Synthesis and antitumor activities of mitomycin C (1----3)-beta-D-glucan conjugate.

The conjugate of mitomycin C (MMC) with linear (1----3)-beta-D-glucan from Alcaligenes faecalis var. myxogenes IFO 13140 was synthesized and its antitumor activities investigated. The conjugate (MMC-carboxymethylated linear (1----3)-beta-D-glucan (CMPS)) was obtained by treatment of CMPS with MMC in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide. In vitro cytotoxicity of MMC-CMPS against L1210 leukemia cells was similar to that of MMC. In i.p.-i.p. system in vivo against P388 leukemia in mice, the maximum increase of MMC-CMPS conjugate in life span (ILSmax) was higher than that of MMC but the therapeutic index was reduced. However, the antitumor activity of MMC-CMPS conjugate against subcutaneously implanted sarcoma 180 solid tumor in mice by i.p. administration was similar to that of MMC at a dose of 1.5 mg eq MMC/kg/d x 7 and the reduction of the number of leukocytes caused by MMC was suppressed by attaching MMC to CMPS. In addition, on assay using serum of sarcoma 180 solid tumor-bearing mice with injection of MMC-CMPS conjugate, a drastic loss of tumor cells and an increase in polymorphonuclear leukocytes (PMN) were observed. This result suggested that MMC-CMPS conjugate induced tumor-regressing factor similar to CMPS.     

Synthesis and biological activity of novel mitomycin C analogs derived from mitomycin A

A variety of mitomycin C analogs were synthesized from mitomycin A and their biological activities were studied. Mitomycin A ( 1 ) underwent nucleophilic displacement reactions involving intramolecular hydrogen migrations upon treatment with nitrogen nucleophiles bearing mobile hydrogens, but the mode of hydrogen migration depended on the nature of the nucleophiles. The reaction with alkoxyamines gave compounds 6 and 7 which have the 5H-6-alkoxyimino-4,7-dione structure in ring A of 1 . However, the reaction with hydroxylamine and benzoylhydrazine afforded compounds 11 and 13 which have the 4-hydroxy-6-hydroxyimino-7-one structure and the 4-hydroxy-6-hydrazono-7-one structure, respectively, in ring A of 1 . These products were converted into various types of mitomycin C derivatives by methylation with methyl iodide or dimethyl sulfate. The mechanistic features of these reactions are discussed. The in vitro and in vivo biological activities were tested by using P388 leukemia and Sarcoma 180 tumor cells. Several of the synthesized compounds exhibited better activity than that of mitomycin C.     

7-N,7'-N'-(1",2"-Dithianyl-3",6"-dimethylenyl)bismitomycin C: synthesis and nucleophilic activation of a dimeric mitomycin

Dimeric alkylating agents that modify complementary DNA strands have engendered significant interest. We have prepared the novel dimeric mitomycin, 7-N,7'-N'-(1",2"-dithianyl-3",6"-dimethylenyl)bismitomycin C (9), in which the mitomycins are bridged by a dithiane unit. Dimer 9, like the clinically tested acyclic disulfides KW-2149 (3) and BMS-181174 (4), was designed to activate under nucleophilic and reductive conditions. Successive nucleophile-mediated disulfide cleavage transformations of 9 are expected to generate thiol species ideally positioned to render the two mitomycin systems vulnerable to nucleophilic attack and permit DNA interstrand cross-link formation. The dithiane linker, strategically positioned between the two mitomycins, distinguished 9 from 3 and 4. Nucleophilic activation of this cyclic disulfide permitted both activated mitomycins to remain tethered to one another. We report the synthesis of 9, and show that the nucleophile Et(3)P markedly enhances the activation and consumption of 9, compared with the reference compound 7-N, 7"-N'-(cyclohexanyl-trans-1",4"-dimethylenyl)bismitomycin C (27). We further demonstrated that provides higher levels of DNA interstrand cross-links than either the dimeric reference compounds, and 7-N,7-N'-(2",5"-dihydroxy-1",6"-hexanediyl)bismitomycin C (28), or the monomeric mitomycins, 1 and 3, when Et(3)P is added to solutions containing EcoRI-linearized pBR322 DNA.     

