SOD-1 transgenic mice as a model for studies of neuroprotection in stroke and brain trauma.
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Animals↗
Biomedical subjects
S F Chen
Publications and source records attributed to S F Chen.
Activity of DMP 840, a new bis-naphthalimide, on primary human tumor colony-forming units.
BACKGROUND: DMP 840 ((R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]-iso[quinoline-1,3(2H)-dione]dimethane- sulfonate; NSC-D640430) is one in a series of bis-naphthalimides that binds DNA with high affinity and has sequence specificity to multiple G and C bases. It is also a potent inhibitor of RNA synthesis. DMP 840 has been selected for clinical evaluation on the basis of a broad spectrum of activity (including cures) in human tumors in murine models. PURPOSE: We evaluated DMP 840 in a human tumor clonogenic assay to estimate what plasma concentrations may be necessary for clinical cytotoxic activity and to determine what types of tumors potentially might be primary targets for initial phase II studies. METHODS: A soft-agar cloning system assay was used to determine the in vitro effects of DMP 840 against cells from biopsy specimens of colorectal, breast, lung ovarian, renal cell, stomach, and bladder cancers and from other tumor types. A total of 260 human tumor specimens were exposed continuously during the assay to DMP 840; 103 were assessable (20 colonies or more on control plates and 30% or less survival for the positive control). An in vitro response was defined as at least a 50% decrease in tumor colony formation resulting from drug exposure compared with controls. RESULTS: In vitro responses were seen in 10% (one of 10), 54% (55 of 101), 80% (82 of 103), and 89% (82 of 92) of specimens tested at 0.01, 0.1, 1.0, and 10.0 micrograms/mL of DMP 840, respectively. At a concentration of 0.1 microgram/mL, specific activity was seen against melanoma (80%) and against renal cell (80%), ovarian (63%), breast (54%), non-small-cell lung (42%), and colorectal cancers (33%). DMP 840 demonstrated activity in tumor specimens resistant in vitro to methotrexate (88%), doxorubicin (58%), platinum (57%), cyclophosphamide (53%), vinblastine (53%), etoposide (53%), fluorouracil (37%), and paclitaxel (36%). CONCLUSIONS: At in vitro concentrations of 0.1 microgram/mL as a continuous exposure, DMP 840 has activity against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. IMPLICATIONS: Further clinical development of DMP 840 is warranted.
Antineoplastic Agents↗
Phospholipase C inhibitors: a new class of cytotoxic agents.
A series of nitrocoumarin and nitrochromene derivatives have been prepared and shown to inhibit the phosphatidylinositol-specific phospholipase C(PLC)(IC50 < 10 micrograms/mL) isolated from human melanoma. The inhibition of PLC by nitrocoumarin 4a was time-dependent and irreversible. The inhibition of PLC was shown to interfere with inositide metabolism in whole cells (IC50 = 4 micrograms/mL) in a manner consistent with their proposed mode of activity. Finally, the compounds were shown to be growth inhibitory to cultured melanoma cells (ID50 = 2 micrograms/mL), suggesting that PLC may be an attractive new target for chemotherapeutic intervention.
Animals↗
Mild intraischemic hypothermia suppresses consumption of endogenous antioxidants after temporary focal ischemia in rats.
Oxidative damage by free radicals has been proposed as a mechanism of cerebral injury due to ischemia and reperfusion. Hypothermia protects against ischemic necrosis; however, its effect on oxidative stress has not been investigated. In this study, the effects of hypothermia on oxidative stress were studied by determining consumption of endogenous antioxidants after temporary focal ischemia in rats. Thirty-two Sprague-Dawley rats anesthetized with 1.5% isoflurane underwent 3 h of middle cerebral artery occlusion under hypothermic (33 degrees C) or normothermic (37 degrees C) conditions followed by 3 h of normothermic reperfusion. In the first study (n = 8 per group), intraischemic hypothermia suppressed the reduction of tissue concentrations of endogenous antioxidants, ascorbate (P < or = 0.05), and glutathione (P < or = 0.05) in ischemic cortex but not in caudoputamen. In a parallel study (n = 8 per group), hypothermia reduced tissue damage in ischemic frontoparietal cortex (P < or = 0.05), but not in caudoputamen. Laser-Doppler estimates of cortical blood flow showed that intraischemic hypothermia significantly attenuated early postischemic hyperperfusion (P < or = 0.01) and delayed postischemic hypoperfusion (P < or = 0.01). These results demonstrate that intraischemic mild hypothermia reduces oxidative stress and cell injury after prolonged focal ischemia followed by reperfusion. The reduction of oxidative stress by hypothermia may be related indirectly to attenuation of postischemic blood flow changes.
