1-苯胺基-5H-哒嗪并[4,5-b]吲哚类化合物的合成及体外抗肿瘤活性

目的设计并合成1-苯胺基-5H-哒嗪并[4,5-b]吲哚类化合物,评价其体外抗肿瘤活性。方法以5-乙酰氧基-6-溴-2-溴甲基-1-环丙基-1H-吲哚-3-羧酸乙酯为起始原料,经8～9步反应合成目标化合物;采用MTT法,测定了目标化合物对肿瘤细胞株Bel-7402和HT-1080的抑制活性。结果与结论合成了12个新化合物,其结构经1H-NMR和MS确证;多个化合物显示出良好的抗肿瘤活性,化合物10a和10d活性突出,对肿瘤细胞株Bel-7402和HT-1080的抑制活性分别是阳性对照药gefitinib的4倍和5倍,值得进一步研究。     

5H-哒嗪并[4,5-b]吲哚类新化合物的合成及 抗肿瘤细胞增殖活性

目的 设计并合成5H-哒嗪并[4,5-b]吲哚类化合物,评价其体外抗肿瘤细胞增殖活性。方法 以7-溴-1-氯-8-(3-氯丙氧基)-5-环丙基-5H-哒嗪并[4,5-b]吲哚为起始原料,经取代、醚化、Mannich 反应、选择性氧化共3步或4步反应合成目标化合物;以吉非替尼(gefitinib)为阳性对照药,采用 MTT 法测定了目标化合物对肿瘤细胞株 Bel-7402 和 HT-1080 的抗增殖活性。结果与结论 合成了13 个化合物,其中12 个是未见文献报道的新化合物,其结构经¹H-NMR、MS 谱确证;8个化合物显示出较好的抗肿瘤细胞增殖活性,其中,化合物4a和5a抗增殖活性突出,分别为吉非替尼的3倍和4倍。     

5,7-二取代吡唑并[1,5-α]嘧啶类化合物的合成及其抗肿瘤活性

目的设计并合成吡唑并[1，5-α]嘧啶类化合物，并评价其抗肿瘤活性。方法根据吡唑并[1，5-α]嘧啶类抗肿瘤药物的基本结构，设计了14个5-胺甲基一7一苯胺基吡唑并[1，5-α]嘧啶类化合物，并以丙二腈和原甲酸三乙酯为起始原料，经5步反应得到目标产物。采用MTT法，顺铂为阳性对照药，以Bel-7402和HT-1080为测试细胞株对目标化合物进行抗肿瘤活性评价。结果与结论合成了14个未见文献报道的新化合物，结构经MS、IR和1H-NMR确证。体外活性实验表明：化合物12显示出较好的抗癌活性。     

新型三环肟醚衍生物的合成及其抗肿瘤活性

目的设计合成8H-噻吩并[2,3-b]吡咯里嗪-8-肟醚类化合物,并对其体外抗肿瘤活性进行初步评价。方法以芳基乙腈为原料,经多步反应合成目标化合物;采用MTT法,以顺铂为阳性对照药,以Bel-7402和HT-1080为测试细胞株对目标化合物的抗肿瘤活性进行了评价。结果与结论合成了12个新化合物,经1H-NMR、MS和IR确认其结构。体外活性实验表明:化合物7d显示出较好的抗肿瘤活性。     

咪唑-[1，2-b]哒嗪类mTOR抑制剂的合成及抗肿瘤活性研究

目的设计合成咪唑-[1,2-b]哒嗪类mTOR抑制剂,并对其抗肿瘤活性及构效关系进行初步研究。方法以3-氨基4-溴-6-氯哒嗪、1-（N-Boc-哌啶4-基）溴乙醛等为原料,通过对咪唑[1,2-b]哒嗪环的构建,Suzuki偶联等5步反应得到目标化合物;分别采用SRB染色法、Z′-LYTE（r）法对目标化合物的抗肿瘤活性、mTOR激酶抑制活性进行评价。结果与结论共合成16个未见文献报道的新化合物,其结构经1H-NMR、13C-NMR、HRMS确证;活性测试结果表明,化合物15、16、27等对肿瘤细胞的生长有显著抑制作用。     

吡唑并[1，5-α]嘧啶类化合物的合成及其抗肿瘤活性

目的设计合成新的吡唑并[1,5-a]嘧啶类化合物,并评价其抗肿瘤活性。方法根据吡唑并[1,5-a]嘧啶类抗肿瘤药物的基本结构设计了一系列5-胺甲基-7-苯胺基吡唑并[1,5-a]嘧啶类化合物,并以丙二腈和原甲酸三乙酯为起始原料,经5步反应得到目标产物。采用MTT法,以顺铂为阳性对照药,以Bel-7402和HT-1080为测试细胞株对目标化合物的抗肿瘤活性进行评价。结果与结论合成了11个未见文献报道的化合物,结构经质谱和核磁共振氢谱确证。化合物6显示出很好的抗肿瘤活性。     

