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1.
A novel series of A-ring modified hexacyclic camptothecin derivatives containing a 1,3-oxazine ring were first designed and synthesized. All of the hexacyclic camptothecins were assayed for in vitro cytotoxicity against nine human cancer cell lines. Among these compounds, 9b and 9c showed most potent cytotoxicity against several cell lines. Particularly, 9c was about 13-fold more potent than camptothecin, and about sixfold more potent than topotecan toward HEPG-2. Furthermore, it was also found that the N-alkyl substituted derivatives were more potent than the N-aryl and N-benzyl substituted compounds against most cell lines. 相似文献
2.
Paola B Arimondo Alexandre Boutorine Brigitte Baldeyrou Christian Bailly Masayasu Kuwahara Sidney M Hecht Jian-Sheng Sun Thérèse Garestier Claude Hélène 《The Journal of biological chemistry》2002,277(5):3132-3140
To achieve a sequence-specific DNA cleavage by topoisomerase I, derivatives of the antitumor drug camptothecin have been covalently linked to triple helix-forming oligonucleotides that bind in a sequence-specific manner to the major groove of double-helical DNA. Triplex formation at the target sequence positions the drug selectively at the triplex site, thereby stimulating topoisomerase I-mediated DNA cleavage at this site. In a continuous effort to optimize this strategy, a broad set of conjugates consisting of (i) 16-20-base-long oligonucleotides, (ii) alkyl linkers of variable length, and (iii) camptothecin derivatives substituted on the A or B quinoline ring were designed and synthesized. Analysis of the cleavage sites at nucleotide resolution reveals that the specificity and efficacy of cleavage depends markedly on the length of both the triple-helical structure and the linker between the oligonucleotide and the poison. The optimized hybrid molecules induced strong and highly specific cleavage at a site adjacent to the triplex. Furthermore, the drug-stabilized DNA-topoisomerase I cleavage complexes were shown to be more resistant to salt-induced reversal than the complexes induced by camptothecin alone. Such rationally designed camptothecin conjugates could provide useful antitumor drugs directed selectively against genes bearing the targeted triplex binding site. In addition, they represent a powerful tool to probe the molecular interactions in the DNA-topoisomerase I complex. 相似文献
3.
Hubert Josien David Bom Dennis P. Curran Yu-Huang Zheng Ting-Chao Chou 《Bioorganic & medicinal chemistry letters》1997,7(24):1574-3194
The synthesis and biological evaluation of about one dozen 7-silylcamptothecin derivatives are described. Most new compounds show potencies comparable to or better than camptothecin itself. The best compound, 11-fluoro-10-amino-7-trimethylsilylcamptothecin, is more than 20 times more potent than camptothecin in cell assays. 相似文献
4.
Synthesis and pharmacological evaluation of novel non-lactone analogues of camptothecin 总被引:3,自引:0,他引:3
Hautefaye P Cimetière B Pierré A Léonce S Hickman J Laine W Bailly C Lavielle G 《Bioorganic & medicinal chemistry letters》2003,13(16):2731-2735
Ten novel camptothecin (CPT) derivatives devoid of the lactone function in the E-ring were synthesized and evaluated as anticancer agents. Several of these CPT analogues bearing a five-membered E-ring are potent inhibitors of the DNA relaxation and cleavage reactions catalyzed by topoisomerase I and exhibit promising cytotoxic activities with IC(50) values in the nM range. This is the first successful design of lactone-free CPT, providing thus a new avenue to the development of topoisomerase I targeted antitumor agents. 相似文献
5.
