3,3'-bi-1,3-thiazolidine]-4,4'-dione system. III. Evaluation of the antimicrobial and antitumor properties of 2,2'-disubstituted derivatives and their 1,1'-disulfones

A series of dl and meso 2,2'-disubstituted-[3,3'-bis-1,3-thiazolidine]-4,4'-diones and their 1,1'-disulfone derivatives have been tested for their antimicrobial activity against gram-positive, gram-negative and Candida strains and for antitumor activity against leukemic P.388 tumor system in mice. None of the tested bi-thiazolidinones showed any significant antitumor properties; only few 1,1'-disulfones exhibited some antibacterial activity.     

Synthesis and biological evaluation of novel (thio)urea derivatives as potential antitumor agents

A series of novel (thio)ureas containing the pyrimidinyl group was designed and synthesized. Their in-vitro antitumor activity against different human tumor cells was examined. Some of the compounds showed potential antitumor activity, which provided some hints for further studies on structure modification.     

六配位R2SnCl2（N—N）型新配合物的合成及其体外抑癌活性

从８０年代初起,有机锡化合物的抗癌活性日益受到重视,研究人员合成了大量的有机锡化合物,并对其进行了较全面的抗癌活性筛选〔１～３〕．吡唑衍生物具有抗菌〔４,５〕和杀虫作用〔６〕,其结构中有多个配位点,本文合成了两个新的吡唑衍生物（见图１）并用其作为双氮螯合配体来合成数个六配位Ｒ２ＳｎＣｌ２（Ｎ（Ｎ）型新配合物,并对它们的结构进行了表征,考察了它们对多种癌细胞的抑制作用,探讨了构效关系,结果表明这些六配位Ｒ２ＳｎＣｌ２（Ｎ（Ｎ）型新配合物主要对Ｐ３８８淋巴白血病有较强的抑制作用．配体的合成配体Ｉ〔Ｎ…     

Relationship between inhibition of mitochondrial respiration by naphthoquinones, their antitumor activity, and their redox potential

The physicochemical properties of a series of 1,4-naphthoquinones were correlated with their activities against Sarcoma-180 by Hodnett et al. [J. med. Chem. 26, 570 (1983)]. Redox potential was the most important molecular parameter determining antitumor activity in this series of compounds, suggesting that interference with electron transport contributes to their cytotoxicity. We evaluated this same series of quinones for their abilities to inhibit the beef heart mitochondrial succinoxidase and NADH-oxidase enzyme systems. They exhibited a broad range of inhibitory potencies. There was a strong relationship between succinoxidase inhibition, antitumor activity (T/C ratio), and redox potential. The redox potentials of the quinones which inhibited succinoxidase lay within the narrow range of endogenous components of the respiratory chain. In contrast, inhibition of NADH-oxidase was related to redox potential but did not significantly predict antitumor activity. These results suggest that inhibition of mitochondrial succinoxidase may be a useful preliminary screen for antitumor activity.     

靛玉红肟衍生物及有关化合物的合成与抗肿瘤作用

靛玉红为治疗慢性粒细胞白血病新药。有效率为87.26％。为了进一步提高靛玉红的疗效,减少副作用,探索其构效关系,制备了十九种衛生物,经药理抗动物肿瘤筛选,N,N′—二甲基靛玉红、N—甲基靛玉红肟、N—甲基靛玉红、N—甲基靛玉红肟甲醚、N—乙酰靛玉红和靛玉红肟等有效.     

Correlation of the in vitro cytotoxic and in vivo antitumor activities of gold(I) coordination complexes

A series of gold(I) coordination complexes including analogues of the antiarthritic agent auranofin 1 were evaluated for in vitro cytotoxic potency against both B16 melanoma cells and P388 leukemia cells and in vivo antitumor activity against P388 leukemia in mice. A number of the complexes showed potent cytotoxic activity in vitro and antitumor activity in vivo, with the phosphine-coordinated gold(I) thiosugar complexes demonstrating the greatest in vitro and in vivo activity. The data compiled for 63 complexes of the general structural formula LAuX provide the basis for the following observations: potent in vitro cytotoxic activity is observed for substituted (phosphine) gold complexes, lack of potency in vitro correlates well with lack of antitumor activity, potent cytotoxicity in vitro is not necessarily predictive of activity in vivo, in vivo antitumor activity is generally optimized by ligation of Au(I) with a substituted phosphine and a thiosugar.     

