Biomedical subjects

J Guan

Publications and source records attributed to J Guan.

At least 19 recordsLinked to original sources

PubMed2000

Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4beta-amino-4'-O-demethylepipodophyllotoxin conjugates.

Two compounds having a camptothecin (CPT) analog conjugated to the 4beta-amino-4'-O-demethylepipodophyllotoxin analog were evaluated for their biochemical and biological activities. W1[camptothecin-(para)-4beta-amino-4'-O-demethylepipodophyllotoxin] had no activity against topoisomerase II (TOP II), but inhibited topoisomerase I (TOP I) with an IC(50) value 2-fold higher than CPT. W2 [camptothecin-(ortho)-4beta-amino-4'-O-demethylepipodophyllotoxin] had inhibitory activity against TOP I and TOP II with IC(50) values 1.5-fold higher than either CPT or etoposide (VP-16). Both conjugates had similar cytotoxicity against the KB cell line, although the protein-linked DNA breaks (PLDBs) generated by W2 in KB cells were about 4-fold more than those of W1. No cross-resistance with the two conjugates was seen in a VP-16-resistant KB subline, which showed down-regulation of TOP II and overexpression of the multiple drug resistance-associated protein, or in a vincristine-resistant KB subline with overexpression of gp-170/mdr-1. The CPT-resistant KB variant (KB CPT 100), which has a reduction in TOP I content and another mechanism that occurs post-PLDB formation, was partially resistant to both compounds. W1 was not affected by this post-PLDB resistance mechanism. Cell cycle analysis demonstrated that W1 and W1 had similar cell cycle effects on KB and KB CPT 100 cells, which accumulated in S-phase upon drug treatment. These results suggested that W1 and W2 exerted their cytotoxicity through TOP I. In CPT-resistant cells, however, an unidentified target also may be involved in the cytotoxic action of W1 and TOP II may still be a target for W1. In vivo, W1 was more effective against the growth of human prostate cancer cells in nude mice than VP-16, CPT, or W2. Given its antitumor activity and unique biochemical mechanism of action, W1 warrants exploration as an antitumor compound.

Animals↗

PubMed2000

The catalytic subunit DNA-dependent protein kinase (DNA-PKcs) facilitates recovery from radiation-induced inhibition of DNA replication.

Exposure of cells to ionizing radiation inhibits DNA replication in a dose-dependent manner. The dose response is biphasic and the initial steep component reflects inhibition of replicon initiation thought to be mediated by activation of the S-phase checkpoint. In mammalian cells, inhibition of replicon initiation requires the ataxia telagiectasia mutated ( ATM ) gene, a member of the phosphatidyl inositol kinase-like (PIKL) family of protein kinases. We studied the effect on replicon initiation of another member of the PI-3 family of protein kinases, the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) by measuring either total DNA synthesis, or size distribution of nascent DNA using alkaline sucrose gradient centrifugation. Exposure of human cells proficient in DNA-PKcs (HeLa or M059-K) to 10 Gy inhibited replicon initiation in a time-dependent manner. Inhibition was at a maximum 1 h after irradiation and recovered at later times. Similar treatment of human cells deficient in DNA-PKcs (M059-J) inhibited replicon initiation to a similar level and with similar kinetics; however, no evidence for recovery, or only limited recovery, was observed for up to 8 h after irradiation. In addition a defect was observed in the maturation of nascent DNA. Similarly, a Chinese hamster cell line deficient in DNA-PKcs (irs-20) showed little evidence for recovery of DNA replication inhibition up to 6 h after irradiation, whereas the parental CHO cells showed significant recovery and an irs-20 derivative expressing the human DNA-PKcs complete recovery within 4 h. Normal kinetics of recovery were observed in xrs-5 cells, deficient in Ku80; in 180BR cells, deficient in DNA ligase IV; as well as XR-1 cells, deficient in XRCC4, an accessory factor of DNA ligase IV. Since all these cell lines share the DNA double strand break rejoining defect of M059-J and irs20 cells, the lack of recovery of DNA replication in the latter cells may not be attributed entirely to the prolonged presence of unrepaired DNA dsb. We propose that DNA-PKcs, in addition to its functions in the rejoining of DNA dsb and in DNA replication, also operates in a pathway that in normal cells facilitates recovery of DNA replication after irradiation.

Animals↗

PubMed2000

Intracerebral transportation and cellular localisation of insulin-like growth factor-1 following central administration to rats with hypoxic-ischemic brain injury.

