Anti-cancer drug design最新文献

{"title":"Synthesis and anticancer activity of nordihydroguaiaretic acid (NDGA) and analogues.","authors":"R W McDonald,&nbsp;W Bunjobpon,&nbsp;T Liu,&nbsp;S Fessler,&nbsp;O E Pardo,&nbsp;I K Freer,&nbsp;M Glaser,&nbsp;M J Seckl,&nbsp;D J Robins","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Nordihydroguaiaretic acid (NDGA) 1 is a constituent of the creosote bush Larrea divaricata and is well known to be a selective inhibitor of lipoxygenases. NDGA can also inhibit the platelet derived growth factor receptor and the protein kinase C intracellular signalling family, which both play an important role in proliferation and survival of cancers. Moreover, NDGA induces apoptosis in tumour xenografts. Although it is likely to have several targets of action, NDGA is well tolerated in animals. These encouraging results have prompted interest in the compound for clinical study. However, high concentrations of NDGA are required for efficacy and more potent analogues are required. We have synthesized five analogues of NDGA with different lengths of carbon bridge between the two catechol moieties in order to establish the spacing required for optimum anticancer effect and to compare their activities with NDGA. In order to ascertain if the catechol moieties are essential for anticancer activity, we prepared five analogues of NDGA containing only one hydroxyl group on each aromatic ring. NDGA 1, its racemic form 2, the catechol derivatives 5, 6 with five or six carbon atom bridges and the phenol analogues 8-11 with bridges of three to six carbon atoms all showed similar activity, with IC50 values of approximately 3-5 microM against the H-69 small cell lung cancer cell line. Analogues with shorter (3) or longer bridges (7, 12) were much less active. The most potent analogue was the biscatechol with a four-carbon bridge 4 which was > 10 times more active than NDGA and therefore represents a new lead compound in this area. Surprisingly, the tetramethyl ether 14 of this compound was slightly more active than NDGA, but the trihydroxy analogue 13 was less active than NDGA. The conformationally restricted analogue 15 was also less active than NDGA. In summary, simplification of the structure of NDGA by removal of the methyl groups has produced a new lead compound 4, which is >10 times more potent than NDGA as a proliferative inhibitor of H-69 small cell lung cancer cells.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"16 6","pages":"261-70"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22062732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The inhibition of protein phosphatases 1 and 2A: a new target for rational anti-cancer drug design?","authors":"A McCluskey,&nbsp;S P Ackland,&nbsp;E Gardiner,&nbsp;C C Walkom,&nbsp;J A Sakoff","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Recent investigations in our laboratories have highlighted that the inhibition of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A) is an excellent target for the development of novel anti-cancer agents. Using a combination of the known crystal structure of PP1 and the modelled structure of PP2A, we have rationally designed a new class of protein phosphatase inhibitors, cantharimides, which exhibit broad-spectrum anti-cancer activity. Synthetic modifications of the simplest known PP1 and PP2A inhibitor, norcantharidin, has led to the development of potent PP1 and PP2A inhibitors.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"16 6","pages":"291-303"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22062735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linker length in podophyllotoxin-acridine conjugates determines potency in vivo and in vitro as well as specificity against MDR cell lines.","authors":"L Rothenborg-Jensen,&nbsp;H F Hansen,&nbsp;I Wessel,&nbsp;J L Nitiss,&nbsp;G Schmidt,&nbsp;P B Jensen,&nbsp;M Sehested,&nbsp;L H Jensen","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We have synthesized two podophyllotoxin-acridine conjugates-pACR6 and pACR8. In these compounds an 9-acridinyl moiety is beta linked to the C4 carbon of the four ring system in 4'-demethylepipodophyllotoxin (epiDPT) via eighter an N-6-aminohexanylamide linker (pACR6) or via an N-8-aminooctanylamide linker containing two more carbon atoms (pACR8). The acridine-linker moiety occupies the position where different glucoside moieties, dispensable for activity, are normally linked to epiDPT in the well known epipodophyllotoxins VP-16 and VM-26. As with VP-16 and VM-26, pACR6 and pACR8 show evidence of being