N-salicylidene derivatives of pirarubicin

The preparation and biological evaluation of N-salicylidene derivatives of pirarubicin are described. Pirarubicin was treated with various kinds of aryl aldehydes. Most of compounds synthesized here were more active than pirarubicin in vitro. Some of them showed significant prolongation of the survival period in experimental mice by oral administration. Interestingly, a derivative containing forphenicine exhibited the broadest dose-response range by intraperitoneal administration.     

Synthesis and antitumor activity of 3'-deamino-3'-hydroxydoxorubicin. A facile procedure for the preparation of doxorubicin analogs

Two successful routes have been developed for preparation of 3'-deamino-3'-hydroxydoxorubicin (11), based on protection of the 14-hydroxyl group of the aglycon by using tert-butylchlorodimethylsilane. The key intermediate, 14-O-tert-butyldimethylsilyl-7-O-(3,4-di-O-acetyl-2,6-dideoxy-alpha-L-ly xo -hexopyranosyl)adriamycinone (9), was successively deacetylated and desilylated in high yield to give the desired product 11. This route constitutes a general method of access to glycon-modified doxorubicin analogs. Compound 11 showed high antitumor activity in vivo in the murine P388 lymphocytic leukemia assay.     

Synthesis and antitumor activity of 3-arylisoquinoline derivatives

In order to study the structure-activity relationship of 7,8-dimethoxy-2-methyl-3-(4,5-methylen-edioxy-2-vinylphenyl)isoquinoline-1 (2H)-one (2), which has exhibited significant antitumor activity, chemical modifications of2 were performed to yield the corresponding products (3–7). Further systematic uses of an efficient procedure for the synthesis of 3-arylisoquinoline derivatives produced the substituted compounds (9a−9g), which were tested forin vitro antitumor activity against five different human cancer cell lines.     

Synthesis and structure of purine derivatives as antitumor effects

The nucleophilic substitution reaction of 6-chloro purines (I) with malononitrile and ethyl cyanoacetate is carried out in DMSO and in the presence of an alkali. The possible tautomeric-ylidene form for the products is considered and discussed in view of IR, UV, NMR and mass spectral determinations. The derivatives were tested for their antitumor activities.     

Synthesis and antitumor activity of tropolone derivatives. 3

As part of a study on the antitumor activities of tropolone derivatives prepared from hinokitiol, which naturally occurs in the plants of Chamaecyparis species, effects of aromatic substituents of alpha,alpha-bis(7-hydroxy-5-isopropyltropon-2-yl)toluenes on the activity were examined. Several of the compounds showed high potency in the P388 leukemia assay. 4-Hydroxy analogue 4d showed the most potent activity (T/C = 195%) at a 5 mg/kg dose. The introduction of large-size substituents, of which the steric influence prevents coplanarity of the substituted aromatic function, resulted in a remarkable decrease in the potency. X-ray structural analysis of highly potent 4-methoxy analogue 4b was undertaken.     

Immunological and antitumor effects of coumarin and some derivatives.

Coumarin and its 4-OH and 7-OH derivatives, as well as o-, m- and p-coumaric acid were tested against P-815 and P-388 tumor cells in vitro. In addition, the compounds were investigated in various in vitro immunological test systems and genuine coumarin was tested furthermore against the Sarcoma-180 in CD1 mice. In vivo, coumarin showed only a moderate antitumor effect against the allogeneic Sarcoma-180 at concentrations of 10 and 40 mg/kg, with inhibition rates of 49 and 60%, respectively. However, both concentrations were markedly toxic. In vitro all compounds were more or less cytotoxic against P-815 and P-388 tumor cell lines starting at a concentration of 100 micrograms/ml. At subtoxic concentrations (less than or equal to 10 micrograms/ml) the samples showed no mitogenic activity against murine spleen lymphocytes and PHA costimulated human peripheral blood lymphocytes. Furthermore, with the coumarin derivatives neither cytotoxic macrophages could be induced against P-815 tumor cells nor an increased release of Il-2 and TNF-alpha could be observed. Only 7-OH coumarin, in concentrations of 2 and 20 micrograms/ml, caused a strong increase in phagocytosis of 124 and 84% in both, human peripheral blood granulocytes and murine peritoneal macrophages, respectively.     