Insulin-like growth factor-1 (IGF-1) has been shown to be neuroprotective when administered centrally following hypoxic-ischemic (HI) brain injury. However, the cerebral distribution and site of action of IGF-1 after intracerebroventricular (i.c.v.) administration are not known. A unilateral HI brain injury was induced in adult rats by a modified Levine method. Either 3H-IGF-1 alone, or in combination with unlabelled IGF-1, was administered into the lateral ventricle 2 h after injury. The activity of 3H-IGF-1 signal in the potentially injured cortex was compared between two treatment groups using image analysis. The regional distribution and cellular localisation of 3H-IGF-1 were examined autoradiographically in potentially injured hemispheres at 0.5 and 6 h after administration. Tritiated IGF-1 was detected predominantly in the pia mater, perivascular spaces and subcortical white matter tracts 0.5 h after administration and decreased by 6 h (p<0.05). The signals associated with the perivascular spaces and pia mater were not blocked by unlabelled IGF-1, suggesting non-saturable binding in these brain areas. IGF-1 signal was co-localised with IGF binding protein (IGFBP)-2 immunostaining in the white matter tracts where the signal was blocked by unlabelled IGF-1, suggesting competitive association. IGF-1 signal associated with neurons and glia was maximal in the cerebral cortex and less in the CA1-2 subregion of the hippocampus which were blocked by unlabelled IGF-1 (p<0.05). The signals from cortical neurons did not decrease 6 h after administration, suggesting specific and persistent binding to these cells. Our results indicate that centrally administered IGF-1 can be translocated to neurons and glia via the perivascular circulation and the ependymal cell-white matter tract pathways.

Animals↗

PubMed2000

Degradation of heterotrimeric Galpha(o) subunits via the proteosome pathway is induced by the hsp90-specific compound geldanamycin.

One mechanism utilized by cells to maintain signaling pathways is to regulate the levels of specific signal transduction proteins. The compound geldanamycin (GA) specifically interacts with heat shock protein 90 (hsp90) complexes and has been widely utilized to study the role of hsp90 in modulating the function of signaling proteins. In this study, we used GA to demonstrate that levels of heterotrimeric Galpha subunits can be regulated through interactions with hsp90. In a dose-dependent manner, GA significantly reduced the steady state levels of endogenous Galpha(o) expression in two cell lines (PC12 and GH3) and had a similar effect on Galpha(o) transiently expressed in COS cells. Galpha(o) synthesis and degradation was studied in PC12 cells and in transiently transfected COS cells. (35)S labeling followed by immunoprecipitation demonstrated no effect of GA on the rate of Galpha(o) synthesis, but GA accelerated degradation of Galpha(o) in both PC12 cells and COS cells. The use of inhibitors, including lactacystin (a proteosome-specific inhibitor), suggests that Galpha(o) is predominantly degraded through the proteosome pathway. In vitro translated (35)S-labeled Galpha(o) could be detected in hsp90 immunoprecipitates, and this interaction did not require N-terminal myristoylation. Taken together, these results suggest that heterotrimeric Galpha(o) subunits are protected from degradation by interaction with hsp90 and that the interaction of Galpha subunits with heat shock proteins may be a general mechanism for regulating Galpha levels in the cell.

Animals↗

PubMed2000

Selective neuroprotective effects with insulin-like growth factor-1 in phenotypic striatal neurons following ischemic brain injury in fetal sheep.