Animals↗
Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells.
BACKGROUND: The creatine kinase (CK) isozymes and their substrates, creatine and creatine phosphate, are believed to play a pivotal role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, and brain. This enzyme system may also be involved in the process of cellular transformation. Inhibition of tumor cell growth by creatine analogues has been observed and may be due to the ability of these analogues to impair cellular energy generation and utilization. PURPOSE: An in vitro human tumor colony-forming assay was used to predict the clinical usefulness of creatine analogues as anticancer agents. METHODS: The ability of cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) and homocyclocreatine (1-carboxyethyl-2-iminoimidazolidine) to inhibit the growth of cells prepared from tumor samples taken directly from patients was evaluated by quantitative measurement of colony formation in a soft-agar cell culture assay system. Cyclocreatine was tested in this human tumor colony-forming assay at concentrations ranging from 0.067 to 20 mM against 128 tumor samples, 51 of which formed colonies in the assay and were considered evaluable. Homocyclocreatine was similarly tested at concentrations from 0.2 to 20 mM against 139 tumor samples; 54 were considered evaluable. The colony-forming assay was also used to compare the efficacy of the creatine analogues to representatives from the six major classes of standard chemotherapeutics (alkylating agents, antimetabolites, DNA intercalators, platinum compounds, topoisomerase inhibitors, and tubulin-interacting agents). In addition, CK levels were measured in 192 tumor samples that were taken from 166 patients. RESULTS: Cyclocreatine and homocyclocreatine, at concentrations previously achieved in animal tissues (7-20 mM), had antitumor activity against 19% and 50%, respectively, of tumor samples that formed colonies in the assay. Cyclocreatine was effective against a subset of tumors sensitive to homocyclocreatine (P = .023; Fisher's exact test), which was the more potent creatine analogue in this assay (P < .001; McNemar's test). No relationships were seen between tumor samples sensitive to the creatine analogues and those sensitive to standard chemotherapeutics. Pairwise Wilcoxon rank sum tests indicated that CK activity was significantly higher in tumors with any growth in the colony assay compared with tumors that did not grow (P < .025). CONCLUSIONS: The creatine analogues, cyclocreatine and homocyclocreatine, effectively reduced colony formation of freshly explanted human tumor cells. The mechanism of action or resistance to these compounds seems to differ from those of standard chemotherapeutics. IMPLICATIONS: Creatine analogues that may alter the energy status of the tumor cell potentially represent promising new anticancer agents that function through a unique mechanism.
Antineoplastic Agents↗
(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-dione] dimethanesulfonate (DMP 840), a novel bis-naphthalimide with potent nonselective tumoricidal activity in vitro.
