5α-reductase inhibitors, antiviral and anti-tumor activities of some steroidal cyanopyridinone derivatives

We herein report the 5α-reductase inhibitors, antiviral and anti-tumor activities of some synthesized heterocyclic cyanopyridone and cyanothiopyridone derivatives fused with steroidal structure. Initially the acute toxicity of the compounds was assayed via the determination of their LD₅₀. All the compounds, except 3b, were interestingly less toxic than the reference drug (Prednisolone^®). Seventeen heterocyclic derivatives containing a cyanopyridone or cyanothiopyridone rings fused to a steroidal moiety were synthesized and screened for their 5α-reductase inhibitors, antiviral and anti-tumor activities comparable to that of Anastrozole, Bicalutamide, Efavirenz, Capravirine, Ribavirin, Oseltamivir and Amantadine as the reference drugs. Some of the compounds exhibited better 5α-reductase inhibitors, antiviral and anti-tumor activities than the reference drugs. The detailed 5α-reductase inhibitors, antiviral and anti-tumor activities of the synthesized compounds were reported.     

Synthesis, characterization and in vitro antitumor activity of di- and triorganotin derivatives of polyoxa- and biologically relevant carboxylic acids

An overview of the development of anti-tumor organotin derivatives, sometimes as active in vitro as doxorubicin, is presented and discussed. Solubility in water is an important issue, dominating the in vivo testing of compounds with promising in vitro properties. Several water-soluble organotin compounds gave the best in vitro activities. Novel, useful organotin anti-tumor compounds should be designed toward improved water solubility.     

Synthesis and cytotoxic activity of 17-carboxylic acid modified 23-hydroxy betulinic acid ester derivatives

New 17-carboxylic acid modified 23-hydroxy betulinic acid ester derivatives were prepared and tested for cytotoxic activity on five cancer cell lines in vitro: all tested compounds showed stronger cytotoxic activity than 23-hydroxy betulinic acid and betulinic acid. In addition, compound 5a was tested for anti-tumor activity in vivo: it had much better anti-tumor activity than 23-OH betulinic acid and had similar anti-tumor activity with cyclophosphamide and 5-fluorouracil.     

Cyclopentenediones, inhibitors of farnesyl protein transferase and anti-tumor compounds, isolated from the fruit of Lindera erythrocarpa Makino

Four cyclopentenediones, farnesyl protein transferase inhibitors, and anti-tumor compounds were isolated from the methanolic extract of the fruits of Lindera erythrocarpa Makino (Lauraceae). The structure of the compounds was determined by spectral data including NMR and mass spectrometry, and cyclopentenediones such as methyllinderone (1), methyllucidone (2), lucidone (3), and linderone (4) were identified by comparing their reported spectral data with that of the literature values. Compounds 1-4 inhibited farnesyl protein transferase with IC50 value of 55.3+/-4.1, 42+/-1.9, 103+/-5.1, and 40+/-3.5 microM, respectively. Isolated compounds also inhibited the growth of various human cancer cell lines in a dose-dependent manner. Especially, Compounds 1 and 2 selectively inhibited the growth of H-ras-transformed rat-2 cell lines in comparison with normal rat-2 cells with a GI50 value of 0.3 and 0.85 microM, respectively. Methyllucidone strongly inhibited the growth of human cancer cells and colon tumor xenografted in nude mice. The anti-tumor effects of the compound were further confirmed with caspase-3 activation and degradation of PARP. The results suggest that methyllucidone can be a potential anti-cancer agent against H-ras-transformed tumor and will also be a good lead molecule for the development of anti-tumor drug.     

Antioxidant activity of new ruthenium compounds

Many biological properties have been attributed to ruthenium complexes including anti-tumor activity and the attenuation of reperfusion damage and infarct size. In this work, we characterize the antioxidant activity of trans-[RuCl2(nic)4] where nic is 3-pyridinecarboxylic acid and trans-[RuCl2(i-nic)4] where i-nic is 4-pyridinecarboxylic acid by (i) evaluation of total antioxidant potential (TRAP); (ii) prevention of DNA damage induced by hydrogen peroxide using the alkaline comet assay; and (iii) the prevention of lipid peroxidation and cell death induced by iron in liver slices. Our results suggest that nic has stronger antioxidant potential when compared to the i-nic. Higher doses (above 200 microM) of these compounds gave genotoxic effects, but the antioxidant potential could be obtained with the use lower doses (0.1-10 microM).     