Wei Guo Wenfeng Liu Lingjian Zhu Yongqiang Zhang Pengfei Cheng Guoqiang Dong Chunlin Zhuang Jianzhong Yao Chunquan Sheng Zhenyuan Miao Wannian Zhang 《化学与生物多样性》2011,8(8):1539-1549
Homocamptothecin (hCPT) is an E‐ring modified camptothecin (CPT) analogue, which showed pronounced inhibitory activity of topoisomerase I. In search of novel hCPT‐type anticancer agents, two series of hCPT derivatives were synthesized and evaluated in vitro against three human tumor cell lines. The results indicated that the 10‐substituted hCPT derivatives had a considerably higher cytotoxic activity than the 12‐substituted ones. Among the 10‐substituted compounds, 8a, 8b, 9b , and 9i showed an equivalent or even more potent activity than the positive control drug topotecan against the lung cancer cell line A‐549. Moreover, the hCPT analogues 8a and 8b exhibited a higher topoisomerase I inhibitory activity than CPT at a concentration of 100 μM . 相似文献
6.
Qingyong Li Hongyan Lv Yuangang Zu Zhenhuan Qu Liping Yao Lin Su Chen Liu Limin Wang 《Bioorganic & medicinal chemistry letters》2009,19(2):513-515
In an effort to decrease the toxicity and improve the stability of labile lactone ring of camptothecin, nitrogenous heterocyclic aromatic groups were introduced into 20-position of camptothecin and seventeen new 20s-camptothecin derivatives were obtained in quantitative yield. The cytotoxicity in vitro on three cancer cell lines and the stability of the lactone in phosphate-buffered solution (PBS) of these derivatives were evaluated. Most of these tested derivatives possessed better cytotoxicity than topotecan. Analogues 6, 12 exhibited the best antitumor activity in vivo in all derivatives we prepared. The results suggested that introduction of pyrazole in 10- or 20-position of camptothecin could promote antitumor activity in vitro and in vivo, simultaneously bring much increase of the stability of lactone. 相似文献
7.
Hirokawa Y Kinoshita H Tanaka T Nakamura T Fujimoto K Kashimoto S Kojima T Kato S 《Bioorganic & medicinal chemistry letters》2008,18(12):3556-3561
In the course of our research aimed at the discovery of metabolic stable pleuromutilin derivatives with more potent antibacterial activity against Gram-positive pathogens than previous analogues, a series of compounds bearing a purine ring were prepared and evaluated. From SAR studies, we identified two promising compounds 85 and 87, which have excellent in vitro activity against a number of Gram-positive pathogens, including existing drug-resistant strains, and potent in vivo efficacy. 相似文献
8.
9.
Analysis of stereoelectronic properties of camptothecin analogues in relation to biological activity
Werbovetz KA Bhattacharjee AK Brendle JJ Scovill JP 《Bioorganic & medicinal chemistry》2000,8(7):1741-1747
Camptothecin and four of its 10,11-methylenedioxy analogues were examined for their activity against the pathogenic protozoan Leishmania donovani in vitro. The methylenedioxy analogues were 36- to 180-fold more potent than the parent camptothecin, possessing IC50 values ranging from 160 to 32 nM against the parasite. Our finding that the methylenedioxy camptothecins possess greater activity than camptothecin, which is also the case for other cell types and for the generation of cleavable complex in the presence of DNA and purified mammalian topoisomerase I, prompted us to examine the molecular features of camptothecin and methylenedioxy camptothecin analogues. A delocalization of positive potential was observed in the methylenedioxy camptothecin analogues, which could increase the affinity of these molecules for DNA. In addition, geometrical and electronic differences between the E ring of camptothecin and its methylenedioxy analogues were noted. One or both of these factors may contribute to the superior biological activity of the methylenedioxy camptothecin analogues. 相似文献
10.