topoisomerase II poisons as they stimulate topoisomerase II mediated DNA cleavage in vitro and induce DNA damage in vivo. This in vivo DNA damage, as well as pACR6/pACR8 mediated cytotoxicity, is antagonized by the catalytic topoisomerase II inhibitors ICRF-187 and aclarubicin, demonstrating that topoisomerase II is a functional biological target for these drugs. Despite their structural similarities, pACR6 was more potent than pACR8 in stimulating topoisomerase II mediated DNA cleavage in vitro as well as DNA damage in vivo and pACR6 was accordingly more cytotoxic towards various human and murine cell lines than pACR8. Further, marked cross-resistance to pACR6 was seen among a panel of multidrug-resistant (MDR) cell lines over-expressing the MDR1 (multidrug resistance protein 1) ABC drug transporter, while these cell lines remained sensitive towards pACR8. pACR8 was also capable of circumventing drug resistance among at-MDR (altered topoisomerase II MDR) cell lines not over-expressing drug transporters, while pACR6 was not. Two resistant cell lines, OC-NYH/pACR6 and OC-NYH/pACR8, were developed by exposure of small cell lung cancer (SCLC) OC-NYH cells to gradually increasing concentrations of pACR6 and pACR8, respectively. Here, OC-NYH/pACR6 cells were found to over-express MDR1 and, accordingly, displayed active transport of 3H-labeled vincristine, while OC-NYH/pACR8 cells did not, further suggesting that pACR6, but not pACR8, is a substrate for MDR1. Our results show that the spatial orientation of podophyllotoxin and acridine moieties in hybrid molecules determine target interaction as well as substrate specificity in active drug transport.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"16 6","pages":"305-15"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22062130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photokilling of cultured tumour cells by the porphyrin derivative CF3.","authors":"A Villanueva,&nbsp;E N Durantini,&nbsp;J C Stockert,&nbsp;S Rello,&nbsp;R Vidania,&nbsp;M Cañete,&nbsp;A Juarranz,&nbsp;R Arranz,&nbsp;V Rivarola","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We have analysed the photosensitizing properties of the new porphyrin 5-(4-N-(N-2',6'-dinitro-4'-trifluoromethylphenyl)aminophenyl)-10,15,20-tris(2,4,6-trimethoxyphenyl) porphyrin (CF3) on HeLa cells. The fluorescence and singlet oxygen quantum yield for CF3 were, respectively, phiF = 0.032 and phidelta = 0.25. Cell treatments were done with 5 x 10(-6) M CF3 incorporated into liposome vesicles. Under violet-blue exciting light, the red fluorescence of CF3 was mainly detected in lysosome-like granules. No dark cytotoxicity was observed using high concentration (5 x 10(-6) M) and long incubation time (18 h). Cell cultures treated for 18 h with CF3 and exposed to light (360 < lambda < 460 nm; 8 mW/cm2) for 7 min revealed a great amount of apoptotic (75.8%) and detached cells (62%) 8 h later, leading to a cell lethality of 85% (LD85). Apoptosis was identified by chromatin fragmentation and DNA ladder in gel electrophoresis. Necrotic cells were found using 15 min irradiation (LD96) and showed first small and then giant bubbles at the cell surface, with homogeneous nuclear condensation. Incubation with CF3 for 3 h followed by 7 min irradiation (LD38) produced a mitotic arrest 18 h later (mitotic index: 25.1%). Forty-eight hours after this metaphase blockage, cultures showed a great number of apoptotic cells. Taking into account these results, CF3 could be a valuable photosensitizer for the photodynamic therapy of cancer.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"16 6","pages":"279-90"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22062734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Topoisomerase I/II selectivity among derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA).","authors":"D J Bridewell,&nbsp;G J Finlay,&nbsp;B C Baguley","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride) has high experimental antitumor activity and has completed phase I/II clinical trials. It targets both topoisomerase (topo) I and II, but the roles of each of these enzymes in the antitumour action of DACA are not known. We have used a series of DACA analogues (mainly monosubstituted halogen derivatives) to relate in vitro and in vivo biological activity. We measured topo II selectivity by comparing the inhibition of Jurkat human leukaemia cell lines with high and low topo II content. We determined survival curves following exposure of H460 human lung carcinoma cells for 1 h. We used plasmid DNA to