Synthesis and anti-tumor activity of β-C-glycoside analogs of the immunostimulant KRN7000

A ring-closing metathesis approach was employed for the synthesis of a β-C-glycoside analog of the immunostimulant KRN7000. The protected C-glycosyl amino acid derivative 18 was converted to amino-olefin 20, and osmylation served to install the diol unit as a mixture of separable syn and anti isomers. Deprotection to the hydroxy-amine 21 was followed by N-acylation and debenzylation to deliver the target compound 5.     

一系列新型三环二萜的合成与抗肿瘤活性研究

对活性天然产物(+)-7-deoxynimbidiol非对映异构体的外消旋体cis-(±)-7-deoxynimbidiol进行了合成和衍生, 共得到了8个新型三环二萜化合物; 对合成的新化合物进行了抗肿瘤活性的实验研究, 其中化合物5d对人体乳腺癌瘤株MCF7表现出了较强的抑制作用(IC50=7.49 μg/mL), 可能作为新型抗肿瘤药物先导化合物.     

Aminoalkoholester von Hydroxyboranen,IX Salicylamid-Bor-Mannichbasen als potentielle Antitumorwirkstoffe

A synthesis of new boron containingMannich bases of salicylamide by reaction of salicylamide, formaldehyde and boron-heterocycles is reported.

VIII. Mitteilung:Stump, R. K., Zimmerman jr., H. K., Schleppnik, A. A., Gutsche, C. D., Liebigs Ann. Chem.667, 18 (1963).     

Synthesis and in vitro biological evaluation of novel 2-aminoimidazolone derivatives as anti-tumor agents

Novel 2-aminoimidazolone derivatives were synthesized.Most compounds displayed strong anticancer activities against human carcinoma cells in vitro.Compounds 8a,8b and 8j exhibited optimal activity superior to 5-FU in most cancer cells tested.Especially,the lC₅₀s of 8b（12.6-21.5μmol/L） against five tumor cells were 1 -4 fold less than those of 5-FU（18.4-56.1μmol/L） in vitro.Furthermore,comp以ound 8b could induce SMMC-7721 cell apoptosis in a dose-dependent manner.Therefore,our novel findings may provide a new framework for the design of new 2-aminoimidazolone derivatives for the treatment of cancer.     

Design of novel bis-benzimidazole derivatives as DNA minor groove binding agents

A new series of bis-benzimidazole derivatives were designed and synthesized.In vitro cytotoxicity evaluation showed that these compounds exhibited high activity against the selected tumor cells.Among them,compound 9 owned the best potential,its IC_(50) values being 5.95 μmol/L(mononuclear tumor cell line(U937)) and 5.58 μmol/L(cervical cancer cell(HeLa)).Fluorescence and UV-vis studies showed that compound 9 could bind into the minor groove of DNA.     

喹喔啉-三唑衍生物的设计与合成及其抗肿瘤活性

喹喔啉和1,2,3-三唑都是具有广泛生物活性的杂环结构母体。本文基于药物设计的拼合原理,以简单易得的邻苯二胺、苯乙炔及有机叠氮为原料,通过三组分"两步一锅法"将喹喔啉和1,2,3-三唑活性亚结构进行拼接,合成了一系列共14个新型喹喔啉-三唑衍生物(3a~3n)。该法操作简单,无需分离中间体,两步总产率52.6%~78.4%。合成的目标化合物结构经~1H NMR、~(13)C NMR和HRMS确证。初步体外抗肿瘤活性测试表明,合成的目标化合物具有一定的抗肿瘤活性。     

Synthesis and Primary Research on Antitumor Activity of Three New Panaxadiol Fatty Acid Esters

