Antitumor and anti-angiogenic activity of Ganoderma lucidum polysaccharides peptide

AIM: To investigate the antitumor and anti-angiogenic activity of Ganoderma lucidum polysaccharides peptide (GLPP). METHODS: Antitumor effect of GLPP was observed in tumor-bearing mice in vivo. At the same time,the effects of GLPP on proliferation of tumor cells and human umbilical cord vascular endothelial cell (HUVEC) were detected by MTr assay in vitro. Subsequently, spleen lymphocytes proliferation of nude mice was stimulated by LPS or ConA. To investigate the anti-angiogenic effect of GLPP, GLPP 80 μg per disc and GLPP-treated serum 10μL per disc were added to the chick chorioallantoic membrane (CAM) respectively in vivo. RESULTS: GLPP 50, 100, and 200 mg/kg inhibited growth of Sarcoma 180 in BALB/c mice markedly by 35.2 %, 45.2 %, and 61.9 %,respectively. GLPP which was directly added to the cultured medium did not inhibit PG cell proliferation in vitro;but GLPP-treated serum 50, 100, 200 mg/kg potently inhibited PG cell proliferation by 22.5 %, 26.8 %, and 30.3 %,respectively; and reduced the xenograft (human lung carcinoma cell PG) in BALB/c nude mice greatly in vivo by 55.5 %, 46.0 %, and 46.8 %, respectively. Lymphocytes proliferation of nude mice could be stimulated by LPS 5 mg/L but not by ConA 2.5 mg/L, indicating that GLPP could not promote the T lymphocyte proliferation and neutral red phagocytosis of peritoneal macrophages of nude mice. The CAM assay showed that GLPP and GLPP-treated serum had anti-angiogenic effect. GLPP (1, 10, and 100 mg/L) inhibited HUVEC proliferation in vitro with the inhibitory rate of 9.4 %, 15.6 %, and 40.4 %, respectively. CONCLUSION: GLPP has antitumor and antiangiogenic activity. The anti-angiogenesis of GLPP may be a new mechanism underlying its anti-tumor effects.     

氧化吲哚类化合物Z24的体内抑瘤活性及其血管生成抑制作用(英文)

目的　从抗血管生成活性的角度 ,寻找新的抗肿瘤药物 ,研究Z2 4的体内抑瘤活性及其对血管内皮细胞的选择性抑制作用。方法　MTT法检测不同浓度的Z2 4作用 72h时对人肝癌细胞系BEL 74 0 2及正常人胚肺二倍体细胞 2BS的生长抑制作用 ,并从浓度 抑制率曲线求出IC50 ;台盼蓝拒染计数法检测不同浓度的Z2 4作用 72h时对人脐静脉内皮细胞 (HUVEC)的生长抑制作用 ,从浓度 抑制率曲线求出IC50 ;小鼠S180 ,H2 2和裸小鼠皮下移植性人肝癌BEL 74 0 2模型研究Z2 4的体内抑瘤作用。鸡胚尿囊膜 (CAM )血管生成模型检测Z2 4的血管生成抑制活性。结果　MTT法测得Z2 4对BEL 74 0 2生长抑制作用的IC50 为 10 6 μmol·L- 1,对 2BS生长抑制作用的IC50 为 116 μmol·L- 1。台盼蓝拒染计数法测得Z2 4对HUVEC生长抑制作用的IC50 为 6 .4 4μmol·L- 1。Z2 4可明显抑制鸡CAM新生血管的形成Z2 4 10 0mg·kg- 1可使S180 ,H2 2和裸小鼠人肝癌BEL 74 0 2模型的肿瘤重量较对照组分别下降 5 2 .5 %(n =10 ,P <0 .0 1) ,4 1.5 % (n =10 ,P <0 .0 1)和5 3.4 % (n =6 ,P <0 .0 1)。Z2 4可显著抑制CAM的血管生成。结论　Z2 4对多种肿瘤动物模型均具有显著的体内抑瘤活性 ,对血管内皮细胞有选择性抑制作用 ,并明显抑制CAM新生血管的生成?     