Sulfamic and succinic acid derivatives of 25-OH-PPD and their activities to MCF-7, A-549, HCT-116, and BGC-823 cell lines

In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents.     

Synthesis and anti-angiogenic activity of 6-(1,2,4-thiadiazol-5-yl)-3-amino pyridazine derivatives

General screening for inhibitors of microvessel growth in vitro in the rat aortic ring assay led to the discovery of a novel series of thiadiazole pyridazine compounds with potential anti-angiogenic activity. Chemical optimization produced orally active compounds with potent in vitro and in vivo anti-angiogenesis and anti-tumor activities.     

Anti-tumor and proapoptotic effect of novel synthetic benzophenone analogues in Ehrlich ascites tumor cells

A series of substituted benzophenone analogues, (2-aroyl-4-methylphenoxy)acetamides 4a-e, have been synthesized via three-step synthesis sequence beginning with the 2-hydroxybenzophenones 1a-e in excellent yield. 1a-e on reaction with ethyl chloroacetate afford ethyl (2-aroyl-4-methylphenoxy)acetates 2a-e which on alkaline hydrolysis afforded (2-aroyl-4-methylphenoxy)ethanoic acid 3a-e. Compounds 3a-e on condensation with p-chloroaniline furnished benzophenone analogues 4a-e. In the present report, we investigated the anti-tumor and proapoptotic effect of benzophenones in Ehrlich ascites tumor (EAT) cells. Treatment of benzophenones in vivo resulted in inhibition of proliferation of EAT cells and ascites formation. Further, we demonstrate that the induction of apoptosis in EAT cells is mediated through activation of caspase-3. These results suggest a further possible clinical application of these synthetic compounds as potent anti-tumor and proapoptotic compounds.     

Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity

There is an urgent need to design and develop new and more potent EGFR inhibitors with improved anti-tumor activity. Here we describe the design and synthesis of two series of 4-benzothienyl amino quinazolines as new analogues of the EGFR inhibitor Gefitinib. The anti-tumor activity of these novel Gefitinib analogues in 6 human cancer cell lines was examined. Compared with the parental Gefitinib, most of the new compounds show a markedly increased cytotoxicity to cancer cells. Furthermore, several of the series B compounds that side chains at position 7 contain either a methyl or ethyl group are potent pan-RTK inhibitors. Two representative compounds in this class, 15 and 17, have an enhanced capability to inhibit cancer cell growth and induce apoptosis in vitro and inhibit tumor formation in vivo in human cancer cells with high HER-2, as compared with the parental Gefitinib. Thus they may be promising lead compounds to be developed as an alternative for current Gefitinib therapy or for Gefitinb-resistant patients, potentially via simultaneously blocking multiple RTK signaling pathways.     

合成芪类化合物抑制肿瘤细胞增殖并诱导Bel-7402细胞凋亡

芪类化合物在癌的起始、促进和发展阶段均有化学抗癌活性,对其化学结构进行改造并进行作用机制研究,提高其抗肿瘤活性,有可能发现新的抗肿瘤药物.在合成23种芪类化合物的基础上,以MTT法测定其对9种肿瘤细胞系的抑制作用,发现多种化合物对SMMC-7721、BGC-823、HepG2、Bel-7402、MCF-7、SGC-7901细胞系具有较明显的抑制活性.以细胞周期分析、Hoechst 33258荧光染色及线粒体膜电位变化进行检测,发现经抑制作用较强的化合物HCQ-10处理后的 Bel-7402细胞发生G₂/M期阻滞,并继发细胞凋亡.实验结果说明,合成芪类化合物对SMMC-7721、BGC-823、HepG2、Bel-7402、MCF-7、SGC-7901细胞具有较为明显的增殖抑制作用,其抑制Bel 7402细胞增殖的作用机制为阻滞细胞于G₂/M期并诱导细胞继发凋亡.     