For making use of Ginseng resources that exhibit an antitumor activity and for finding new anticancer drugs,three new fatty acid ester compounds: 3β-acetoxy panaxadiol ( Ⅰ ), 3β-palmitic acid aceloxy panaxadiol ( Ⅱ ), and 3β-octadecanoic acid aceloxy panaxadiol( Ⅰ , Ⅱ , and Ⅲ ) were synthesized with panaxadiol, diacetyl oxide, palmityl chloride and stearyl chloride, and their structures were determined via MS, 13C NMR, IR, TLC, and so on. The molar yields of the three compounds are 75.14%, 79. 08%, and 72. 57%, respectively. Meanwhile, the antitumor activity of the three new panaxadiol fatty acid ester derivatives and panaxadiol was compared by using the method of MTT. Tumor cell used was Vero cell line. Positive control was 5-FU, blank was an RPMI1640 culture medium, negative control was an RPMI1640 culture medium and the solvent for drugs to be tested. Compound Ⅰ has the strongest antitumor activity followed by panaxadiol; compounds Ⅱ and Ⅲ have similar and weakest antitumor activities.Furthermore, the antitumor activities of the panaxadiol fatty acid ester derivatives show positive correlation with the concentration of the test group, but show no relationship with the molecular weight of fatty acid. The methods that are used to synthesize the three compounds with high yields and strong antitumor activities are simple and show a great potential for meeting the needs of industrial manufacture of these drugs.     

O2-2,4-二硝基苯基偶氮二醇盐类化合物的设计、合成及抗肿瘤活性

以O2-2,4-二硝基苯基偶氮二醇盐(PABA/NO)为先导化合物,选择适当的仲胺作为偶氮二醇盐中相应的胺片段,并用碳氮键取代苯环5位的碳氧酯键,设计合成了化合物2a,2b和4a~4j,以期获得活性更强且稳定性好的抗肿瘤药物.目标化合物经1H NMR,13C NMR及HRMS进行了结构确证.生物活性测试结果表明,目标化合物可不同程度地抑制结肠癌HCT-116细胞的增殖,其中化合物4h的活性最强(IC50=7.945±0.421 μmol/L),优于PABA/NO(IC50=12.134±0.675 μmol/L).NO释放实验结果表明,此类化合物的NO释放量与细胞毒性呈正相关.化合物4h在HCT-116细胞中释放NO的量最多,约是正常细胞的2倍.此外,化合物4h在大鼠血浆中的体外稳定性显著优于PABA/NO,值得进一步研究.     

Sonodynamically induced anti-tumor effect with protoporphyrin IX on hepatoma-22 solid tumor

Objective

The purpose of this study was to evaluate sonodynamically induced anti-tumor effect of protoporphyrin IX (PPIX) in mice bearing hepatoma-22 (H-22) solid tumors, and the possible in vivo cell damage mechanism was also investigated.

Methods

The pharmacokinetics of PPIX was analyzed in plasma, skin, muscle and tumor of H-22 bearing mice. Tumors were irradiated with ultrasound (1.43 MHz, I_SATA 3 W/cm², 3 min) for three times at 8, 12 and 24 h after 5.0 mg/kg PPIX administration, respectively. The anti-tumor effects of sonodynamic therapy (SDT) were estimated by the tumor inhibition ratio (volume and weight). The bio-effects of SDT were evaluated by hematoxylin and eosin (H&E) staining, transmission electron microscope (TEM) observation, lipid peroxidation (LPO) measurement and anti-oxidative enzymes (glutathione peroxidase (GSH-PX), catalase (CAT) and superoxide dismutase (SOD)) assay.

Results

A significant anti-tumor effect was obtained by PPIX-mediated sonodynamic therapy (PPIX-SDT). At the fifteenth day after PPIX-SDT, the tumor growth and tumor weight inhibition ratios were 53.84% and 45.86%, respectively. In addition, the structure of tumor tissues and the anti-oxidative enzymes were obviously destroyed after SDT treatment.

Conclusions

A biochemical mechanism was involved in PPIX-SDT in vivo, and the free radicals produced by the synergistic treatment destroying the anti-oxidative system of tumor cells in vivo may play an important role in this action. Also, the thermal effect could not be excluded in inducing damage of cellular structures, like membrane disruption and chromatin condensation under current evaluation in this paper.     

Novel NO-releasing derivatives of betulinic acid with antitumor activity

Thirteen novel NO-releasing derivatives of betulinic acid (BA) bearing two types of NO-donors (nitrates and furoxans) were synthesized and evaluated for their antitumor activity. The results showed that furoxan-based derivatives exhibited higher antitumor activity than nitrate-based derivatives, with compounds 11a and 11b displaying promising potency against B16 cell lines and HepG2 cell lines (IC50 < 1 μmol/L). Wesupposed that NO-releasing amount of these derivatives which can be detected by Griess method may contribute more to their antitumor activity. As a result, furoxan-based derivatives released larger amount of NO than that of nitrate-based derivatives, which partially explained the higher anti-tumor activity of the former.