蝎毒多肽提取物抗肿瘤血管生成作用的实验研究

目的探讨东亚钳蝎蝎毒的多肽提取物PESV的抗血管生成活性和对肿瘤生长的抑制作用。方法①用不同浓度的PESV(4～20mg·L-1)作用于人脐静脉内皮细胞(HUVEC),采用BrdU参入的ELISA法观察HUVEC增殖活性和凋亡水平变化,流式细胞术检测凋亡细胞比例,免疫组化法检测Bal和Bax表达。②观察PESV对鸡胚尿囊膜(CAM)新生血管生成的影响。③皮下注射PESV(0.3mg·kg-1),观察对S180肉瘤和H22肝癌荷瘤小鼠肿瘤生长、肿瘤血管生成和血管生成因子(VEGF和bFGF)表达的影响。结果①体外实验显示,PESV在8～20mg·L-1范围明显抑制HUVEC的增殖活性(与对照组比较,P<0.01),而对乳腺癌细胞MDAMB231的增殖无影响;PESV作用后HUVEC凋亡细胞比例较对照组增加,P<0.05,Bax表达增加;Bcl2表达降低。②0.5mg/CAM和0.8mg/CAM的PESV能明显抑制CAM新生血管的形成。③体内实验显示PESV能明显抑制小鼠S180肉瘤和H22肝癌的肿瘤生长和血管生成水平,并降低肿瘤组织内血管生成相关因子VEGF和bFGF的表达。结论PESV具有良好的体内和体外抗肿瘤血管生成活性,并籍此抑制肿瘤的生长。     

Grateloupia longifolia polysaccharide inhibits angiogenesis by downregulating tissue factor expression in HMEC-1 endothelial cells

1. The antiangiogenic and antitumor properties of Grateloupia longifolia polysaccharide (GLP), a new type of polysaccharide isolated from the marine alga, were investigated with several in vitro and in vivo models. Possible mechanisms underlying its antiangiogenic activity were also assessed. 2. GLP dose-dependently inhibited proliferation of human microvascular endothelial cells (HMEC-1) and human umbilical vein endothelial cells (HUVEC), with IC50 values of 0.86 and 0.64 mg ml(-1), respectively. In tube formation and cell migration assays using HMEC-1 cells, noncytotoxic doses of GLP significantly inhibited formation of intact tube networks and reduced the number of migratory cells. Inhibition by GLP was VEGF-independent. 3. In the chick chorioallantoic membrane (CAM) assay, GLP (2.5 microg egg(-1)) reduced new vessel formation compared with the vehicle control. GLP (0.1 mg plug(-1)) also reduced the vessel density in Matrigel plugs implanted in mice. 4. The levels of pan and phosphorylated receptors for VEGF, VEGFR-1 (flt-1) and VEGFR-2 (KDR) were not significantly altered by 5 mg ml(-1) GLP treatment of HMEC-1, although tissue factor (TF) showed significant decreases at both mRNA and protein levels following GLP treatment. 5. In mice bearing sarcoma-180 cells, intravenous administration of GLP (200 mg kg(-1)) decreased tumor weight by 52% without obvious toxicity. Vascular density in sections of the tumor was reduced by 64% after GLP treatment. 6. Collectively, these results indicate that GLP has antitumor properties, associated at least, in part, with the antiangiogenesis induced by downregulation of TF.     

2,3-吲哚醌抗肿瘤作用研究

目的研究2,3-吲哚醌的抗肿瘤作用及机制。方法观察2,3-吲哚醌对小鼠肉瘤(S180)、小鼠肝癌(H22)、小鼠艾氏腹水瘤实体型(EC)和腹水型(EAC)的抗肿瘤作用;免疫组化法测定药物对S180肿瘤组织中PCNA、Bcl-2蛋白表达的影响;核染色法(Hoechst33258染色)和MTT法观察2,3-吲哚醌对人神经母瘤(SH-SY5Y)细胞体外促凋亡和抗增殖作用。结果2,3-吲哚醌对3种小鼠移植性肿瘤有抑制作用,对荷瘤鼠血液白细胞水平无影响;2,3-吲哚醌可抑制S180肿瘤组织中PCNA,Bcl-2蛋白表达;2,3-吲哚醌可促进人神经母瘤细胞凋亡并抑制其增殖。结论2,3-吲哚醌有抗肿瘤作用,其机制与抑制肿瘤细胞增殖,诱导肿瘤细胞凋亡有关。     