Synthesis and antitumor activity of 7-(N-glycosylamino)-indolo[3,2-b]quinolines

Novel indolo[3,2-b]quinolines (1d-g), introduced at the 7-position with an N-glycosylamino group, were prepared and their antitumor activities against leukemia P388 in mice were examined. The N-Galactopyranosylamino derivative (1e) was a much more potent anti-leukemia compound (optimal dose = 25 mg/kg, T/C greater than 333%, cure 5/6) than lead compound 1a.     

Synthesis and Antitumor Activity of 2-[1-(2-Formylamido-3-phenylpropionyloxy)alkyl]-1,4dihydroxy-9,10-anthraquinone Derivatives

A series of 2-[1-(2-formylamido-3-phenylpropionyloxy)alkyl]-1,4-dihydroxy-9,10-anthraquinone(2FPADHAQ) derivatives was designed and synthesized.Their antitumor activities were tested against L1210 tumor cells and P388 mouse leukemic tumor cells in vitro and in ICR mice bearing sarcoma 180 cells in vivo.Overall,the introduction of 2-formylamido-3-phenyl-propanoic acid(2-FPPA) into the C-2-alkyl side chain C’-1 hydroxy group in 2-(1-hydroxyalkyl)-1,4-dihydroxy-9,10-anthraquinones(2-HDHAQ) enhanced the antitumor activity compared with the starting materials.2-FPADHAQ with alkyl chains longer than the pentyl group had negligible activity,whereas compounds 2b,2c,2d and 2e possessing shorter chains demonstrated moderate cytotoxic activity[50% effective dose(ED 50) of L1210 and P388 are 2.61―4.75 and 5.84―8.74 μg/mL],whereas compound 2l with an aromatic system showed strong cytotoxic activity.T/C(%) values[(average survival days in the test group)/(average survival days in the control group)×100%] also show that the introduction of 2-FPPA into the side chain of 2-HDHAQ enhanced antitumor activity.These data suggest that the introduction of an amino acid into the starting material may increase its affinity for DNA or its selectivity for proliferating cancer cells.     

Synthesis and antitumor activity of new amphiphilic alkylglycerolipids substituted with a polar head group, 2-(2-trimethylammonioethoxy)ethyl or a congeneric oligo(ethyleneoxy)ethyl group

A new series of amphiphilic 1-octadecyl glycerolipids (eleven compounds, 1a-k) were designed and synthesized, in which the 3-phosphocholine portion of platelet-activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) was replaced by the 2-(2-trimethylammonioethoxy)ethyl group and congeneric groups having oligo(ethyleneoxy)ethyl bridges of various lengths at position 3, together with modification at position 2 (lower alkyl, acetonyl, acetoacetyl, carboxymethyl and pyrimidin-2-yl groups). These ether lipids, characterized by a nonphosphorus lysoglycerolipid structure, showed potent antitumor activity in vitro (human promyelocytic leukemia cells, HL-60, and human epidermoid carcinoma cells, KB) and in vivo (mouse sarcoma S180 and mouse mammary carcinoma MM46). Maximal in vitro potency was obtained with 1-O-octadecyl-2-O-(2-pyrimidinyl)-3-O-[2-(2-trimethylammonioethoxy )ethyl] glycerol (1g; IC50 values for both HL-60 and KB were 0.32 microgram/ml, indicating a higher activity than alkyl-lysophospholipid, ET18-OMe). Several appropriately 2-substituted 1-octadecylglycerolipids with the 3-[2-(2-trimethylammonioethoxy)ethyl] group (e.g., methyl, 1b; butyl, 1f; 2,2,2-trifluoroethyl, 1j; and acetonyl, 1k) showed a potent life-span-prolonging effect on mice with ascites sarcoma S180 and on those with mammary carcinoma MM46, when administered intraperitoneally at 16.5 and 12.5 mg/kg/d, respectively. Compounds 1b and 1k showed definite tumor growth inhibition against solid sarcoma S180 in mice, whether given p.o. or i.v. at 16.5 mg/kg/d. Studies on the structure-activity relationships indicate that the metabolic stability to phospholipase C or related enzymes is at least partly responsible for the potent antitumor activity of this series of ether lipids.     