Severe perinatal asphyxia can lead to injury and dysfunction of the basal ganglia. Post insult administration of insulin-like growth factor-1 is neuroprotective, particularly in the striatum. Insulin-like growth factor-1 is also known to be a neuromodulator of several types of striatal neurons. The striatum comprises various phenotypic neurons with a complex neurochemical anatomy and physiology. In the present study, we examined the specificity of neuronal rescue with insulin-like growth factor-1 on different striatal neurons. Bilateral brain injury was induced in near term fetal sheep by 30 min of reversible carotid artery occlusion. A single dose of 3 microg of insulin-like growth factor-1 was infused over 1 h into the lateral ventricle 90 min following ischemia. The histological and immunohistochemical outcome were examined after 4 days recovery using paraffin tissue preparations. Insulin-like growth factor-1 treatment (n = 11) significantly reduced the percentage of neuronal loss in the striatum compared with the vehicle treated group (n = 10, 28.3+/-5.1% vs 55.5+/-17.3%, P < 0.005). Immunohistochemical studies showed that ischemia resulted in a significant loss of calbindin-28kd, choline acetyltransferase, parvalbumin, glutamate acid decarboxylase, neuronal nitric oxide synthase and neuropeptide Y immunopositive neurons, compared with sham controls. Insulin-like growth factor-1 markedly prevented the loss of calbindin-28kd (n = 7, P < 0.05), choline acetyltransferase (n = 7, P < 0.05), neuropeptide Y (n = 7, P < 0.05), neuronal nitric oxide synthase (n = 8, P < 0.05) and glutamate acid decarboxylase (n = 9, P < 0.05) immunopositive neurons, but failed to protect parvalbumin (n = 6) immunopositive neurons. The present study indicates that the therapeutic effect of insulin-like growth factor-1 in the basal ganglia is selectively associated with cholinergic and some phenotypic GABAergic neurons. These data suggest a potential role for insulin-like growth factor-1 in preventing cerebral palsy due to perinatal asphyxia.

Animals↗

PubMed1999

Characterization of the mouse von Willebrand factor promoter.

Expression of the von Willebrand factor (vWF) gene is restricted to the endothelial and megakaryocyte lineages. Within the endothelium, expression of vWF varies between different vascular beds. We have previously shown that the human vWF promoter spanning a region between -2182 (relative to the start site of transcription) and the end of the first intron contains information for environmentally responsive, vascular bed-specific expression in the heart, skeletal muscle, and brain. In the present study, we cloned the mouse vWF (mvWF) promoter and studied its function in cultured endothelial cells and transgenic mice. In transient transfection assays, the mvWF gene was found to be regulated by distinct mechanisms in different endothelial cell subtypes. In independent lines of transgenic mice, an mvWF promoter fragment containing DNA sequences between -2645 and the end of the first intron directed endothelial cell-specific expression in the microvascular beds of the heart, brain, and skeletal muscle as well as the endothelial lining of the aorta. In 1 line of mice, reporter gene activity was also detected in bone marrow megakaryocytes. Taken together, these findings suggest that both the mouse and human vWF promoters are regulated by vascular bed-specific mechanisms.

Animals↗

PubMed1999

Repair of DNA double-strand breaks and radiosensitivity to killing in an isogenic group of p53 mutant cell lines.

PURPOSE: Accumulation of the p53 protein can result in G1 arrest that may facilitate DNA repair, or alternatively, it may lead to apoptosis. Mutations that alter p53's ability to mediate these responses are expected to alter cell radiosensitivity to killing. However, the relationship between p53 status and cell radiosensitivity has proven to be complex. Several studies have suggested that p53 mutations are associated with increased radioresistance to killing, while others have shown no such correlation. These differences may be derived from the fact that different mutations of p53 exert different effects on cell radiosensitivity. METHODS AND MATERIALS: To address this question, we examined a group of isogenic cell lines that express different "hot spot" mutant forms of p53. These cells were generated from human osteosarcoma (SAOS) cells, a p53 null cell line, by transfection with vectors expressing different p53 mutants. Vectors with the following p53 mutations were utilized: 143Ala, 175His, 248Try, 273His, and 281Gly. As controls, we used the original SAOS cells and cells transfected with the vector alone. Results were compared to those obtained with a cell line expressing wild-type p53 (wt p53). Radiosensitivity to killing was determined in the exponential phase of growth by measuring loss of colony-forming ability. Induction and repair of DNA double-strand breaks (dsb) was measured in irradiated cells using pulsed-field gel electrophoresis. Apoptosis was assessed using morphologic evaluation of DAPI-stained cells after treatment either with radiation or paclitaxel. RESULTS: Transfected SAOS-2 cell lines expressed a mutant form of p53 that could not be induced by radiation, and which was transcriptionally inactive. Among the 7 cell lines studied, we observed no difference in cellular radiosensitivity to killing (p = NS). When examining DNA repair, no difference in either the induction or repair of DNA dsb was noted in any of the cell lines studied (p = NS). Also, induction of apoptosis, either after exposure to radiation or paclitaxel, was low, and similar in all cell lines (p = NS). Non-isogenic cells expressing wt p53 were more radioresistant to killing by radiation, but showed similar kinetics of dsb rejoining. CONCLUSION: The results suggest that expression of different p53 mutants does not alter the yields of radiation-induced dsb, or the ability of cells to repair this type of lesion. In addition, the same p53 mutants do not affect cellular radiosensitivity to killing, or the induction of apoptosis after exposure to radiation or paclitaxel.