Structure-antioxidant and anti-tumor activity of Teucrium polium phytochemicals

Chemical characterization as well as antioxidant and anti-tumor activity are reported for isolated metabolites from Teucrium polium L. (Lamiaceae). Structures were identified using standard MS and NMR spectroscopic methods. Sesquiterpene absolute stereochemistry was determined based on a modified Mosher’s reaction. Biological activity was evaluated by a cupric reducing antioxidant capacity (CUPRAC) assay and select compounds screened for anti-tumor activity. (1R,4S,10R) 10,11-dimethyl-dicyclohex-5(6)-en-1,4-diol-7-one and (R)-mandelonitrile-β-laminaribioside, together with ten previously reported compounds were identified. Antioxidant versus tumor-inhibition relationships was examined.     

几种中药及其有效成分对人体肿瘤细胞增殖的抑制作用

通过建立的抗肿瘤体外模型,对临床上有抗肿瘤作用的几种中药提取物的抗肿瘤的活性进行检测。并与其中用作标准品的化学成分的活性进行比较。结果发现所检测的中药牛蒡子、蛇床子、三七、大黄、茯苓、延胡索、川乌和黄芪等的水提物和醇提物对肿瘤细胞株均有一定的抑制作用,醇提物的活性明显高于水挺物。一部分用作标准品的化学成分也有抗肿瘤活性。这项工作为抗肿瘤活性成分的筛选建立了有效的方法和基础。     

Synthesis and biological evaluation of dimeric cinnamaldehydes as potent antitumor agents

It has been reported that 2-hydroxycinnamaldehyde and 2-benzoyl-oxycinnamaldehyde inhibited the activity of farnesyl protein transferase, angiogenesis, cell-cell adhesion, and tumor growth in vivo model. In order to improve its anti-tumor activity, dimeric cinnamaldehydes have been synthesized based on 2-hydroxycinnamaldehyde. The synthesized compounds strongly inhibited the growth of human colon tumor cells with GI50 values of 0.6-10 microM. Especially, 2-piperazine derivative blocked in vivo growth of human colon tumor xenograft in nude mice at 10 mg/kg. It was found that their anti-tumor effects induce apoptosis and cell cycle arrest at G2/M phase by the compounds. It was confirmed by detection of apoptosis markers such as activated caspase-3 and cleaved PARP, and cell cycle analysis. The dimeric compounds also inhibited Cdc25B phosphatase which is essential for preinitiating G2/M transition and S phase progression.     

Discovery of IACS-8803 and IACS-8779, potent agonists of stimulator of interferon genes (STING) with robust systemic antitumor efficacy

Activation of the stimulator of interferon genes (STING) pathway by both exogenous and endogenous cytosolic DNA results in the production of interferon beta (IFN-β) and is required for the generation of cytotoxic T-cell priming against tumor antigens. In the clinical setting, pharmacological stimulation of the STING pathway has the potential to synergize with immunotherapy antibodies by boosting anti-tumor immune responses. We report the discovery of two highly potent cyclic dinucleotide STING agonists, IACS-8803 and IACS-8779, which show robust activation of the STING pathway in vitro and a superior systemic anti-tumor response in the B16 murine model of melanoma when compared to one of the clinical benchmark compounds.     

Synthesis and biological activity of 5-aza-ellipticine derivatives

Novel 5-aza-ellipticine derivatives were synthesized and tested as antitumor agents. The new compounds were prepared more readily than the analogous ellipticine derivatives, which are known to be potent anti-tumor agents Although the novel 5-aza-ellipticine derivatives are not as biologically active as their corresponding ellipticine analogues, the new compounds represent a new, readily accessible class of heteroaromatic catalytic inhibitors of topoisomerase II and possible anti-tumor agents.     