Determination of the new anticancer agent KW 2149, 7-N-[2-[2-(gamma-L-glutamylamino)ethyl)dithio)ethyl]mitomycin C, an analogue of mitomycin C.

The new mitomycin 7-N-[2-[2-(gamma-L-glutamylamino)ethyl)dithio)ethyl] mitomycin C (KW 2149) (I) proved to be active against a wide variety of experimental tumours. In order to perform pharmacokinetic studies with the new drug in Phase I sessions, a fast and reliable method has been developed based on the data of previous assays for mitomycin C. XAD-2 was preferred for isolation of I from blood plasma. The recovery of I was 50% whereas that of mitomycin C was 85%. Optimal separation was obtained on octadecyl silica columns with methanol-water (45:55, v/v) as mobile phase, while ultraviolet absorbance detection was performed at 375 nm. The assay enabled determination of I in a plasma concentration range of 20-1000 ng/ml using porfiromycin as internal standard.     

Crystal Structure and Antitumor Activity of Tri[2-[N-（4′-methyl-benzylsulfonyl）amino]ethyl]-amine

The crystal structure of the title compound (C27H38N4O7S3, Mr = 626.79) has been determined by single-crystal X-ray diffraction. The crystal is of triclinic, space group Pīwith a = 9.411(1), b = 11.645(2), c = 14.672(2) (A。), α = 91.80(1), β = 95.36(1), γ =104.56(1)o, V = 1547.0 (A。)3, Z = 2, Dc = 1.346 g/cm3, λ = 0.71073 (A。), μ(MoKα) = 0.289 mm－1 and F(000) = 664. The structure was refined to R = 0.0406 and wR = 0.1177 for 4103 observed reflections with I > 2σ(I). X-ray diffraction analysis reveals that the title compound is a practically distorted tetrahedron and each molecule contains one lattice H2O by hydrogen bond. The antitumor activity of the title compound against HL-60 human leukemia cells has also been studied by MTT method.     

Synthesis and antitumor activity of fused quinoline derivatives. II. Novel 4- and 7-hydroxyindolo-[3,2-b]quinolines.

Novel indolo[3,2-b]quinoline derivatives (1c--f), which carried a methoxy or a hydroxy group at the 4- or 7-position of the lead compound 1a, were prepared and their antitumor activities against P388 in mice were examined. Except for the 4-hydroxy derivative (1d), these showed remarkably potent activity. Among these compounds, the 7-hydroxy derivative (1f) was the most potent one (optimal dose = 50 mg/kg, the median survival time of treated group/control group (T/C) greater than 330%, cure = 5/6).     

Synthesis and antitumor activity of fused quinoline derivatives. III. Novel N-glycosylamino-indolo[3,2-b]quinolines.

Novel indolo[3,2-b]quinolines (1b-k), having a nitro, amino, acetamido, methanesulfonamido, or glycosylamino group at the 2, 7, or 8-position, were prepared and their antitumor activities against P388 leukemia in mice were examined. The 7-galactopyranosylamino derivative (1g) showed the most potent activity (optimal dose = 25 mg/kg, T/C greater than 333%, cure rate 5/6).     

2-[1-(4-甲酰氨基苯基乙酰氧)烷基]-1,4-二羟基-9,10-蒽醌类衍生物的 合成及其抗肿瘤作用研究

为寻找抗肿瘤作用强、毒性低并且对癌细胞具有靶向性的新蒽醌类化合物, 合成了未见报道的12个2-[1-(4-甲酰氨苯基乙酰氧)烷基]-1,4-二羟基-9,10-蒽醌类衍生物, 分别用L1210癌细胞进行细胞毒性实验及小鼠S180腹水癌做了体内抗肿瘤实验. 实验结果表明, 蒽醌侧链中引入对甲酰氨基苯乙酰基后细胞毒性增强. 随着侧链碳链数的增加细胞毒性随之逐渐减小, 当烷基侧链中的碳数超过7以上时, 细胞毒性消失. 当侧链R基为苯环时与脂肪烃链或环己基相比细胞毒性更大, 说明芳香环对癌细胞具有更强的抑制作用. S180小鼠抗肿瘤实验结果表明, 蒽醌侧链中引入对甲酰氨基苯甲酰基后活性无显著性变化.     