(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-dione] dimethanesulfonate (DMP 840), is a bis-naphthalimide anticancer tumoricidal agent currently in phase I clinical trials. DMP 840 exhibits curative activity in human tumor xenografts, where it shows selectivity for human solid tumors over murine leukemias. In contrast to the selectivity found for DMP 840 in vivo, DMP 840 exhibits potent antiproliferative activity in vitro against a variety of human and murine leukemia and solid tumor cell lines in culture, with inhibitory doses that reduce the number of treated cells to one half (IC50) values ranging from 2.3 to 53 nM. DMP 840 was growth inhibitory to three doxorubicin-resistant cell lines with IC50 values also in the nanomolar range. Clonogenic survival experiments showed that DMP 840 was equally cytotoxic to both exponentially growing and quiescent human clone A colon carcinoma cells. A 1-h incubation of DMP 840 (1.22-12 microM) caused 5-log cell kill in KB-3-1 human epidermoid carcinoma, clone A human colon carcinoma, and L1210 murine leukemia cell lines. The rapid cell killing by DMP 840 in clonogenic survival experiments and initial mechanism of action studies was consistent with a DNA-interactive mechanism for DMP 840 cytotoxicity. Mechanism of action studies in L1210 leukemia cells demonstrated that DMP 840 inhibited the incorporation of thymidine and uridine into DNA and RNA with IC50 values of 0.55 and 0.08 microM, respectively. DMP 840 produced DNA single-strand breaks in a dose-dependent manner. Double-strand breaks were not observed with DMP 840 treatment, even at higher concentrations of compound. Chinese hamster ovary (CHO) and P388 cells resistant to camptothecin and containing a mutant form of topoisomerase I were also used to evaluate whether DMP 840 was cross-resistant with agents active against topoisomerase I. While the CHOR line was 163-fold resistant to camptothecin, the CHOR line was only 1.7-fold resistant to DMP 840. In summary, DMP 840 is a DNA-interactive agent that demonstrates excellent antiproliferative activity in vitro against cultured tumor cells from both human and murine sources. Its mechanism of tumoricidal activity may be novel.
Amsacrine↗
Efficacy of DMP 840: a novel bis-naphthalimide cytotoxic agent with human solid tumor xenograft selectivity.
DMP 840, a novel bis-naphthalimide, was evaluated for antitumor efficacy in several tumor models in mice. As measured by a tumor growth inhibition assay, i.v. administration of DMP 840 to athymic nude mice at doses at or below the maximum tolerated dose resulted in curative activity against four human solid tumor xenografts, MX-1 mammary carcinoma, CX-1 and DLD-2 colon adenocarcinomas, and LX-1 lung carcinoma, producing full or incomplete regressions and/or percent tumor growth inhibition of > or = 96%. The efficacy of DMP 840 in the models was dose dependent. The activity of DMP 840 against the human tumors surpassed that demonstrated by several clinically used and investigational anticancer agents. In long-term growth delay studies, DMP 840 induced full regressions in 20 of 20 mice bearing MX-1 tumors, and tumors in one-half of these mice remained regressed for over 5 months. In addition, DMP 840 was curative against exponentially growing DLD-2 tumors staged at 500 mg and MX-1 tumors staged at 1000 mg. The bis-naphthalimide was equally efficacious when administered i.v. or i.p. but was slightly less active after oral dosing. Against both the MX-1 mammary carcinoma and the DLD-2 colon adenocarcinoma, some measure of schedule dependence was observed; the optimum schedule was daily for 9 days. Against L1210 and P388 murine leukemias, DMP 840 demonstrated little or no activity and was inactive against B16 murine melanoma. Overall, these results suggest that DMP 840 may be a human solid tumor selective cytotoxic agent.
Animals↗
Preclinical and phase I trials of topoisomerase I inhibitors.
A total of three topoisomerase I inhibitors, including topotecan, CPT-11 (irinotecan), and intoplicine, have been studied in both preclinical and clinical/clinical pharmacology studies. In in vitro testing against human tumor colony-forming units, all three compounds were significantly more effective when tested as a continuous exposure as compared with a 1-h exposure. The dose-limiting toxicities were different for all three of the agents, with neutropenia and thrombocytopenia being dose-limiting for topotecan; diarrhea, for CPT-11; and hepatotoxicity, for intoplicine. In these phase I studies a number of marginal responses were noted with topotecan; partial and marginal responses, with CPT-11 (particularly in patients with colon cancer); and no response, with intoplicine. The detailed pharmacology of all three agents documented a very short half-life for topotecan, an intermediate half-life for CPT-11, and a prolonged half-life for intoplicine. Based on our experience to date, these compounds (particularly CPT-11) have promise as useful additions to our tremendous therapeutic armamentarium.
Antineoplastic Agents↗
The topography of the furcation entrance in Chinese molars. Furcation entrance dimensions.