基于UPLC-QTOF-MS技术分析多脂鳞伞特征性成分及体外抗肿瘤作用

多脂鳞伞是一种较为珍贵的药食用真菌。对其化学成分及体外抗肿瘤作用进行了研究。通过UPLC-QTOF-MS法、电喷雾离子源（ESI）及负离子全扫描模式测定了人工栽培多脂鳞伞的化学成分组成;体外培养HepG-2、A549、Hela及MCF-7,用不同质量浓度多脂鳞伞乙醇提物处理细胞,应用CCK-8法及流式细胞术进行细胞毒性测试,并应用流式细胞术选择HepG-2细胞系以进一步评估其对HepG-2细胞凋亡分析。结果表明：经UPLC-QTOF-MS分析,从多脂鳞伞子实体分析得到的化学成分与食药用菌成分数据库中的38种成分相吻合,其中棕榈酸与9E,12E-octadecadienoic acid含量最高,甾醇类化合物与多糖类化合物占比较高;多脂鳞伞乙醇提取物对HepG-2细胞毒性最强,其浓度为50μg/mL时凋亡率能够达到(23.71±1.59)%。多脂鳞伞具有多种功能性化学成分,并具有潜在的抗肿瘤应用价值,初步断定其抗肿瘤活性是功能性成分通过诱导细胞凋亡实现的。     

Synthesis and biological evaluation of novel synthetic chalcone derivatives as anti-tumor agents targeting Cat L and Cat K

A series of chalcone derivatives bearing benzamide or benzenesulfonamide moieties were synthesized and evaluated for their anti-tumor effect on HCT116, MCF7 and 143B cell lines in vitro. SAR analysis showed that compounds bearing a benzenesulfonamide group had greater potency than those bearing a benzamide group. It was also shown that compounds with a mono-methyl or mono-halogen group at the 3-position on the terminal phenyl ring were more effective than those with trifluoromethyl or methoxy groups. Compound 8e exhibited the most potent anti-tumor activities against HCT116, MCF7 and 143B cell lines, with IC₅₀ values of 0.597, 0.886 and 0.791 μM, respectively. Molecular docking studies and enzymatic assays demonstrated that the anti-tumor activity of compound 8e might be regulated by Cat L and Cat K.     

The GRIMs: a new interface between cell death regulation and interferon/retinoid induced growth suppression

Cytokines and vitamins play a central role in controlling neoplastic cell growth. The interferon (IFN) family of cytokines regulates antiviral, anti-tumor, antimicrobial, differentiation, and immune responses in mammals. Significant advances have been made with respect to IFN-induced signal transduction pathways and antiviral responses. However, the IFN-induced anti-tumor actions are poorly defined. Although IFNs themselves inhibit tumor growth, combination of IFNs with retinoids (a class of Vitamin A related compounds) strongly potentiates the IFN-regulated anti-tumor action in a number of cell types. To define the molecular mechanisms involved in IFN/retinoid (RA)-induced apoptosis we have employed a genetic approach and identified several critical genes. In this review, I provide the current picture of IFN- RA- and IFN/RA-regulated growth suppressive pathways. In particular, I focus on a novel set of genes, the genes-associated with retinoid-interferon induced mortality (GRIM). GRIMs may be novel types of tumor suppressors, useful as biological response markers and potentially novel targets for drug development.     

Novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) with high anti-tumor activity and low side reaction

To discover whether novel anti-tumor platinum agents are capable of selectively accumulating in tumor tissue, three novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) were prepared. At a dose of 1.67 μmol kg(-1) the in vivo anti-tumor potencies of two of the compounds were higher than that of oxaliplatin. The mortality analysis indicated that these compounds resulted in a 100% survival rate, whereas oxaliplatin lead to an 80% survival rate. The organ damage examination indicated that these compounds induced less damage than oxaliplatin. The platinum accumulation in the organs, blood and bone was significantly lower than that of oxaliplatin treated mice, while the platinum accumulation in the tumor tissue was significantly higher than that of the oxaliplatin treated mice.     

Synthesis and anti-tumor activity of glycosyl oxadiazoles derivatives

A new series of glycosyl oxadiazoles compounds were synthesized and characterized through ¹H NMR, ¹³C NMR, IR and HRMS. The anti-tumor activities for MDA-MB-231 of all these new compounds were screened in vitro by MTT assay. Due to the modification of gastrodin analogues, the anti-tumor activities of these 1,3,4-oxadiazoles derivatives were greatly improved. Six compounds (6c, 6d, 6i, 6j, 6k and 6l) displayed relatively higher MDA-MB-231 potency with IC₅₀ values (0.89, 0.26, 1.35, 3.60, 0.95 and 1.08 μM) compared with the reference medicine Rosiglitazone (5.23 μM).