Design, synthesis and evaluation of novel rhodanine-containing sorafenib analogs as potential antitumor agents

A series of rhodanine-containing sorafenib analogs was designed, synthesized and evaluated for their in-vitro antitumor activity against three cancer cell lines (A549, H460 and HT29). Pharmacological data indicated that some of the target compounds possessed marked antiproliferative activity superior to the reference drug sorafenib, especially the most promising compound 7r (with the IC(50) value of 0.8, 1.3 and 2.8 μM against A549, H460 and HT29 cell lines, respectively). The activity was found to strongly depend on the substitution pattern of the rhodanine motif at C-5″ position. Results suggested that this series of compounds could serve as the bases for the development of novel antitumor agents.     

1,2,3,4,-Tetrahydro-1,2-diazepine derivatives: synthesis and evaluation of antileukemic activity

A series of 3-aryl or etheroaryl-6-cyano-7-phenyl-1,2,3,4-tetrahydro-1,2-diazepin- 5-ones was synthesized and evaluated for its antitumor activity against P388 leukemic tumor system in mice. None of the tested compounds showed significant antitumor properties.     

Structural studies on bioactive compounds. 8. Synthesis, crystal structure, and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line

A series of 2,4-diamino-5-aryl-6-ethylpyrimidines embracing basic substituents in the 5-aryl ring was synthesized and evaluated for inhibitory activity against rat liver dihydrofolate reductase (DHFR). Maximal enzyme inhibition was observed for compounds bearing a benzylamino (19) or N-alkylbenzylamino substituent (29 and 30) in the 4-position of the phenyl ring and a nitro group in the 3-position, the corresponding 3-amino, 3-azido, or unsubstituted analogues proving only weakly active or inactive as DHFR inhibitors. Selected compounds were also screened in vivo against a methotrexate-resistant tumor, the M5076 murine reticulosarcoma, and antitumor activity in general paralleled activity against DHFR, the (3,4-dichlorobenzyl)amino analogue 26 proving the least toxic compound to exhibit significant antitumor activity. The X-ray crystal structure of the ethanesulfonic acid salt of the N-methylbenzylamino compound 29 has been determined to facilitate future molecular modeling studies in this new series of DHFR inhibitors.     

13-酰胺基取代苦参碱衍生物的合成及抗肿瘤活性研究

目的 合成13-酰胺基取代苦参碱衍生物及研究该类化合物的体外抗肿瘤活性。方法 以槐果碱为原料,通过迈克尔加成（Michael addition）,叠氮还原酰化反应,制得系列13-位酰胺取代的衍生物,所有化合物结构均经¹H NMR等谱确证;选取人肝癌细胞（BEL-7404）和小鼠黑色素瘤细胞（K111）对所合成的目标化合物进行体外抗肿瘤药理活性筛选。结果 设计合成了9个新化合物,大多数化合物对两株肿瘤细胞都具有较强的抑制活性。结论 化合物4b和4e对人肝癌细胞（BEL-7404）有较强的抑制活性。     

Synthesis and bioactivities of novel pyrazole and triazole derivatives containing 5-phenyl-2-furan

A series of novel pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized. Their toxicities were predicted using in silico assays and proven to be less toxic. The antitumor results showed that the activity of compounds containing 1,3,4-triazole (series II) was higher than that of pyrazole-attached derivatives (series I). Among them, IIa and IIg showed much higher activity against Bel-7402 than doxorubicin. The fungicidal tests showed that most title compounds II exhibited great selectivity against Phytophthora capsici in vivo.     

Compounds with potential antitumor activity. VI--2-Alkyl-3-[2-(1,3,4-thiadiazolyl)]-4-thiazolidinones

The antitumor activity of a series of 2-alkyl-3-[2-(1,3,4-thiadiazolyl)]-4-thiazolidinones was tested against the leukemic P 388 tumor system in mice. Only compounds (V-VII) showed significant activity.     