The purpose of the present study was to document the furcation entrance dimensions (FEDs) of the maxillary and mandibular 1st and 2nd molars and relate them to the choice of periodontal therapy. Study samples consisted of 89 maxillary molars (49 1st and 40 2nd molars) and 93 mandibular molars (50 1st and 43 2nd molars). All the FEDs of the molars were examined and measured under a stereomicroscope at 2.5 x equipped with a Bioscan OPTIMAS Image Analyzer (BOIA). The results may be summarized as follows. (1) The mean FEDs in the buccal, distal and mesial furcations of maxillary 1st and 2nd molars were 0.74 mm, 0.99 mm and 1.04 mm in the 1st molars, and 0.63 mm, 0.67 mm, 0.90 mm in the 2nd molars, respectively. In the buccal and lingual furcations of mandibular 1st and 2nd molars, they measured 0.88 mm and 0.81 mm, and 0.73 mm and 0.71 mm, respectively. (2) The %s of FEDs of 0.56 mm or less (the tip width of a Cavitron tip being 0.56 mm) in the buccal, distal and mesial furcations of maxillary 1st and 2nd molars, accounted for 32%, 8% and 6% of 1st molars, and 40%, 40% and 18% of 2nd molars. In the buccal and lingual areas of mandibular 1st and 2nd molars, they accounted for 16% and 26%, and 35% and 33% of the furcations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effects of III-IV linker mutations on human heart Na+ channel inactivation gating.
Na+ channel inactivation, a critical determinant of refractoriness, differs in cardiomyocytes and neurons. In rat brain type IIa (rB2a) Na+ channels, a critical residue in the cytoplasmic linker between domains III and IV regulates fast inactivation such that a Phe-->Gln substitution (F1489Q) inhibits inactivation by at least 85%. Since this residue is conserved in voltage-gated Na+ channels, we tested whether F1485Q, the analogous mutation in human heart (hH1a) Na+ channels, has a similar functional effect. We found that fast inactivation in wild-type (WT) channels expressed in Xenopus oocytes was complete within 15 milliseconds at a test potential of 0 mV, and its time course was biexponential with time constants of 0.4 and 2 milliseconds. But in contrast to rB2a, the FQ mutation inhibited inactivation by < 50% and increased mean single-channel open time by only twofold. Residual fast inactivation was monoexponential, with a time constant similar to that of the slower phase of normal inactivation (2 milliseconds). In the mutant channels, unlike WT, null tracings were absent at holding potentials in the range of -140 to -120 mV, and the voltage range of steady-state inactivation coincided exactly with that of activation, suggesting that residual inactivation was tightly coupled to the open state. As in rB2a, simultaneous mutations of I1484Q and M1486Q, in addition to mutation F1485Q, completely inhibited fast inactivation. Our results show that in heart Na+ channels, the IFM cluster controls the stability of both open- and closed-channel inactivation in a manner qualitatively similar to that in the brain. Structural differences in the putative inactivation receptor may explain the distinct gating patterns in channel subtypes.
Amino Acid Sequence↗
Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia.