Isolation of isoguanosine fromCroton tiglium and its antitumor activity

This paper describes the isolation of isoguanosine from Croton tiglium L. and its cytotoxic effect against several tumor cell lines in culture and newly reports that isoguanosine has an antitumor activity against implanted S-180 ascitic tumor mice. Isoguanosine is effective at the dose of 24 mg/kg/day x 5, with T/C value of 168%. Isoguanosine inhibits the growth of S-180 and Ehrlich solid tumor in mice at the optimal doses of 96 mg/kg/day x 12 and 48 mg/kg/day x 12, with 1-T/C values of 65% and 60%, respectively.     

钩吻生物碱化合物抗肿瘤效应及其诱导凋亡作用

目的研究钩吻生物碱化合物抗肿瘤效应及其诱导凋亡作用。方法①在小鼠H22肝癌细胞小鼠移植性肿瘤模型上观察钩吻生物碱化合物对H22小鼠实体瘤的抑制作用;②AO／EB荧光染色法观察凋亡细胞的形态学变化;流式细胞仪PI染色检测细胞周期变化及凋亡率。结果腹腔注射钩吻素子对H22小鼠实体瘤的抑瘤率为40．29％、36．57％、22．89％;钩吻素甲对小鼠H22实体瘤的生长具有一定的抑制作用,抑瘤率为28．91％、16．85％、9．68％;但1-甲氧基钩吻碱小鼠H22实体瘤没有明显的抑制作用。钩吻素子可诱导SW480细胞发生凋亡形态学改变．并且可使SW480细胞周期阻滞于s期,阻止细胞从s期至G2期转移,从而诱导其凋亡。结论钩吻生物碱化合物特别是钩吻素子具有较强的抗肿瘤活性并具有一定的构效关系,钩吻索子的抗肿瘤作用机制可能与阻滞肿瘤细胞周期和促进肿瘤细胞凋亡作用有关。     

单子叶植物内生菌多糖抗肿瘤活性的研究

目的:研究单子叶植物内生菌多糖抗肿瘤活性。方法:用单子叶植物内生菌多糖对S-180和H22肝癌荷瘤小鼠进行体内和体外抑瘤实验,单子叶植物内生菌多糖对S-180荷瘤小鼠细胞分裂指数实验。结果:单子叶植物内生菌多糖对小鼠S-180实体瘤和H22小鼠肝癌具有抑制作用(P<0.001);单子叶植物内生菌多糖可干扰肿瘤细胞的细胞周期,抑制其分裂。结论:单子叶植物内生菌多糖具有一定的抗肿瘤活性。     

Synthesis and evaluation of ethylnitrosoureas of substituted naphthalimides as anticancer compounds

Four new ethylnitrosourea derivatives of substituted naphthalimides 3a-d have been synthesized from the respective N-(2-ethylamino) naphthalimides. Their chemical alkylating activity compared with the clinical drug CCNU and an experimental compound Mitonafide indicated that they possess lower alkylating activity than CCNU and comparable activity with the latter. Their anti-tumor efficacies were assessed in vivo in two murine ascites tumors namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. CCNU and Mitonafide were used as positive controls for comparison. The representative compound 3a has displayed marginal anti-tumoral activity in these tumors. Three compounds were further screened in vitro in 4 different human tumor cell lines but no significant activity was observed in those lines. These compounds moderately inhibit the synthesis of DNA and RNA in S-180 tumor cells.     

Fascaplysin对ICR小鼠S180移植瘤的抑制作用及体内安全性的初步观察

目的：研究Fascaplysin对ICR小鼠移植性骨肉瘤S180瘤体的体内抑制作用。方法：急性毒性实验采用LD50数据处理程序1.01版计算LD50。皮下注射技术建立荷S180骨肉瘤的ICR小鼠动物模型,并随机分为空白对照组（注射生理盐水）、阳性对照组（CTX,30 mg.kg-1.d-1）、Fascaplysin高剂量组（20 mg.kg-1.d-1）和Fascaplysin低剂量组（5 mg.kg-1.d-1）共4组,观察相应处理10 d后各组小鼠移植瘤生长状况（抑瘤率）及瘤组织病理学形态变化。结果：阳性对照组、Fascaplysin高剂量组和Fascaplysin低剂量组的抑瘤率分别为（53±9）%、（52±10）%和（30±12）%;给药期间Fascaplysin对ICR小鼠肝、肾组织未产生明显的病理性影响,而对ICR小鼠体内S180移植瘤组织的病理性影响较为明显。结论：一定剂量的Fascaplysin对ICR小鼠S180移植性骨肉瘤生长具有较好的抑制作用,是一个有潜力的抗癌药物。     