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。     

Synthesis and biological activity of analogues of diazaquinomycin A, a new thymidylate synthase inhibitor

Diazaquinomycin A (1), a new thymidylate (TMP) synthase inhibitor, is poorly soluble in various solvents and exhibits no antitumor activity, while a series of the analogues prepared from 1 are more soluble in water and chloroform than 1, and some of them exhibit antitumor activity in mice. Some analogues in which the lactam rings are replaced by pyridine rings did not inhibit TMP synthase. The diethoxy analogue 25 is a 10-fold more potent inhibitor of TMP synthase than 1. The diacetoxy analogue 23 exhibits significant antitumor activity (T/C: 175%) against Meth-A fibrosarcoma in mice.     

New potent mitomycin derivatives: synthesis and antitumor activity of 7,7-(ethylenedioxy)mitomycins.

A series of 6,7-dihydro-7,7-(ethylenedioxy)mitomycins was synthesized and evaluated for antitumor and anticellular activities. These compounds were prepared by basic treatment of 7-methoxymitomycins with ethylene glycol, and were structurally novel mitomycin derivatives containing a masked quinone moiety. 5,6-Enol or 6-chloro derivatives of 6,7-dihydro-7,7-(ethylenedioxy)mitomycins were also prepared and the (allyloxy)carbonyl group at the aziridine nitrogen has proved to be an efficient protecting group in chemical modification of mitomycins. Most of these mitomycin derivatives displayed potent antitumor activity against P388 leukemia in mice and anticellular activity against HeLa S3 cells.     

Design,synthesis, and evaluation of novel boronic-chalcone derivatives as antitumor agents

A series of boronic-chalcone derivatives were synthesized and tested for antitumor activity against human breast cancer cell lines. The results show the boronic-chalcones are more toxic to breast cancer cells compared to normal breast cells than other known chalcones.     

Synthesis and antitumor activity evaluation of lamiridosin A derivatives

A series of lamiridosin A derivatives were synthesized through simple procedures. Their antitumor activities were evaluated against EC9706, MGC803, and B16 cell lines in vitro. Several compounds showed potent antitumor activity, especially compound 10, with IC₅₀ value of 2.36 μmol/L against MGC803 cell lines, is more potent than marketed positive drug 5-fluorouridine (5-FU).     

新型微管稳定剂吲哚美辛衍生物的合成与抗肿瘤活性研究

目的设计合成一系列吲哚美辛衍生物并测定其体外抗肿瘤和微管蛋白抑制活性。方法以5-甲氧基-2-甲基-3-吲哚乙酸为起始原料经两步酰化反应合成12个化合物,MTT法检测目标化合物对HT29、A549、Hep-2、MCF-7肿瘤细胞的抑制活性,同时采用浊度法评价其体外微管蛋白的抑制作用。结果 12种目标化合物均呈现了优于吲哚美辛的体外抗肿瘤作用和微管蛋白抑制活性,其中3位羧基侧链苯乙基取代的化合物12作用于人结肠癌细胞HT29的IC_(50)(2.2μmol)为吲哚美辛的400倍,并且可以干扰微管聚合,其作用于微管蛋白的IC_(50)为5.6μmol。结论改变吲哚美辛1位酰胺和3位羧酸侧链所得的系列衍生物是一类新型的以微管为靶点的抗肿瘤候选药物。     

New water-soluble duocarmycin derivatives: synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups

A series of A-ring pyrrole compounds of duocarmycin bearing 4'-methoxy-beta-heteroarylacryloyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the 4'-methoxy-beta-heteroarylacrylates displayed in vitro anticellular activity equivalent to that of 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates, compound 15b having a (4-methoxy-3,5-pyrimidinyl)acryloyl as segment-B (Seg-B) showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B, which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates. Moreover, these 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates had high aqueous solubility.     

Synthesis and antitumor activity of duocarmycin derivatives: modification of segment-A of A-ring pyrrole compounds.

A series of 3-substituted A-ring pyrrole compounds of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S(3) cells and in vivo antitumor activity against murine sarcoma 180 in mice. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among 3-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.