Synthesis and evaluation of novel pyrimido-acridone, -phenoxadine, and -carbazole as topoisomerase II inhibitors

As part of a series of studies to discover new topoisomerase II inhibitors, novel pyrimidoacridones, pyrimidophenoxadines, and pyrimidocarbazoles were synthesized, and in vitro and in vivo antitumor activities and DNA-protein and/or DNA-topoisomerase II cross-linking activity as an indicator of topoisomerase II-DNA cleavable complex formation were evaluated. The pyrimidocarbazoles possessed high in vitro and in vivo potencies. Compound 26 (ER-37326), 8-acetyl-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]carbazole-1,3(2H)-dione, showed in vitro growth inhibitory activity with respective IC(50) values of 0.049 microM and 0.35 microM against mouse leukemia P388 and human oral cancer KB. In vivo, this compound inhibited the tumor growth of mouse sarcoma M5076 implanted into mice with T/C values of 42% and 13% at 3.13 and 6.25 mg/kg/d respectively without significantly affecting the body weight. In addition, compound 26 (ER-37326) increased the formation of DNA-topoisomerase II cross-linking in P388 cells.     

Studies on the biological activity of tocotrienols

Tocotrienols were evaluated for activity against transplantable murine tumors inoculated i.p. into mouse, and the activities of two tocotrienols and alpha-tocopherols were compared. When the compounds were injected i.p., alpha- and gamma-tocotrienols were effective against sarcoma 180, Ehrlich carcinoma, and IMC carcinoma, and gamma-tocotrienol showed a slight life-prolonging effect in mice with Meth A fibrosarcoma, but the tocotrienols had no antitumor activity against P388 leukemia at doses of 5-40 mg/kg/d. On the other hand alpha-tocopherol had only a slight effect against sarcoma 180 and IMC carcinoma. The antitumor activity of gamma-tocotrienol was higher than that of alpha-tocotrienol. Tocotrienols showed growth inhibition of human and mouse tumor cells when the cells were exposed to these agents for 72 h in vitro, whereas tocopherol did not show any marked cytotoxic activity. Alpha- and gamma-tocotrienols had inhibitory effects on lipid peroxidation of murine microsomes by adriamycin.     

Synthesis and Crystal Structure of 1-[(1-Phenyl-4-cyano)pyrazol-5-yliminomethyl]- 2-nitroiminoimidazolidine

1　INTRODUCTIONNeonicotinoids[1～2]areanovelanddistinctclassofinsecticides.Theycombineselectiveactivityagainstinsectswithafavourablesafetyprofile.Neonicotinoidsactatthenicotinicacetylcholinereceptor(nAChR)[3～4].Sincethefirstneonicotinoid,imi-dacloprid(IMI)1wasintroducedtothemarketbyBayerin1991,alotofitsanalogswerereported.Thesecompoundshavethesamestructuralunit,asshowedindashedlineareainIMI.AccordingtothemodelproposedbyYamamotoetal[5],thedistancebetweenthetwonitrogenatomsofIMIisthe…     

(Z)-1-[2-(三苄基锡基)乙烯基]环庚醇及其衍生物的合成和性质

通过三苄基氢化锡与1-乙快基环庚醇发生加成反应，得到了一种有机锡化合物 ：(Z)-1-[2-(三苄基锡基)乙烯基]环庚醇(1)．化合物1与I2，Br2和IC1按1：1和1 ：2摩尔比投料进行卤化反应，得到6种构型保持的有机锡一卤化物2-4及二卤化物 5-7．有机锡一卤化物3与KOH乙醇溶液反应，得到了相应的有机锡氢氧化物8．以上 8种新化合物均通过熔点测定、元素分析、锡含量测定、红外光谱、核磁共振氢谱 对其结构进行了表征．并对其中的有机锡化合物1，3，4，6，7进行了体外抗P388 血癌活性测定，其中有机锡化合物4，6，7表现出强效．     

CRYSTAL STRUCTURE OF THE METHYL 4—（N—（1—OXYPROPYL）—N—PHENYLAMINO]—1—[2—（2—THIENYL）ETHYL]—4—PIPERIDINECARBOXYLATE（R31826）HYDROCHLORIDE

<正> C22H28N2O3S.HCl, Mr = 436.9, triclinic,P1;a=8.557(3),b= 10.299(2),c= 13.894(2)A;α= 99.25(1),β=86.64(2),γ= 107.68(2)°;V= 1151.2(3)A3,Z= 2, DC = 1.27g/cm3,R=0.064. The torsion angle C(14)-C(1)-N(2)-0(19) in the title compound is 137.5 being much larger than that (106°) in R30730. The dihedral angle between mean planes of the thiophene ring and piperidine ring is about 83 .     