Apoptosis↗

PubMed1999

Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles.

As a continuation of our structure-activity relationship studies, several new 4-beta-substituted 4'-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, or trisubstituted anilines have been synthesized and evaluated as inhibitors of DNA topoisomerase II and tumor cell growth in tissue culture. Selected compounds were further evaluated as cytotoxic agents using a clonogenic survival assay. The target compounds include 4'-O-demethyl-4beta-[(4' '-(benzimidazol-2' '-yl)anilino]-4-desoxypodophyllotoxin (21), 4'-O-demethyl-4beta-(-)-(4' '-camphanamido-anilino)-4-desoxypodophyllotoxin (25), 4-beta-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxins (18-20, 26), 4-alpha-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxin (27), 4-beta-trisubstituted-anilino-4'-demethyl-desoxypodophyllotoxin (22, 23), and 4'-O-demethyl-4beta-[4' '-(benzimidazol-2' '-yl)amino]-4-desoxypodophyllotoxin (24). Among the target series, 19, 21, and 24 displayed significant growth inhibitory action against a panel of tumor cell lines including human epidermoid carcinoma of the nasopharynx (KB) and its etoposide-resistant (KB7B) and vincristine-resistant (vin20c KB) subclones, lung carcinoma (A549), human ileocecal carcinoma (HCT-8), human kidney carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), and human malignant melanoma (SK-MEL-2) cells. Compounds 19, 21, 24, and 25 were "cleavable-complex"-forming DNA topoisomerase II inhibitors with either improved or similar activity compared with the prototype drug etoposide (VP-16). Compound 21 was the most active analogue, being 10-fold more potent than etoposide in both cell killing and topoisomerase II inhibition in vitro assays. Using mouse models of antitumor activity, 21 was effective against (P388/0) leukemia but not against the growth of a (MCF7) mammary tumor.

Animals↗

PubMed1999

Neuroprotective effects of Gly-Pro-Glu, the N-terminal tripeptide of IGF-1, in the hippocampus in vitro.

Insulin-like growth factor 1 (IGF-1) plays a critical role in CNS development. IGF-1 can block neuronal apoptosis in vitro and in vivo. IGF-1 is thought to be cleaved into des-N-(1-3)-IGF-1 and an amino terminal glycine-proline-glutamate (GPE tripeptide). Here we report a neuroprotective role for GPE tripeptide, with enhanced survival of the CA1-2 hippocampal neurons following an excitotoxic insult in vitro. Binding and displacement studies suggest uniquely distributed sites of action within the rat including the hippocampal CA1-2, pyriform cortex, amygdala, choroid plexus, blood vessels and to a lesser extent in the cortical regions. A similar pattern of binding was seen in the human. This finding could lead to new strategies to reduce neuronal death after injury and in disease.

Animals↗

PubMed1999

Melanocortin-4 receptor messenger RNA expression is up-regulated in the non-damaged striatum following unilateral hypoxic-ischaemic brain injury.

Melanocortin peptides (alpha-melanocyte-stimulating hormone, adrenocorticotropin and fragments thereof) have been shown to have numerous effects on the central nervous system, including recovery from nerve injury and retention of learned behaviour, but the mechanism of action of these peptides is unknown. A family of five melanocortin receptors have recently been discovered, two of which (melanocortin-3 and melanocortin-4 receptors) have been mapped in the rat brain. We have tested the hypothesis that the expression of one or more of the messenger RNAs for three melanocortin receptors (melanocortin-3, melanocortin-4 and melanocortin-5 receptors) would be altered in rat brain following unilateral transient hypoxic-ischaemic brain injury. In this study, using in situ hybridization, we show that melanocortin-4 receptor messenger RNA was up-regulated in the striatum in the non-damaged hemisphere within 24 h after severe hypoxic-ischaemic injury compared with control brains (P<0.05). In a small group of animals, this induction was not blocked by treatment with the anticonvulsant, carbamazepine. Expression of melanocortin-3 receptor messenger RNA in the brain was not altered in this hypoxic-ischaemic injury model and melanocortin-5 receptor messenger RNA was not detected in either control or hypoxic-ischaemic injured rat brains. We hypothesize that the up-regulation of melanocortin-4 receptor messenger RNA expression in the contralateral striatum may be involved in transfer of function to the uninjured hemisphere following unilateral brain injury.