4,6-双苯基-2-氨基-3-氰基吡啶类化合物的合成及其 抗肿瘤活性研究

目的 设计合成一系列4,6-双苯基-2-氨基-3-氰基吡啶类化合物,并对其体外抗肿瘤活性进行初步评价。方法 以取代苯甲醛、取代苯乙酮、丙二腈和醋酸铵为原料,经一步反应制得目标化合物。采用MTT法,以 MX-58151 为阳性对照药,以 A549、HT-29 和 SMMC-7721为测试细胞株对目标化合物进行体外抗肿瘤活性评价。 结果与结论 合成了13 个未见报道的4,6-双苯基-2-氨基-3-氰基吡啶类化合物, 其结构经¹H-NMR、MS 和 IR 谱确证。体外活性测试结果显示,多数化合物能够在较低的浓度下抑制肿瘤细胞增殖。其中,2-氨基-6-（4-氟苯基）-4-（2,3,4-三甲氧基苯基）-3-氰基吡啶 具有显著的抗肿瘤细胞增殖活性,IC₅₀值达纳摩尔级水平,明显优于阳性对照药MX-58151。     

Reactions of purine derivatives with phosphorus pentaoxide and triethylamine and their antitumor effects

6-Arylamino-3,7-dihydro-3,7-dimethy-2-oxo-1H-purine and 2-arylimino-6-arylamino-3,7-dihydro-3,7-dimethyl-1H-purine were obtained in a one-pot reaction when 3,7-dihydro-3,7-dimethyl-1H-purine-3,6-dione, phosphorus pentaoxide, triethylamine hydrochloride and appropriate amine amine are heated at 170°. Some derivatives were tested for their antitumor activity.     

青蒿素类药物抗肿瘤作用的基础与临床研究

青蒿素类(Art)抗疟药具有多种药理活性,近年来对其抗肿瘤作用的基础研究较多,相关的临床研究也逐渐开展。大量体外和动物体内实验结果显示:Art可抑制或杀伤肿瘤细胞;诱导肿瘤细胞凋亡:阻滞细胞周期;抑制血管生成;延缓或逆转肿瘤细胞的多药耐药性;与铁制剂合用或与转铁蛋白结合可提高对肿增细胞的选择性杀伤作用。临床探索提示Art对肿瘤具有治疗或辅助治疗作用。Art对人体毒性低,与传统化学治疗药物有协同增效作用且无交叉耐药性。应加强Art抗肿瘤的临床研究以明确其抗肿瘤性质、范围、剂量、疗程及不良反应。     

抗肿瘤药来曲唑的合成工艺改进

目的研究来曲唑的合成新工艺。方法以对甲基苯甲腈和对氯苯甲腈为原料,经缩合、溴化、N-烃化、重氮化脱氨基制得来曲唑。结果与结论目标产物的结构通过1H-NMR和ESI-MS谱确证,摩尔总收率为44.6%。改进后的制备工艺具有原料价廉易得、反应条件温和、收率高、选择性好等优点,适合来曲唑的工业化生产。     

抗肿瘤药pomalidomide的合成工艺改进

目的合成具有抗肿瘤活性和免疫调节作用的3-氨基-N-（2,6-二氧代-3-哌啶基）-邻苯二甲酰亚胺（pomalidomide,1）。方法N-Boc-L-谷氨酰胺（2）经羰基二咪唑缩合、脱保护得到3-氨基哌啶-2,6-二酮盐酸盐（4）;3．硝基邻苯二甲酸（5）环合得到3．硝基邻苯二甲酸酐（6）;4与6在乙酸中缩合,再经甲酸铵／钯炭还原得到目标产物。结果与结论经过5步反应合成目标化合物,总收率为46．5％（以5计）,目标化合物结构经^1H-NMR和MS谱确证。     

抗肿瘤药奥沙利铂的合成工艺改进

目的合成抗肿瘤药物奥沙利铂。方法以氯亚铂酸钾为起始原料,先后与亚硝酸钠、（1R,2R）-环己二胺、硫酸肼、一水合草酸钾反应合成目标化合物。合成的化合物采用元素分析、质谱、红外光谱、核磁共振氢谱和比旋光度对其结构进行表征。结果与结论合成的化合物结构与标题化合物一致,精品收率为52％。本方法为奥沙利铂的合成提供了一条新型的工艺路线。     

Acronycine derivatives as promising antitumor agents

Originally isolated from an Australian plant, acronycine is an antitumor alkaloid with poor water solubility and low potency. The modest antitumor activity of this compound was markedly improved by the total synthesis of original analogs resulting in the selection of S23906-1, a diester derivative of 1,2-dihydrobenzo[b]acronycine. S23906-1 is characterized in vitro by a high potency in clonogenic assays and uncommon cell cycle pertubations. In vivo, this compound demonstrated a selectivity for human solid tumors as compared to murine transplantable tumors. The unique pharmacological profile of S23906-1 was particularly defined by a broad antitumor efficacy when administered i.v. or orally on aggressive orthotopic models of human lung, ovarian and colon models with comparable or better activity than clinically used anticancer drugs. The molecular mechanism of action of S23906-1 could involve DNA alkylation, modulation of cyclin E protein levels and inhibition of DNA synthesis leading to apoptosis. Ongoing preclinical toxicological studies will help to define the potential of this novel agent which is already considered as a valuable candidate for clinical studies.     