BACKGROUND AND PURPOSE: We have demonstrated in a previous study that superoxide radicals play a role in the pathogenesis of cerebral infarction, using a transgenic mouse model of distal middle cerebral artery occlusion, permanent ipsilateral cerebral carotid artery occlusion, and 1-hour contralateral cerebral carotid artery occlusion that produced infarction only in the cortex. However, the role of superoxide radicals in reperfusion injury in transgenic mice overexpressing superoxide dismutase (SOD) is unknown. Using a mouse model of intraluminal blockade of middle cerebral artery that produced both cortical and striatal infarction, we now further examined the role of superoxide radicals in ischemic cerebral infarction after reperfusion in transgenic mice overexpressing human CuZn-SOD activity. METHODS: Transgenic mice of strain Tg HS/SF-218, carrying human SOD-1 genes, and nontransgenic littermates were anesthetized with chloral hydrate (350 mg/kg IP) and xylazine (4 mg/kg IP). Physiological parameters were maintained at a normal range using a 30% O2/70% N2O gas mixture inserted via an inhalation mask. Body temperature was maintained at 37 +/- 0.5 degrees C by using a heating pad throughout the studies. The middle cerebral artery occlusion was achieved with a 5-0 rounded nylon suture placed within the internal cerebral artery for 3 hours followed by the removal of the suture to allow reperfusion for another 3 hours. Cerebral infarct size in brain slices and infarct volume, neurological deficit, cortical blood flow, and glutathione levels were measured in both transgenic and nontransgenic mice. RESULTS: Compared with the nontransgenic mice, the infarcted areas were significantly decreased in coronal slices from transgenic mice. The infarct volume (in cubic millimeters) was reduced by 26% in transgenic mice after ischemia and reperfusion. This decrease in the infarct volume in transgenic mice closely paralleled the reduced neurological deficits. Introduction of the suture to block blood supply to the middle cerebral artery territory produced a rapid decrease in the relative surface blood flow in the ipsilateral core and the peri-ischemic (penumbra) areas. There were no significant differences in the local cerebral blood flow in the ischemic core or the penumbra areas between the transgenic and nontransgenic groups. However, the level of reduced glutathione in the penumbra area was significantly higher in transgenic mice than in nontransgenic mice, whereas there was no difference in the reduced glutathione levels in the ischemic core between these two groups. CONCLUSIONS: Our study demonstrated that superoxide radicals play a major role in the pathogenesis of cerebral infarction in reperfusion injury after a focal stroke. The reduction in infarct volume and neurological deficits is not dependent on the changes in cerebral blood flow but rather correlate with reduced oxidative stress in the ischemic brain tissue, which was indicated by the relatively high levels of endogenous reduced glutathione in transgenic mice.
Animals↗
Reduction of vasogenic edema and infarction by MK-801 in rats after temporary focal cerebral ischemia.
Blood-brain barrier permeability alteration, vasogenic brain edema, and infarction, which are more extensive after 3 hours of temporary middle cerebral artery occlusion (MCAO) and 3 hours of reperfusion than after 6 hours of permanent MCAO, develop in rats after prolonged focal cerebral ischemia. Protective effects of excitatory amino acid receptor antagonists have been previously demonstrated after temporary global ischemia and permanent focal ischemia in rats. The purpose of this study was to evaluate the effectiveness of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, in temporary middle cerebral artery occlusion in rats maintained at physiological levels of brain temperature. Rats were anesthetized with chloral hydrate (350 mg/kg, intraperitoneally). The MCAO of rats was occluded by cannulation with a nylon suture for 3 hours, followed by 3 hours of reperfusion accomplished by withdrawing the suture. MK-801 (1 mg/kg, intravenously) or saline (S) was injected immediately before the onset of MCAO. Water content (MK-801, n = 6; S, n = 6), Evans blue dye extravasation (MK-801, n = 6; S, n = 6), infarct volume (MK-801, n = 10; S, n = 10), histology (MK-801, n = 6; S, n = 6), and neurological deficit (MK-801, n = 15; S, n = 18) were measured at the end of 3 hours of reperfusion. Brain temperature was monitored during the experiment. The infarction area (measured by 2, 3, 5-triphenyltetrazolium chloride staining) was reduced (P < 0.001) in the MK-801-treated rats, as was the infarct volume and the severity of neuronal damage (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Effect of electroacupuncture on gastric acid secretion and gut hormones].
21 patients with mild type of chronic superficial gastritis were selected in this study. The effect of electroacupuncture in Zhongwan (RM12), Neiguan (P6) and Sanyinjiao (Sp6) on gastric acid secretion, serum gastrin, plasma somatostatin, plasma motilin concentration and erythrocyte acetylcholinesterase (AchE) activity were observed. The results were as follows: There were significant decreases in gastric acid output, serum gastrin concentration and AchE activity (P < 0.05), but no significant changes in plasma somatostatin and motilin concentration (P > 0.05) after simultaneous electroacupuncture in Zhongwan, Neiguan and Sanyinjiao.
Acetylcholinesterase↗
Three drugs inhibit phospholipase A2-induced high permeability of endothelial monolayers.