compare the effects of DACA analogues on isolated topo I and II, measuring in particular the inhibition of topo I- and II-mediated DNA relaxation. The results indicate that 5-halogen substituted derivatives are the most active in clonogenic cytotoxicity assays and that this activity is related to their selective activity towards Jurkat cells with high topo II activity. In isolated topo assays, 5-halogen substituted derivatives were also the most potent and in each case the concentration required for inhibition of topo II relaxation was greater than that for inhibition of topo I relaxation. The drug concentration providing efficient cytotoxicity corresponded to that which suppressed the activity of topo I but not of topo II. We hypothesize that DACA analogues act both in vitro and in vivo to simultaneously poison topo II and inhibit topo I catalytic activity, and that this combination contributes to the high antitumour activity of DACA analogues.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"16 6","pages":"317-24"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22062131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclohexylamino-demethoxy-hypocrellin B and photodynamic therapy decreases human cancer in vitro.","authors":"S Xu,&nbsp;S Chen,&nbsp;M Zhang,&nbsp;T Shen,&nbsp;Z Liu,&nbsp;Y Zhao,&nbsp;Y Wu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>2-Cyclohexylamino-2-demethoxy-hypocrellin B (CHAHB) is a new photosensitizer synthesized by the mild reaction between hypocrellin B (HB) and cyclohexylamine, in which the peri-hydroxylated perylenequinone structure of the parent HB is preserved and the photoresponse is enhanced markedly. Electron paramagnetic resonance (EPR) spin trapping measurements and 9,10-diphenylanthracene (DPA) bleaching studies were employed to investigate the photodynamic action of CHAHB in the presence of oxygen. Singlet oxygen ((1)O2) and superoxide anion radical (O2*-) generated by illuminating CHAHB in aerobic solution have been observed. Compared with HB, CHAHB distinctly enhanced the O2(*-)-generating abilities, although (1)O2-generating abilities were lowered. The photodynamic action of CHAHB in the therapy of cancer was investigated in vitro. The results in vitro revealed a much more significant decrease in cancer cell growth than with HB. Laser or dye alone had no effect, indicating that intratumor CHAHB and laser therapy may prove useful in unresectable cancer.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"16 6","pages":"271-7"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22062733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antineoplastic agents 429. Syntheses of the combretastatin A-1 and combretastatin B-1 prodrugs.","authors":"G R Pettit,&nbsp;J W Lippert","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The original synthesis of combretastatin A-1 (1) was modified to allow an efficient scale-up procedure for obtaining this anti-neoplastic stilbene. Subsequent conversion to a useful prodrug was accomplished by diphosphorylation (to 10), with in situ formation of dibenzylchlorophosphite, followed by cleavage of the benzyl ester protecting groups with trimethyliodosilane. The phosphoric acid intermediate was treated with sodium methoxide to complete a practical route to the sodium phosphate prodrug (4). Selective hydrogenation of phosphate 10 and treatment of the product with sodium methoxide led to combretastatin B-1 prodrug (5). The phosphoric acid precursor of prodrug 4 was employed in a parallel series of reactions to produce a selection of metal and ammonium cation prodrug candidates. Each of the phosphate salts was evaluated from the perspective of relative solubility behavior and cancer cell growth inhibition. The sodium phosphate prodrug of combretastatin A-1 (4) was selected for detailed antineoplastic studies.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 3","pages":"203-16"},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21877054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimetastatic and antitumor effects of 2,4-diamino-6-(pyridine-4-yl)-1,3,5-triazine (4PyDAT) on the high lung metastatic colon 26 tumor in mice.","authors":"M Maeda,&nbsp;M Ligo,&nbsp;H Tsuda,&nbsp;H Fujita,&nbsp;Y Yonemura,&nbsp;K Nakagawa,&nbsp;Y Endo,&nbsp;T Sasaki","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The therapeutic potential of a diaminotriazine, 2,4-diamino-6-(pyridine-4-yl)-1,3,5-triazine (4PyDAT), was investigated in a metastatic model using the mouse colon 26 carcinoma variant (Co26Lu), which preferentially metastasizes to the lung of mouse. The compound had a moderate antimetastatic activity as well as antitumor activity, without toxicity to the host, when administered orally. In the cytotoxicity test in vitro, 4PyDAT showed very weak direct cytotoxicity against the Co26Lu cell line, Co26Lu(F55) (IC50 < or = 1000 microM). Less microcapiral formation on tumors were observed for the treated group with a hemorrhage than the control group under microscopy. 