DNA binding by antitumor anthracene derivatives

The relative DNA binding strengths of bisantrene and nine new analogues were measured by spectrophotometric titration and melt transition temperature (Tm) techniques. Data from the spectrophotometric titrations could not be fit by simple Scatchard plots. However, they were fit by a McGhee-von Hippel equation over part of the binding range. The entire range of data was fit by a smoothing cubic spline function. The first derivative of this function gave, for each compound, a curve whose intercept provided a measure of relative binding strength. The delta Tm values agreed qualitatively with the spectrophotometric titration results, although there was not a precise linear relationship. Determinations of macroscopic pKas revealed that most of the compounds were dications at pH 7.0, but a few were mixtures of monocations and dications. No correlation was found between these binding studies and antitumor potencies in a clonogenic assay, which suggests that factors other than DNA binding can determine cytotoxicity for some of the analogues.     

抗肿瘤青蒿素衍生物的研究

目的:为抗肿瘤青蒿素衍生物的深入研究和开发提供参考.方法:查阅文献,对抗肿瘤青蒿素衍生物的研究新进展进行归纳总结.结果:高活性的抗肿瘤青蒿素衍生物多为C-10位取代物;青蒿素二聚体及三聚体的抗肿瘤活性可能优于单体衍生物.结论:青蒿素衍生物有望在不久的将来应用于肿瘤治疗.     

In-vitro antitumor activity evaluation of hyperforin derivatives

The derivatives of hyperforin, namely hyperforin acetate (2), 17,18,22,23,27,28,32,33-octahydrohyperforin acetate (3), and N,N-dicyclohexylamine salt of hyperforin (4), have been investigated for their antitumor properties. In-vitro studies demonstrated that 2 and 4 were active against HeLa (human cervical cancer), A375 (human malignant melanoma), HepG2 (human hepatocellular carcinoma), MCF-7 (human breast cancer), A549 (human nonsmall cell lung cancer), K562 (human chronic myeloid leukemia), and K562/ADR (human adriamycin-resistant K562) cell lines with IC₅₀ values in the range of 3.2–64.1 μM. The energy differences between highest occupied molecular orbital and lowest unoccupied molecular orbital of 2–4 were calculated to be 0.39778, 0.43106, and 0.30900 a.u., respectively, using the Gaussian 03 software package and ab initio method with the HF/6-311 G* basis set. The result indicated that the biological activity of 4 might be the strongest and that of 3 might be the weakest, which was in accordance with their corresponding antiproliferative effects against the tested tumor cell lines. Compound 4 caused cell cycle arrest at G2/M phase in flow cytometry experiment and induced apoptosis by 4′,6-diamidino-2-phenylindole staining and Annexin V-FITC/PI (propidium iodide) double-labeled staining in HepG2 cells. The results indicated a potential for N,N-dicyclohexylamine salt of hyperforin as a new antitumor drug.     

二氢黄酮类衍生物的合成及抗肿瘤活性研究

目的 设计合成一系列全新二氢黄酮类化合物,并评价其抗肿瘤活性。方法 以间二甲苯为原料,经硝化、还原、水解、缩合等反应制得目标化合物。采用SRB法、MTT法,以顺铂为阳性对照药,以人肿瘤细胞Bel-7402、HL-60、BGC-823和KB为测试细胞株对目标化合物进行体外抗肿瘤活性评价。 结果与结论 合成了 11 个二氢黄酮类化合物,目标化合物的结构经质谱、核磁共振氢谱确证。化合物5b、5c、5d、5f、5h对人肿瘤细胞KB具有很好的抑制活性,化合物5f、5h同时也对人肿瘤细胞Bel-7402、BGC-823 具有一定的抑制作用。     

司他夫定衍生物的合成及抗肿瘤活性评价

目的设计合成一系列司他夫定类衍生物,并评价其抗肿瘤活性。方法以司他夫定为原料,经磺酸酯化后与叠氮化钠反应生成5'-叠氮基司他夫定,再通过Huisgen 1,3-偶极环加成反应得到目标化合物。采用MTT法分别以人肝癌细胞(BEL-7402)、人胃癌细胞(BGC-823)、肺癌细胞(A549)为测试细胞株对目标化合物进行体外抗肿瘤活性评价。结果与结论合成了14个5'-脱氧司他夫定衍生物,目标化合物的结构经核磁共振氢谱和碳谱确证。其中化合物4k对人肝癌细胞(BEL-7402)、人胃癌细胞(BGC-823)、肺癌细胞(A549)具有中等的抑制作用。     

新型鬼臼毒素衍生物的合成及其抗肿瘤活性

目的 设计并合成新型鬼臼毒素类衍生物。方法 5-甲氧基吲哚与氯代物或酰氯反应得到一位氮取代的5-甲氧基吲哚;其与草酰氯反应,再以4-氨基4-脱氧表鬼臼毒素为原料,经缩合反应得到目标化合物。体外活性采用Hela细胞筛选模型进行评价。结果与结论 合成了7个新化合物,其中化合物7a, 7b 的活性优于阳性对照依托泊苷（etoposide）。