槲皮素抑制血管生成作用的实验研究

目的　研究槲皮素 (Quercetin)对血管生成和培养的人脐静脉内皮细胞 (HUVEC)的影响。方法　采用生长因子 (血管内皮细胞生长因子VEGF、碱性成纤维细胞生长因子bFGF)诱导的鸡胚绒毛尿囊膜 (CAM)血管增生模型观察槲皮素对血管生成的影响 ;利用培养的HUVEC ,用MTT法观察槲皮素抑制内皮细胞增殖的作用 ;流式细胞仪观察槲皮素对HUVEC细胞周期的影响。结果　槲皮素 (0 1、0 0 5和 0 0 2 5mmol·L-1)能明显抑制VEGF诱导的CAM小血管生成 ;槲皮素 (0 1和 0 0 5mmol·L-1)能明显抑制bFGF诱导的CAM小血管生成 ;槲皮素 (2 4 0、12 0 μmol·L-1和 6 0 μmol·L-1)对内皮细胞增殖有抑制作用 ,抑制率分别为 6 7 0 %、5 8 1%和39 7% ;槲皮素 (2 4 0、12 0 μmol·L-1)能显著导致HUVEC的S、G2 期阻滞。结论　槲皮素能抑制VEGF和bFGF诱导的血管生成 ,且对内皮细胞增殖具有抑制作用。     

Vascular disrupting activity of combretastatin analogues

Tubulin binding agents (TBAs) are drugs commonly used in cancer therapy as antimitotics. In the last years it has been described that TBAs, like combretastatin A-4 (CA-4), present also vascular disrupting activity and among its derivatives we identified three analogues endowed with potent microtubule depolymerizing activity, higher than that of the lead compound. In this paper we have investigated the anti-vascular activity of these derivatives. We tested the anti-angiogenic effects in human umbilical endothelial cells (HUVEC) and in vivo in chick chorioallantoic membrane assay (CAM), and in a syngeneic tumor mouse model. The three molecules, compound 1: 1-(3,4,5-trimethoxyphenyl)-5-(4-ethoxyphenyl)-1H-1,2,4-triazole; compound 2: (1-(3,4,5-trimethoxyphenyl)-5-(4-ethoxyphenyl)-1H-tetrazole, compound-3 (4-amino-2-p-tolylaminothiazol-5-yl)-(3,4,5-trimethoxyphenyl)-methanone) showed a moderate effect on the growth of HUVEC cells at concentrations below 200 nM. At lower concentrations (5–20 nM), in particular compound 2, they induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the alteration of the microfilaments network. Moreover, they also increased permeability of HUVEC cells in a time dependent manner. In addition, compounds 1 and 3, as well as the reference compound CA-4, inhibited VEGF-induced phosphorylation of VE-cadherin and in addition compound 3 prevented the VEGF-induced phosphorylation of FAK. In CAM assay, both compounds 2 and 3 efficiently counteracted the strong angiogenic response induced by bFGF, even at the lowest concentration used (1 pmol/egg). Moreover in a syngenic mouse model, compounds 1–3 after a single i.p. injection (30 mg/kg), showed a stronger reduction of microvascular density.Altogether our results identified these derivatives as potential new vascular disrupting agents candidates.     

Antitumor activity ofBifidobacterium spp. isolated from a healthy Korean

The antitumor activity of Bifidobacterium breve K-110, and K-111, and B. infantis K-525 was investigated. These Bifidobacterial cells and their cell wall preparations (WPG) significantly increased the survival rate of mice who had been intraperitoneally implanted with sarcoma 180 cells. Solid tumor growth was inhibited even when the sarcoma 180 cells were implanted into the groins of the mice. However, the Bifidobacterial cells did not show in vitro cytotoxicity against tumor cell lines. Cell kinetic studies revealed that these WPGs induced neutrophils, which were followed by macrophages, at the site of peritoneal injection. The WPGs directly activated these cells to inhibit the growth of tumor cells in in vitro assays. Our results suggest that Bifidobacterial WPGs induce and activate nonspecific phagocytes in situ to reject growing tumor cells in the mouse peritoneal cavity.     