5,7-二取代吡唑并[1,5-a]嘧啶类化合物的合成及其抗肿瘤活性

目的设计并合成吡唑并[1,5-a]嘧啶类化合物,并评价其抗肿瘤活性。方法根据吡唑并[1,5-a]嘧啶类抗肿瘤药物的基本结构,设计了14个5-胺甲基-7-苯胺基吡唑并[1,5-a]嘧啶类化合物,并以丙二腈和原甲酸三乙酯为起始原料,经5步反应得到目标产物。采用MTT法,顺铂为阳性对照药,以Bel-7402和HT-1080为测试细胞株对目标化合物进行抗肿瘤活性评价。结果与结论合成了14个未见文献报道的新化合物,结构经MS、IR和1H-NMR确证。体外活性实验表明:化合物12显示出较好的抗癌活性。     

[1,2,4]三氮唑并[1,5-a]嘧啶类化合物的合成及其抗肿瘤活性

目的寻找具有抗肿瘤活性的新化合物,设计合成[1,2,4]三氮唑并[1,5-a]嘧啶衍生物,并评价其体外抗肿瘤活性。方法以γ-丁内酯为起始原料,经环合、氯代、取代、硫醚化和氨甲基化等反应合成7-苯基氨基-2-[3-(5-取代氨基甲基-呋喃-2-基-甲硫基)丙基]-5-甲基-[1,2,4]三氮唑并[1,5-a]嘧啶类化合物。采用MTT法,以顺铂为阳性对照药,以Bel-7402和HT-1080为测试细胞株对目标化合物的抗肿瘤活性进行了评价。结果与结论合成了12个未见文献报道的新化合物,结构经质谱、红外光谱和核磁共振氢谱确证。体外活性实验表明:化合物16显示出很好的抗肿瘤活性。     

吡唑并[1,5-a]嘧啶类化合物的合成及其抗肿瘤活性

目的 设计合成新的吡唑并[1,5-a]嘧啶类化合物,并评价其抗肿瘤活性.方法 根据吡唑并[1,5-a]嘧啶类抗肿瘤药物的基本结构设计了一系列5-胺甲基-7-苯胺基吡唑并[1,5-a]嘧啶类化合物,并以丙二腈和原甲酸三乙酯为起始原料,经5步反应得到目标产物.采用MTT法,以顺铂为阳性对照药,以Bel-7402和HT-1080为测试细胞株对目标化合物的抗肿瘤活性进行评价.结果与结论 合成了11个未见文献报道的化合物,结构经质谱和核磁共振氢谱确证.化合物6显示出很好的抗肿瘤活性.     

3-芳基-6-(溴代芳甲基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成及其乙酰胆碱酯酶抑制活性研究

目的设计合成3-芳基-6-(溴代芳甲基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物,并探讨C-6位芳甲基上引入溴原子对其乙酰胆碱酯酶抑制活性的影响。方法以4-羟基苯甲醛为原料,经溴代反应,得到3-溴-4-羟基苯甲醛和3,5-二溴-4-羟基苯甲醛,再将溴代的4-羟基苯甲醛与乙酰甘氨酸经Erlenmeyer-Plchl反应、水解反应、缩合反应合成目标化合物3-芳基-6-(溴代芳甲基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。采用Ellman法对目标化合物进行体外乙酰胆碱酯酶抑制活性筛选。结果所有目标化合物的结构均经红外光谱、质谱和核磁共振氢谱确证。目标化合物经体外乙酰胆碱酯酶抑制活性筛选,结果显示:所有目标化合物均具有乙酰胆碱酯酶抑制活性,其中8个化合物在10μmol.L-1浓度水平抑制活性超过了40%。结论在7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物母核C-6位芳甲基中引入溴原子的3-芳基-6-(溴代芳甲基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物普遍具有较高的AChE抑制活性,并且引入2个溴原子的化合物抑制活性明显高于引入1个溴原子的化合物。     

Synthesis and anti-tumor activities of a novel series of tricyclic 1-anilino-5H-pyridazino[4,5-b]indoles

A novel series of 1-anilino-5H-pyridazino[4,5-b]indoles was designed and synthesized in order to find novel potent anti-tumor compounds. Their structures were confirmed by MS, (1)H-NMR, and elemental analysis. All compounds were screened for their cytotoxic activity against two human cancer cell lines (Bel-7420, HT-1080). The compounds 8, 9, and 17 showed 50% growth inhibitory activity in low micromolar concentration (IC(50 )= 7.7 approximately 12.8 microM). Among them, compound 17 displayed the most potent anti-tumor activity with IC(50) values of 8.2 microM and 7.9 microM against Bel-7402 and HT-1080, respectively.     

New heterocyclic ring systems--V synthesis and pharmacological activity of 6H-1,3,4-thiadiazolo [3',2':1,2]-5-oxopyrimido [5,4-b] indole derivatives and of 1-phenyl-6H-1,2,4-triazolo [1',5':1,2]-5-oxopyrimido[5,4-b] indole

As a part of a study on analgesic and antiinflammatory active condensed heterocyclic compounds containing the pyrimidinic ring, a number of 6H-1,3,4-thiadiazolo [3',2':1,2]-5-oxopyrimido [5,4-b]indole and 1-phenyl-6H-1,2,4-triazolo [1',5':1,2]-5-oxopyrimido [5,4-b] indole were synthesized and tested. The results of pharmacological assays are reported and discussed.     