In situ binding of thiol-reactive prodrugs to the cysteine-34 position of circulating albumin is a new approach in drug delivery. Therefore, five maleimide-bearing derivatives of the anticancer drug camptothecin (CPT) were developed as albumin-binding prodrugs. These compounds were synthesized by reacting heterobifunctional cross-linkers based on oligo(ethylene glycols) [3-6 (O-CH(2)-CH(2)) units] bearing a maleimide group on one end and a carboxylic acid group on the other with camptothecin 20-O-glycinate. Incorporating oligo(ethylene glycol) chains into the prodrugs enhanced their water-solubility when compared to the parent compound (up to 27-fold). HPLC studies showed that the prodrugs react almost quantitatively with the cysteine-34 position of endogenous albumin within a few minutes after incubation of the CPT derivatives with human blood plasma. The therapeutic potential of two of the prodrugs was assessed in nude mice bearing a colon xenograft (HT-29). Both albumin-binding derivatives of camptothecin were well-tolerated and showed enhanced antitumor efficacy when compared to CPT. 相似文献
11.
Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action. 相似文献
12.
Hui-Kang Wang Su-Yin Liu Kou-Maou Hwang Glen Taylor Kuo-Hsiung Lee 《Bioorganic & medicinal chemistry》1994,2(12):1397-1402
Eighteen new water-soluble 7-(aminoacylhydrazono)-formyl camptothecins were synthesized and evaluated for their ability to cause protein-linked DNA breaks and to inhibit topoisomerase I activity. Compared with camptothecin, five of the compounds were as potent or more potent in these two assays but were less toxic in several cancer cell lines. The results suggest that the 7 position in the B ring is a suitable location for introducing a polar moiety into camptothecin producing analogues with enhanced topoisomerase I inhibiting activity. 相似文献
13.
Sano K Yoshikawa M Hayasaka S Satake K Ikegami Y Yoshida H Ishikawa T Sawada S Tanabe S 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2003,795(1):25-34
SN-38 (7-ethyl-10-hydroxycamptothecin) is an active metabolite derived from the semi-synthetic compound camptothecin (CPT) named Irinotecan (CPT-11). The antitumor activity of SN-38 is 1000-fold more potent than the parent CPT-11. Fourteen new derivatives of camptothecin have recently been developed by Yakult Honsha (Tokyo, Japan). Here we describe a simple and cost-effective high-performance liquid chromatography (HPLC) method without an ion-pairing agent, which allows the simultaneous determination of both lactone and carboxylate forms of SN-38 and other camptothecin derivatives. A weak linear relationship between the HPLC retention factors (ln k') and the cellular concentrations of these compounds was observed. These results suggest that low-polarity compounds easily accumulate in cancer cells and may circumvent drug resistance. The HPLC analysis herein described is expected to greatly assist in derivative synthesis and chemical modification of camptothecin-based antitumor drugs. 相似文献
14.
《Bioorganic & medicinal chemistry》2016,24(22):5781-5786
A series of novel lapachol derivatives possessing indole scaffolds was designed and synthesized. The in vitro anti-proliferative activity of these novel compounds was evaluated in Eca109 and Hela cell lines. Almost all the tested compounds showed manifested potent inhibitory activity against the two tested cancer cell lines. Topo I-mediated DNA relaxation activity indicated that these novel compounds have potent Topoisomerase I inhibition activity. The most potent compounds 4n and 4k demonstrated more cytotoxicity than camptothecin and was comparable to camptothecin in inhibitory activities on Topoisomerase I in our biological assay. In addition, the Hoechst 33342 staining method also showed that the complex can induce Hela cell apoptosis. 相似文献
15.
Xiao-Dong Yang Xiang-Hui Zeng Yan-Li Zhang Chen Qing Wen-Jian Song Liang Li Hong-Bin Zhang 《Bioorganic & medicinal chemistry letters》2009,19(7):1892-1895
A series of novel phenacylimidazolium derivatives, bearing an aryl or alkyl substituent at position-1 and a phenacyl substituent at position-3 of the imidazole ring, has been prepared and evaluated in vitro against a panel of human tumor cell lines. Phenacylimidazolium bromides bearing a highly sterically hindered aryl group at position-1 and an electron-rich phenacyl or naphthylacyl substituent at position-3 of imidazole ring proved to be more active than imidazolium bromides with other substituted groups. In particular, compound 5j was found to be the most potent compounds with IC50 values lower than 5.0 μM against 8 strains human tumor cell lines and more active than cisplatin (DDP). 相似文献
16.