Saikosaponins-b suppresses tumor growth and angiogenesis of hepatocellular carcinoma by regulating VEGF/ERK/HIF-1α signal pathway

OBJECTIVE Angiogenesis therapy has attracted interest as a potential treatment for hepatocellular carcinoma(HCC).In this study,we investigated the anti-proliferative activities and antiangiogenesis effects of saikosaponins(SS)-b on hepatocellular carcinoma(HCC)and its regulation on VEGF/ERK/HIF-1 αsignal pathway.METHODS H22 hepatoma-bearing mice model and HepG-2 cells were used to study the anti-tumor and anti-angiogenesis effects of SS-b in vivo and in vitro.Pathological change of tumor tissue was observed by HE staining,the microvascular changes were detected by immunohistochemical method.The effects of SS-b on angiogenesis were examined by using the chick embryo chorioallantoic membrane(CAM)model.The effects of SS-b on proliferation,migration and invasion were investigated by MTT assay,scratch wound healing assay and transwell assay inhuman umbilical vein endothelial cell(HUVEC)and HepG2 cells in vitro.Vascular endothelial growth factor(VEGF),matrix metalloproteinase-2/9(MMP-2/9),hypoxia-inducible factor-1α(HIF-1α)expression and the phosphorylation of extracellular regulated kinase(ERK)were analyzed using RT-PCR and Westernblot.RESULTS SS-b effectively inhibited the tumor growth of H22 mice in vivo.The inhibitory rate of tumor was 49.1%,50.7%,66.1%in SS-b 5,10 and 20 mg·kg-1group respectively.HE staining results showed that SS-b induced tumor necrosis and nuclear dissolution in H22 mice.Moreover,SS-b also reduced the number of microvessels of tumor tissue in H22 mice significantly and suppressed the angiogenesis of CAM induced by b-FGF.SS-b had an obvious inhibitory effect on cell proliferation,migration and invasion of HUVEC cells and HepG-2 cells.These effects were associated with downregulation of the expression of MMP2/9 and suppression of VEGF/ERK/HIF-1αsignaling in H22 mice and Hep-G2 cells.CONCLUSION Our findings showed that SS-b exerts anti-tumor effects by inhibiting tumor angiogenesis via regulating VEGF/ERK/HIF-1α signal pathway in vivo and in vitro.     

Enhanced anti-tumor effect of 9-nitro-camptothecin complexed by hydroxypropyl-β-cyclodextrin and safety evaluation

The aim of this study was to evaluate the safety and anti-tumor effect of 9-nitro-camptothecin/hydroxypropyl-β-cyclodextrin (9-NC/HP-β-CD) complex on tumor-bearing mice. The in vitro anti-tumor activity was tested by MTT assay. Our study revealed that the 9-NC/HP-β-CD complex showed significant anti-tumor activity towards Skov-3, MCF-7, HeLa and S180 cell lines with IC(50) values of 0.24 ± 0.09, 0.59 ± 0.20, 0.83 ± 0.11, and 6.30 ± 2.42 μg/ml, respectively, significantly superior to the free 9-NC. The in vivo therapeutic efficacy was investigated in ICR mice bearing mouse sarcoma S180. Both the high (3mg/kg) and low (1mg/kg) doses of 9-NC/HP-β-CD complex demonstrated high inhibition ratio of tumor growth (>75%). The subacute toxicity test was performed by measuring the body weight, histopathology, blood cell counts and clinical chemistry parameters (total bilirubin, alanine transferase, aspartate transferase, blood urea nitrogen and creatinine), and the results indicated the good safety profile of the complex. Taken together, the results suggested that the 9-NC complexed in HP-β-CD, instead of dissolved in the organic solvent, presented significant anti-tumor activity and low toxicity for the treatment of cancer.     

A novel human tumor necrosis factor alpha mutant showed potent antitumor activity and reduced toxicity in vivo.