Selective thromboxane synthetase inhibitors and antihypertensive agents. New derivatives of 4-hydrazino-5H-pyridazino[4,5-b]indole, 4-hydrazinopyridazino[4,5-a]indole, and related compounds

A series of new derivatives of 4-hydrazino-5H-pyridazino[4,5-b]indole (5) and 4-hydrazinopyridazino[4,5-a]indole (12) have been synthesized to investigate their activities as selective thromboxane synthetase inhibitors as well as antihypertensive agents. Several of the prepared compounds were found to be selective thromboxane synthetase inhibitors, in concordance with the Gorman model. The most potent were 8-(benzyloxy)-3,4-dihydro-4-oxo-5H-pyridazino[4,5-b]indole (3c) and 8-methoxy-4-hydrazino-5H-pyridazino[4,5-b]indole (5). This last compound did not inhibit prostacyclin formation and showed an antihypertensive activity similar to that of hydralazine. The acute toxicity in mice for 5a . HCl is about 2.2 times less than that for hydralazine.     

Synthesis of heterobicyclic nitrogen systems bearing the 1,2,4-triazine moiety as anti-HIV and anticancer drugs, part III

Some new fused heterobicyclic nitrogen systems such as 1,2,4-triazino[3,4-b] [1,3,4] thiadiazolones/thiadiazinones 4-15 and the related compounds 16-21 have been synthesized from treatment of 4-amino-3-mercapto-6-substituted-1,2,4-triazin-5-ones 1 with bifunctional oxygen and halogen compounds via heterocyclization reactions. Structures of the products have been deduced from their elemental analysis and spectral data. Significant anti-HIV and anticancer activities were observed in vitro for some members of the series, compounds 1e, 4e, 4f, 5, 6 and 16 showing a significant activity in Leukemia, Lung, Breast and CNS anticancer evaluation.     

Synthesis and evaluation of anticancer activity of some imidazothiazolyl,imidazobenzothiazolyl and dihydroimidazothiazolyl coumarins

A series of 6-(2H-1-benzopyran-2-one-3-yl)imidazo[2,1-b]thiazoles (1), 2-(2H-1-benzopyran-2-one-3-yl)imidazo[2,1-b]benzothiazoles (2) and 3-(2H-1-benzopyran-2-one-3-yl)-5,6-dihydroimidazo[2,1-b]thiazoles (3) have been synthesized and evaluated for anticancer activity in vitro. The compounds showed very good activity against different tumor cell lines.     

Synthesis and cytostatic properties of some 6H-Indolo[2, 3-b][1, 8]naphthyridine derivatives

The new and efficient synthesis of the title heterocyclic ring system is described starting from suitable 2-chloro-1, 8-naphthyridines. The synthesized 6H-indolo[2, 3-b][1, 8]naphthyridine derivatives were tested in vitro on 55 tumor cell lines for their anticancer properties. The presence of the acetylamino moiety at position 3 in the main ring system proved to be crucial for the cytostatic activity of this class of compounds.     

Pyrimido[5,4-b]indole derivatives. 1. A new class of potent and selective alpha 1 adrenoceptor ligands.

A number of 3-substituted pyrimido[5,4-b]indole-2,4-diones (7-23) were evaluated for their in vitro alpha 1 adrenoceptor affinity by radioligand receptor binding assays. Some compounds bearing a (phenylpiperazinyl)alkyl side chain were potent alpha 1 adrenoceptor ligands. The most active derivative in displacement of [3H]prazosin from rat cortical membranes was 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]pyrimido[5,4-b]indol e- 2,4-dione (10) (Ki = 0.21 nM). Discrete modifications in the structure resulted in higher selectivity (greater than 10,000 times) for alpha 1 than alpha 2, beta 2, and 5HT1A receptors. Some compounds also had affinity for the 5HT1A receptor. The most selective alpha 1 ligand was 3-[2-[4-(2-chlorophenyl)piperazin-1-yl]ethyl]pyrimido[5,4-b)indole - 2,4-dione (13).     

Structure-activity studies of 4,6-disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives with analgesic and antiinflammatory activities

4,6-Disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives showed analgesic and antiinflammatory activities when assayed by the acetic acid writhing test in mice and the carrageenin edema test in rats. To understand how the substituents affect the biological activities, the quantitative structure-activity relationships (QSAR) of 38 compounds were analyzed using the adaptive least-squares method (ALS method). The resulting QSAR suggested that some chemical modifications of 4,6-disubstituted furo[3,2-b]indole derivatives would improve their biological activities. Thus, 15 additional compounds were synthesized to reinforce and confirm the correlation. Among these compounds, particularly 4-(2-ethylhexanoyl)-2-(morpholinocarbonyl)-6-(trifluoromethy l) furo[3,2-b]indole showed pronounced biological activities. This compound gave a pharmacological activity spectrum similar to that of tiaramide but exhibited much higher potency.