4PyDAT significantly inhibited the production of urokinase-type plasminogen activator (u-PA) in Co26Lu(F55) cells. These results suggest that the antimetastatic and antitumor activities of 4PyDAT are due in part to inhibition of angiogenesis, rather than direct antiproliferative action on the tumor cells. 4PyDAT may become a lead compound to develop antitumor triazine derivatives based on antiangiogenic action.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 3","pages":"217-23"},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21876972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photosensitization of pancreatic tumour cells by delta-aminolaevulinic acid esters.","authors":"C J Whitaker,&nbsp;S H Battah,&nbsp;M J Forsyth,&nbsp;C Edwards,&nbsp;R W Boyle,&nbsp;E K Matthews","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A series of straight chain, branched and cyclo-delta-aminolaevulinic acid (ALA) esters have been synthesized and their photosensitizing properties analysed using an in vitro system of rat pancreatoma cells. Structurally favourable ALA esters not only induced the formation of more of the endogenous photosensitizer, protoporphyrin IX (PpIX), but they did so at a faster rate than ALA itself. This action was reflected in a substantial increase in photocytotoxicity of some 270 times, using the more potent ALA esters. An important structural feature was identified in two of the ALA esters which greatly limited PpIX production, i.e. a branch point located next to the site of ester cleavage. Experiments on the transport of ALA and of ALA esters across the cell membrane showed that ALA, but not ALA esters, gain access to the cell via the di- and tripeptide transporter, PEPTI. Finally, these results show that the esterification of ALA can greatly increase its cellular uptake, so generating more intracellular PpIX, improved tumour cell photosensitization and enhanced photocytotoxicity.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 3","pages":"161-70"},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21877050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adriamycin-induced inhibition of mitochondrial-encoded polypeptides as a model system for the identification of hotspots for DNA-damaging agents.","authors":"R A Sharples,&nbsp;C Cullinane,&nbsp;D R Phillips","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>It has recently been shown that the anti-cancer drug Adriamycin forms drug-DNA adducts which function as 'virtual' interstrand cross-links in cells, and these cross-links are specific for GpC sequences. The objective of this work was to determine whether all GpC sites are equally susceptible to the formation of Adriamycin-DNA adducts in the mitochondrial genome or whether any 'hotspots' exist whereby lesions are formed preferentially at particular GpC-containing sequences. The mitochondrial genome was used as a model system as it provides a series of contiguous genes, all of which lack introns and in which transcription is driven from a single promoter. With the absence of nucleotide excision repair, this provides an excellent system with which to observe Adriamycin-induced DNA damage since such lesions are reflected as an inhibition of mitochondrial protein synthesis. HeLa cells were treated with Adriamycin and the extent to which synthesis of individual mitochondrial-encoded proteins was inhibited was quantitated. Mitochondrial protein synthesis was found to be inhibited in a discontinuous manner, corresponding to regions rich in 5'-GpC sequences. These results therefore indicate that Adriamycin-DNA adducts do not form randomly with GpC sites throughout the mitochondrial genome, but instead appear to form preferentially at regions of high GpC content. This selective inhibition of mitochondrial-encoded proteins demonstrates the potential of this method for the in situ detection of localized regions of binding by DNA-acting drugs.</p>","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 3","pages":"183-90"},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21877052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}