AIM: To study the antitumor activity and systemic toxicity of human tumor necrosis factor alpha (hTNFalpha) mutant M2 (R2K-N30S-R32W-L157F-hTNFalpha). METHODS: Mouse sarcoma S180 tumors and hepatoma HAC tumors were implanted into mice, and human urocyst carcinoma CP-3 tumors were implanted into nude mice. The xenografted mice were injected with wild-type hTNFalpha and its mutant M2 at different doses. After 7 d (mice) or 10 d (nude mice) of injection, the tumor weight was measured to calculate the inhibition rate of hTNFalpha and M2. Systemic toxicity experiments were done on Rhesus monkeys by injecting them with wild-type hTNFalpha and mutant M2 respectively for 10 consecutive d. Observations were made on the monkeys both before and after the injection. RESULTS: For mice implanted with sarcoma S180 and hepatoma HAC tumors, the inhibition rate of M2 was similar to that of wild-type hTNFalpha at the dose of 0.025 mg/kg, while for nude mice implanted with human urocyst carcinoma CP-3, the inhibition rate of M2 (45.5 %) was much higher than that of wild-type hTNFalpha (15.5 %). When the dose came to 0.25 and 2.5 mg/kg respectively, however, the inhibition rate of M2 greatly increased (the highest was 75.9 %). The tests of systemic toxicity of hTNFalpha and its mutant M2 in monkeys proved that M2 presented lower toxicity than wild-type hTNFalpha did. CONCLUSION: hTNFalpha mutant M2 not only presented higher antitumor activity than wild-type hTNFalpha did on mouse tumor (S180 and HAC)- and human tumor (CP-3)-implanted mice, but also showed lower systemic toxicity in the Rhesus monkey.     

Synthesis and evaluation of antitumor activity of 2- and 6-[(1,3-benzothiazol-2-yl)aminomethyl]-5,8-dimethoxy-1,4-naphthoquinone derivatives

2- or 6-substituted BZT-N derivatives were synthesized, and their cytotoxic activity against cancer L1210 and SNU-1 cells was examined. The antitumor action was also assessed in mice bearing S-180 cells in peritoneal cavity. In a comparison, it was found that 6-substituted BZT-N derivatives exhibited higher potencies in both bioactivities than 2-substituted BZT-N derivatives against L1210 cells in in vitro and S-180 in vitro tests exception of compound 36. Interestingly, it was observed that 2-substituted compound 36, which has methyl group at R1 position, exhibited a better antitumor activity than 6-substituted compounds against L1210 and SNU-1 in vitro. The ED50 value of 2-substituted compound 36 against L1210 was found to be comparable to the ED50 value of adriamycin and was even better against the solid cancer cell line SNU-1. It was also observed that 2-substituted compound 36 showed better antitumor activity in mice bearing S-180 cells in the peritoneal cavity. The T/C (%) value of 2-substituted compound 36 was similar to that of adriamycin. Quantitative structure-activity relationship (QSAR) tests reveal that the experimental ED50 values against SNU-1 closely correlate with both the calculated HOMO energies (E(HOMO)) and the measured 1H-NMR chemical shift of 3-H (deltaH). The results suggests that a compound having higher E(HOMO) and deltaH values usually should have a lower ED50 (SNU-1) value.     

仙鹤草抗突变和抑制肿瘤作用实验研究

目的:对仙鹤草的抗突变和抗肿瘤作用进行研究,为开发仙鹤草的保健作用提供依据。方法:以小鼠骨髓细胞微核实验和睾丸染色体畸变实验观察仙鹤草的抗突变作用,以S-180和H-22移植性肿瘤观察仙鹤草的抗肿瘤效果。结果:仙鹤草对环磷酰胺诱发的小鼠骨髓细胞微核发生和丝裂霉素诱发的小鼠睾丸细胞染色体畸变均有明显的抑制效果。对S-180和H-22小鼠移植性肿瘤生长也有明显的抑制作用。结论:仙鹤草对体细胞和生殖细胞的DNA损伤均有保护作用,对小鼠移植性肿瘤也有一定的抑瘤作用。     

Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents

Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI(50): 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11 and 15 on corresponding replication initiation complexes. Compound 11 also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.