Animals↗

PubMed1999

The effects of the N-terminal tripeptide of insulin-like growth factor-1, glycine-proline-glutamate in different regions following hypoxic-ischemic brain injury in adult rats.

Insulin-like growth factor-1 has pleiotropic effects in the central nervous system and can act both as a survival and a differentiation factor. Insulin-like growth factor-1 can be proteolytically cleaved into des-N-(1-3)-insulin-like growth factor-1 and a N-terminal tripeptide fragment, glycine-proline-glutamate. Both insulin-like growth factor-1 and des-N-(1-3)-insulin-like growth factor-1 can improve neuronal survival after hypoxic-ischemic brain injury in vivo. The present study investigates the effects of glycine-proline-glutamate on different brain regions and neuronal populations after hypoxic-ischemic injury. Unilateral hypoxic-ischemic injury was induced in adult rats. Glycine-proline-glutamate (3 microg) was administered centrally 2 h after the injury and the extent of brain damage determined five days later. In a separate trial immunohistochemical techniques were used to determine the effects of glycine-proline-glutamate on specific populations of neurons in the striatum after the injury. Compared to the vehicle treatment, glycine-proline-glutamate (n=19) treatment reduced the extent of cortical damage and neuronal loss in the CA1-2 subregions of the hippocampus (P<0.05). In the striatum, there was a trend towards a reduction in neuronal loss after glycine-proline-glutamate treatment (P=0.053) compared to the vehicle (n=21)-treated animals. In a separate study, glycine-proline-glutamate (n=8) treatment prevented the loss of choline acetyltransferase (P<0.05), glutamate acid decarboxylase (P<0.05) and somatostatin (P<0.05) containing neurons in the ipsilateral striatum following hypoxic-ischemic brain injury and also increased the numbers of neuronal nitric oxide synthase (P<0.05) containing neurons in the contralateral side. These studies suggest that in addition to neuroprotective effects, glycine-proline-glutamate can influence neuronal activity after hypoxic-ischemic injury.

Animals↗

PubMed1999

A vascular bed-specific pathway.

The endothelial nitric oxide synthase (eNOS) gene is induced by a variety of extracellular signals under both in vitro and in vivo conditions. To gain insight into the mechanisms underlying environmental regulation of eNos expression, transgenic mice were generated with the 1,600-bp 5' flanking region of the human eNos promoter coupled to the coding region of the LacZ gene. In multiple independent lines of mice, transgene expression was detected within the endothelium of the brain, heart, skeletal muscle, and aorta. beta-galactosidase activity was consistently absent in the vascular beds of the liver, kidney, and spleen. In stable transfection assays of murine endothelial progenitor cells, the 1,600-bp promoter region was selectively induced by conditioned media from cardiac myocytes, skeletal myocytes, and brain astrocytes. Cardiac myocyte-mediated induction was partly abrogated by neutralizing anti-platelet-derived growth factor (PDGF) antibodies. In addition, promoter activity was upregulated by PDGF-AB. Analysis of promoter deletions revealed that a PDGF response element lies between -744 and -1,600 relative to the start site of transcription, whereas a PDGF-independent cardiac myocyte response element is present within the first 166 bp of the 5' flanking region. Taken together, these results suggest that the eNos gene is regulated in the cardiac endothelium by both a PDGF-dependent and PDGF-independent microvascular bed-specific signaling pathway.

Animals↗

PubMed1999

Apoptosis as a predictor of paclitaxel-induced radiosensitization in human tumor cell lines.

Paclitaxel is a deterpene with antitumor activity against a variety of human neoplasms. Paclitaxel cytotoxicity is thought to derive mainly from a stabilization of microtubules as a result of enhanced tubulin polymerization that leads to an accumulation of cells in the mitotic (M) phase of the cell cycle. Because cells in this phase of the cell cycle are known to be radiosensitive, it was thought that paclitaxel, in addition to its direct toxicity, may also sensitize tumor cell populations to radiation. Studies evaluating the radiosensitizing potential of paclitaxel in cultured cells have been equivocal, with only approximately 50% of the tested cell lines showing radiosensitization. To explain this variability, we advanced the hypothesis that the ability of paclitaxel to radiosensitize cells may be inversely correlated to the efficiency with which it induces apoptosis. To test this hypothesis, we studied paclitaxel-induced apoptosis and radiosensitization in seven human tumor cell lines. Approximately one-half of these cell lines showed radiosensitization that was associated with a low apoptotic index (<20% after a 48-h treatment with 10 or 20 nM paclitaxel). The results suggest that the level of apoptosis, after paclitaxel treatment, may predict for paclitaxel-induced radiosensitization, and that it could be introduced as a parameter for the optimization of combined treatment protocols.

