘菲特.而利用1,4-丁二醇修饰4-溴-1,8-萘酐芳环上溴原子得到的化合物3与阳性对照及其它两种衍生物相比对肝癌细胞HepG2具有较低的IC_(50)值.     

氯硝柳胺衍生物的合成及抗肿瘤活性研究

以氯硝柳胺为起始原料,经醚化、亲核取代反应得到目标化合物,采用MTT法考察所合成化合物对人类乳腺癌细胞(MDA-MB-231)和人类胰腺癌细胞(ASPC-1)的体外抗肿瘤活性。合成了5个氯硝柳胺衍生物,其结构均经IR、1H-NMR、13C-NMR和MS确证。初步的体外抗肿瘤活性结果显示目标化合物9b和9c的抗肿瘤活性强于阳性对照药,其中化合物9b的活性对所测两种肿瘤株的抑制活性均强于阳性对照药,展现出较强的应用前景。     

Synthesis and biological evaluation of picroside derivatives as hepatoprotective agents

Picrorhizae Rhizoma as a hepatoprotective herb, has been applied for thousands of years, and picroside was proved to be its active constituent. In this study, twelve derivatives of picroside were synthesized and the hepatoprotective activity of the derivatives was evaluated on SMMC-7721 cells. Six out of the derivatives had shown a better protective effect on H₂O₂-induced SMMC-7221 cells than picroside, and the activity of two derivatives (2 and 4) was stronger than that of the reference compound, silybin. Compound 2 shown the strongest protective effect (EC₅₀?=?6.064?±?1.295?μM).     

Synthesis and evaluation of nitrate derivatives of colchicine as anticancer agents

To search for more potent antitumor agent,a series of novel nitric oxide-donating colchicine(Col) derivatives(6a-f,8a and b) were synthesized by coupling nitrates with N-methyl colchiceinamide.Their cytotoxicity against four human cancer cell lines in vitro were evaluated by MTT assay.It was found that many of the derivatives displayed significant activity,particularly,compounds 6c,8a and 8b showed more potent cytotoxic activities than Col.     

Synthesis and biological evaluation of n-butylphthalide derivatives as anti-platelet aggregation agents

New analogues of n-butylphthalide (NBP) bearing various lengths of alkyl and different substitution at the two-position of phthalide were designed and synthesised. Preliminary evaluation and prediction of ACD LogP software indicate that the derivatives display significant improvement in water solubility than NBP does. Further biological analysis showed that NBP analogues specifically inhibit platelet aggregation induced by arachidonic acid but have no effect on that induced by adenosine 5-diphosphate. Especially compounds 1 and 3 were stronger than classical anti-platelet drug, aspirin, and equal potent with NBP, respectively. These findings provide an alternative approach to the development of NBP analogues with anti-platelet aggregation activity with good water solubility for the intervention of ischemic stroke.     

Synthesis and biological evaluation of novel triazole derivatives as antifungal agents

A series of 1-(benzylamino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-l-yl)propan-2-ols compounds were synthesized and evaluated for their antifungal activities in vitro.The results showed that compounds 6A and 6B exhibited good antifungal activity.Compound 6A8 showed the strongest antifungal activity,which was significantly higher than that of the lead compounds and positive-control drugs Fluconazole and Itraconazole.In particular,the antifungal activity of compound 6A8 against Candida albicans and Candida krusei(MIC80 both at 0.00097μg/mL) was 515 and 64 times that of Fluconazole,respectively.The structure-activity relationships of the synthesized compounds were discussed,and the docking model of the target compounds with fungal lanosterol 14α-demethylase (CYP51) was analyzed.     

Synthesis and biological evaluation of new ligustrazine derivatives as anti-tumor agents

To discover new anti-cancer agents with multi-effect and low toxicity, a series of ligustrazine derivatives were synthesized using several effective anti-tumor ingredients of Shiquandabu Wan as starting materials. Our idea was enlightened by the "combination principle" in drug discovery. The ligustrazine derivatives' anti-tumor activities were evaluated on the HCT-8, Bel-7402, BGC-823, A-549 and A2780 human cancer cell lines. In addition the angiogenesis activities were valued by the chick chorioallantoic membrane (CAM) assay. 1,7-bis(4-(3,5,6-Trimethylpyrazin-2-yl)-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (4) and 3 α,12 α-dihydroxy-5β-dholanic acid-3,5,6-trimethylpyrazin-2-methyl ester (5) not only displayed antiproliferative activities on these cancer cells, but also dramatically suppressed normal angiogenesis in CAM. The LD?? value of the compound 5 exceeded 3.0 g/kg by oral administration in mice.     

Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents

A series of Andro derivatives were described and evaluated for their anti-HIV activity in vitro.Compound 10 and 16b,of which TI were>10,had some anti-HTV-l activity in vitro.Therein,compound 10 which was the best potent compound,could serve as a new lead for further development of anti-AIDS agents.     

Synthesis and biological evaluation of novel oxophenylarcyriaflavins as potential anticancer agents

We report the synthesis and biological evaluation of new oxophenylarcyriaflavins designed as potential anticancer agents. An efficient synthesis involving palladium-catalyzed Suzuki and Stille reactions is presented, without any indolic protective group. The central ring closure of the scaffold was performed through an electrophilic reaction on the position C-2 of the indole ring. The use of indole and 5-benzyloxyindole, along with substituted phenyl rings, generated three different scaffolds, which were successively exploited to modulate the structure. The cytotoxicity of the newly designed compounds on four cancer cell lines and activities against three kinases (CDK1, CDK5 and GSK3) were evaluated. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range, and induced important cell cycle perturbations, with a G2/M arrest. Some compounds revealed DNA binding properties and were found to inhibit topoisomerase-mediated DNA relaxation of supercoiled DNA, but these properties are not mandatory for a cytotoxic action. A novel lead compound () has been identified and warrants further investigations.     

Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial agents

A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains(including multidrug-resistant clinical isolates) and Gramnegative bacterial strains, with minimum inhibitory concentrations(MICs) in the range of 2.1–181.2 mmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Grampositive bacteria(e.g., Staphylococcus aureus 4220), Gram-negative bacteria(e.g., Escherichia coli 1924),and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1 mmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1 mmol/L against four multidrug-resistant, Gram-positive bacterial strains.The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.     

Synthesis and biological evaluation of 16E-arylidenosteroids as cytotoxic and anti-aromatase agents

Taking into consideration the structural requirements for cytotoxicity and aromatase inhibition, several new 16E-arylidenosteroidal derivatives have been prepared and evaluated for their cytotoxic and aromatase inhibitory activity. The new steroidal analogues 3, 5-8 and 11 exhibited significant cytotoxic effects when screened against three cancer cell lines, MCF-7 (breast), NCl-H460 (lung) and SF-268 central nervous system (CNS) at 100 μM and sensible cytotoxic effects subsequently in sixty cancer cell lines derived from nine cancers types (leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers). The imidazolyl substituted steroidal derivatives 5 and 7 exhibited strong inhibition of the aromatase enzyme with 16-[4-{3-(imidazol-1-yl)propoxy}-3-methoxybenzylidene]-5-androstene-3β,17β-diol (7) displaying 13 times more potency in comparison to aminoglutethimide.     

Synthesis and in vitro evaluation of new benzothiazole derivatives as schistosomicidal agents

A series of benzothiazol-2-yl-dithiocarbamates 3a-d along with their copper complexes 4a-c were synthesized via the reaction of suitable alkyl, aralkyl or heteroaryl halides with the sodium salt of benzothiazol-2-yl-dithiocarbamic acid, followed by complexation with copper sulphate. N-(4-Acetyl-5-aryl-4,5-dihydro-1,3,4-thiadiazol-2-yl)-N-benzothiazol-2-yl-acetamides 7a-c were synthesized by cyclization of the appropriate thiosemicarbazones 6a-c in acetic anhydride. Selected compounds were screened for in vitro schistosomicidal activity against Schistosoma mansoni at three different dosage levels (10, 50 and 100 microg/mL). Three of these products, 4a-c, showed schistosomicidal activity similar to praziquantel, with 100% worm mortality at 10 microg/mL. These compounds would constitute a new class of potent schistosomicidal agents.     

Synthesis and biological evaluation of theophylline acetohydrazide hydrazone derivatives as antituberculosis agents

A series of small molecules, theophylline acetohydrazide hydrazone derivatives were obtained via condensation of theophylline-7-acetohydrazide with different aromatic/heterocyclic aldehydes. The compounds were synthesized and characterized by using conventional methods. Further, the compounds and standard drugs were evaluated against Mycobacterium tuberculosis H37Rv strain, the activity obtained was varying depending on the functional group attached to theophylline acetohydrazide hydrazone compounds. Among these, Br-substituted compounds showed more potent against M. tuberculosis with MIC 3.6–4 μM and better than the reference drugs used. The molecular docking studies have shown the possible binding modes of the compounds with protein (PDB ID: 4RHX); the compound 4h has shown highest glide score and binding energy. For all compounds, ADME properties were predicted.     

Synthesis and biological evaluation of new pyrrolopyrazinone compounds as potential antitumor agents

A series of pyrrolo[1,2-a]pyrazinone compounds(5a-9f) were synthesized,and their cytotoxic activity against SKOV-3,A549.HeLa cells in vitro were evaluated by the MTT method.Some of the compounds showed potential antitumor activity against three tumor cell lines.Among them,compounds 9c and 9d showed the most potent cytotoxic activity.The preliminary mechanism of action was discussed.     

Synthesis and biological evaluation of benzimidazole pendant cyanopyrimidine derivatives as anticancer agents

Thirteen new benzimidazole pendant cyanopyrimidine derivatives were synthesized. The compounds were synthesized through multistep reaction protocol. The structures of synthesized derivatives were studied by EI-MS, ¹H NMR, FT-IR and elemental analysis. All the compounds were studied for their anticancer activity at National Cancer Institute. Except compound 7j , all the compounds unveiled cytotoxicity against cancer cells. The most active compound 7a had shown highest value of growth inhibition of 88.44% and 84.19% against HOP-92 and T-47D cancer cell lines.     

Synthesis and biological evaluation of novel acenaphthene derivatives as potential antitumor agents

Twelve novel acenaphthene derivatives have been synthesized. The structures of all compounds were confirmed by 1H-NMR, MS and elemental analysis. Their antitumor activities were evaluated in six human solid tumor cell lines, namely non-small cell lung cancer (H460), human colon adenocarcinoma (SW480), human breast cancer cell (MDA-MB-468 and SKRB-3), human melanoma cell (A375) and human pancreatic cancer (BxPC-3). Among them, compound 3c shows the best antitumor activity against SKRB-3 cell line, as high as the positive control adriamycin.