Studies on thermophile products. IV. Structural elucidation of cytotoxic substance, BS-1, derived from Bacillus stearothermophilus.

A new cytotoxic substance designated as BS-1 was isolated from the autolysate and culture filtrate of Bacillus stearothermophilus UK563. On the basis of spectral data, the structure of BS-1 was determined as bis(2-hydroxyethyl) trisulfide and confirmed by direct comparison with the synthetic compound. BS-1 exhibited potent cytotoxicity against leukemia P388-D1, leukemia P388, mastocytoma P815, lymphoma EL4 and lymphoma MOLT4.     

Synthesis and evaluation of novel N-substituted-6-methoxynaphthalene-2-carboxamides as potential chemosensitizing agents for cancer

A novel class of molecules with structure N-[3-(heteroaryl)propyl]-6-methoxynaphthalene-2-carboxamides 8-13 were synthesized by condensing 6-methoxy-2-naphthoyl chloride 1 with 3-(heteroaryl)propyl amines 2-7. Compounds 8-12 were evaluated in vitro, in P388 murine lymphocytic leukemia cell line (P388) using SRB assay for cytotoxicity and in adriamycin resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Compounds 8-12 were non-toxic at lower dose of 20 microg/ml, and effectively reversed adriamycin resistance. However, at higher doses (40, 80 microg/ml) they showed significant cytotxicity and hence reversal potency was not determined at these concentrations.     

(R)-N-乙酰基-四氢噻唑-2-硫酮-4-甲酰TT的合成及其晶体结构

由N-乙酰(R)-四氢噻唑-2-硫酮-4-羧酸在三聚氯氰及三乙胺存在下与四氢噻唑-2-硫酮反应得到标题化合物，[α]^2^0~D +11.18°。用X射线衍射法测得其晶体结构，属单斜晶系，空间群为P2~1/c。晶体学数据：a=0.9959(4)nm，b=1.1469(4)nm，c=1.1108(3)nm，β=92.72(3)°，V=1.2673(8)nm^3，Z=4。分子中两个C=O基，两个C=S基团处于C(1)-N(1)-C(4)及C(6)-N(2)-C(7)键两侧呈反式。用PM3分子轨道方法研究了该化合物的电子结构，电荷和键序分布，得到该化合物前线轨道性质。     

Crystal structure, thermal behaviour, protonation and mass spectroscopic studies of racemic 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochlorides

The crystal structure, thermal behaviour, mass spectrum and protonation of 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (medetomidine) hydrochloride have been investigated. The title compound crystallizes in both hydrated and anhydrous forms, and their structures have been determined by three-dimensional X-ray structure analysis. The crystals of the anhydrous form are monoclinic and those of the hydrated form (containing one hydrate water molecule) are triclinic with unit-cell dimensions: a = 23.861(9), b = 7.721(4), c = 22.037(9) A, beta = 140.20(4) degrees, Z = 8, and space group C2/c, and a = 7.841(4), b = 8.380(3), c = 12.743(6) A, alpha = 93.66(3), beta = 102.90(3), gamma = 116.85(3) degrees, Z = 2, and space group P1, respectively. Thermal decomposition of the title compound has been interpreted from the TG, DTG and DSC curves with the help of mass spectrometry. Medetomidine hydrochloride monohydrate decomposes in four stages. The first is dehydration at 45-100 degrees C, the second is evaporation of HCl and medetomidine base at 200-320 degrees C, and the third and fourth are decomposition at 340-570 degrees C. The protonation constant is 7.04 in aqueous 0.1 M NaClO4 (25 degrees C).