Antineoplastic Agents, Phytogenic↗

PubMed1998

SAR studies of diaryltriazoles against bacterial two-component regulatory systems and their antibacterial activities.

A series of diaryltriazole analogs was discovered to inhibit bacterial two-component regulatory systems in our primary assays, KinA/Spo0F and NRII/NRI. They also showed inhibitory activity in whole cell mechanism-based assays, and they possessed potent activities against several strains of Gram-positive pathogenic bacteria in the standard MIC broth assay.

Anti-Bacterial Agents↗

PubMed1998

Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity: pharmacophore identification based on the screening hit closantel.

This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic requirements also exist. Closantel (1) was found to inhibit a two-component system and to have antibacterial activity against drug resistant S. aureus and E. faecium.

Anti-Bacterial Agents↗

PubMed1998

Asphyxial brain injury--the role of the IGF system.

Transient neural injuries, such as asphyxia, can trigger considerable delayed neuronal death. Inappropriate induction of apoptosis is thought to play an important role in this process. Our studies have shown marked changes in the IGF system in the brain in response to these injuries with an induction of insulin growth factor (IGF)-1 and insulin growth factor binding protein (IGFBP)-2 and IGFBP-3 in glial cells in the region of injury. This suggests that the IGF-1 system may be an endogenous neuroprotective system. Earlier administration of IGF-1 - 2 h after injury reduced the phase of secondary neuronal loss suggesting that IGF-1 may well have therapeutic potential as a neuronal rescue agent. The action of IGF-1 appears to involve binding proteins, transport to the site of injury and the IGF-1 receptor and inhibition of apoptosis, but might also involve generation of GPE which itself appears to be neuroprotective. Together these results indicate considerable potential of these agents to treat stroke, perinatal asphyxia and other forms of acute brain injury.

Animals↗

PubMed1998

Antitumor agents. 185. Synthesis and biological evaluation of tridemethylthiocolchicine analogues as novel topoisomerase II inhibitors.

Several 1,2,3-tridemethyldeacetylthiocolchicine derivatives have been synthesized and evaluated for cytotoxic activity against various human tumor cell lines and for their inhibitory effects on DNA topoisomerases in vitro. Exhaustive demethylation of thiocolchicine analogues completely changes their biological profiles. Instead of displaying antitubulin activity, most target compounds inhibited topoisomerase II activity. Only compounds with a larger side chain, such as 15a, 23a, and 24a, did not interfere with topoisomerase II enzymatic functions. The cytotoxicity of target compounds was reduced by 3 orders of magnitude compared to that of colchicine in most cell lines. The hydrophilicity of phenolic compounds might prevent drug passage through the cell plasma membrane and, thus, be responsible for the relatively weak cytotoxicity. To test this hypothesis, 27-30 were prepared from 16a by protecting all hydroxy groups with esters with an aim to facilitate drug transportation. In vitro cytotoxicity assays indicated that 27 was more potent than its parent compound in all tested tumor cell lines and showed tissue selective cytotoxicity with a significant inhibitory effect against KB cells (IC50 = 2.7 microg/mL). Therefore, we propose that 27 acts as a prodrug, liberating 16a to exert its antitopoisomerase activity and, finally, to cause cell death.

Antineoplastic Agents↗

PubMed1998

Antitumor agents. Part 186: Synthesis and biological evaluation of demethylcolchiceinamide analogues as cytotoxic DNA topoisomerase II inhibitors.

Demethylation of colchiceinamide (2) and its analogues (3-10) afforded a novel class of mammalian DNA topoisomerase II inhibitors (2a-10a) without displaying tubulin inhibitory activity. All target compounds inhibited the catalytic activity of topoisomerase II at drug concentrations at 100 microM. An in vitro cytotoxicity assay indicated that compounds 3a and 8a were strong and tissue-selective cytotoxic agents against the MCF-7 breast cancer cell line (IC50 = 0.36 and 0.48 microgram/mL, respectively) and the CAKI-1 renal cancer cell line (IC50 = 0.72 and 0.96 microgram/mL, respectively).

Antineoplastic Agents↗