Design and synthesis of substituted pyridine derivatives as HIF-1alpha prolyl hydroxylase inhibitors
Warshakoon NC Wu S Boyer A Kawamoto R Sheville J Bhatt RT Renock S Xu K Pokross M Zhou S Walter R Mekel M Evdokimov AG East S 《Bioorganic & medicinal chemistry letters》2006,16(21):5616-5620
Structure-guided de novo drug design led to the identification of a novel series of substituted pyridine derivatives as HIF-1alpha prolyl hydroxylase inhibitors. Pyridine carboxyamide derivatives bearing a substituted aryl group at the 5-position of the pyridine ring show appreciable activity, while constraining the side chain by placing a pyrazole carboxylic acid generated a potent lead series with consistent activity against EGLN-1. 相似文献
17.
DNA topoisomerase I (Top1) is an essential nuclear enzyme and a validated target for anticancer agent screening. In a previous study, we found that indolizinoquinoline-5,12-dione derivatives show significant biological activity against several human cancer cell lines. To understand their mechanism of inhibition of cancer cell growth, one indolizinoquinoline-5,12-dione derivative, CY13II, was further studied as lead. Our present results indicate that CY13II shows more potent antiproliferative activity against K562 cells than camptothecin. Additionally, K562 cells were arrested in G2/M, and their growth rate decreased after treatment with CY13II at micromolar concentration. Biochemical Top1 assays indicate that CY13II exhibits a different inhibitory mechanism from camptothecin. Unlike camptothecin, CY13II specifically inhibits the catalytic cleavage activity of Top1 instead of forming the drug-enzyme-DNA covalent ternary complex. 相似文献
18.
Dallavalle S Merlini L Beretta GL Tinelli S Zunino F 《Bioorganic & medicinal chemistry letters》2004,14(23):5757-5761
Luotonin A is a cytotoxic alkaloid that has been shown to inhibit topoisomerase I via stabilization of the binary complex topoisomerase-DNA in the same fashion as camptothecin. The synthesis and the cytotoxic activity on the lung carcinoma cell line H460 of a series of derivatives of Luotonin A is reported. The compounds inhibit topoisomerase I but show weak cytotoxic activity, thus confirming the peculiarity of ring E of camptothecin for antitumor activity. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2020,30(22):127527
We describe herein the synthesis of a series of carboplatin derivatives with different functional groups at position 3 of the cyclobutane ring. This pharmacomodulation approach aims at facilitating the vectorisation of these analogues, via their subsequent conjugation to a drug delivery system. Five different derivatives bearing a hydroxy, keto, iodo, azido or amino function at position 3 were synthesised. One of these compounds was coupled to a bifunctional maleimide-containing linker. All compounds were tested in vitro for their cytotoxicity on four different cell lines including two platinum-resistant colorectal cancer cell line (SK-OV-3, HCT116, D3E2, D5B7) using an MTS assay. Overall, the tested compounds were up to six times more potent than carboplatin, especially on D5B7 human colorectal cancer cells. We demonstrated that these modifications led to potent analogues which are compatible with conjugation to a drug delivery system. 相似文献
20.
Wakabayashi K Miyachi H Hashimoto Y Tanatani A 《Bioorganic & medicinal chemistry》2005,13(8):2837-2846
We designed and synthesized novel pyrrole-2-carboxamide derivatives as androgen antagonists. Compounds 10 and 13 bearing benzylamine or aniline at the 4-position of the pyrrole ring showed moderate androgen antagonistic activity, and inhibited the androgen-dependent growth of Shionogi carcinoma cells (SC-3). Study of the structure-activity relationships of compound 13 led to a potent androgen antagonist 36, which has higher affinity than flutamide (4) for androgen nuclear receptor (AR). Thus, pyrrole-2-carboxamide is a new scaffold for developing AR antagonists. 相似文献