The permeability of aortic endothelial monolayers to fluid and albumin increased 13.5 and 16.1 times respectively after pretreatment with phospholipase A2 (PLA2, 100 U.ml-1) for 30 min. 1-(p-Chlorobenzoyl)-5-methylindole-3-acetic acid (1.16 mmol.L-1), SRI 63-441 (30 nmol.L-1), and 1,25-dihydroxycholecalciferol (0.1 mumol.L-1) decreased PLA2-induced high permeability. PLA2 did not damage the endothelial cells significantly. Our results indicate that the action of PLA2 to increase the permeability of endothelial monolayers is mainly due to PLA2-induced lipid mediators released from endothelial cells.
Animals↗
[Effect of Saussurea lappa on gastric functions].
The patients with chronic superficial gastritis were selected in the study. The variation in gastric acidity output, serum gastrin and plasma somatostatin concentration were observed during the Saussurea lappa decoction (SLD) perfusion into the stomach. There was no significant changes in acidity output, serum gastrin and plasma somatostatin concentration after the perfusion of SLD (P > 0.05). Changes in gastric emptying and plasma motilin concentration were observed after oral administration of the SLD in 5 healthy volunteers. The time of gastric emptying was markedly shortened after oral administration of SLD (P < 0.01). A significant increase occurred in plasma motilin concentration at 30 min. after oral administration of SLD (P < 0.01). It revealed that SLD could accelerate the gastric emptying and increase the endogenous motilin release.
Adult↗
Pentoxifylline attenuates platelet activating factor-induced permeable edema in isolated perfused guinea pig lungs.
The effect of pentoxifylline (Pen) on platelet activating factor (PAF)-induced pulmonary injury was studied in isolated guinea pig lungs perfused with cell-free Tris buffered Ringer solution. PAF (1.0 nmol.L-1) increased lung weight and pulmonary filtration coefficient (Kf), which indicated the formation of high permeable pulmonary edema. Pen (0.5 and 1.0 mmol.L-1) markedly attenuated the PAF-induced increment of lung weight and vascular permeability, but not the increment of pulmonary capillary pressure and venous resistance. There was no correlation between the severity of lung edema and the number of leukocytes in the perfusates. These results suggest that Pen has direct anti-permeability effect on pulmonary microvessels.
Animals↗
Rheumatoid factor in hepatitis B virus surface antigen positive patients.
Rheumatoid factor (RF) is often found in the sera of patients with nonrheumatic diseases in comparison with normal individuals. We collected 95 healthy HBs antigen positive adults and 98 healthy HBs antigen negative adults. RF was present in 14.74% (14/95) of the HBs antigen positive group while it was present in 3.06% (3/98) of the HBs antigen negative group (p < 0.05). RF was positive in 15.38% (2/13) of the HBe antigen positive patients whereas it was positive in 14.63% (12/82) of the HBe antigen negative patients (p > 0.05). RF was found positive in 16.90% (12/71) of the anti-HBe antibody positive group while it was positive in 8.33% (2/24) of the anti-HBe antibody negative group (p > 0.05). We conclude that the positive rate of RF in HBs antigen positive patients is significantly higher than in that of HBs antigen negative patients. The incidence of RF positivity of the HBe antigen positive group is not higher than that of the HBe antigen negative group. The positive rate of RF in anti-HBe antibody positive group has a tendency to be higher than in that of their negative counterparts though there was no significant difference between them.
Adult↗
Synthesis and biological evaluation of N4-substituted imidazo- and v-triazolo[4,5-d]pyridazine nucleosides.
The chemical synthesis of certain N4-substituted imidazo[4,5-d]pyridazine and v-triazolo[4,5-d]-pyridazine nucleosides is described. In both series, the 4-chloro analogues, i.e., 4-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazo[4,5-d]pyr idazine (5a) and 4-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-v-triazolo[4,5- d]pyridazine (5b), were used as synthons to the target nucleosides. Nucleoside 5b was far more reactive toward nucleophilic displacements than 5a. Attempted deprotection of 5b was always accompanied with displacement of the 4-chloro substituent, whereas 5a was conveniently deacetylated without loss of the chloro group. Biological evaluation of the title nucleosides included antitumor studies and substrate/inhibition studies with certain purine-metabolizing enzymes. The corresponding adenosine analogues, i.e., 2-aza-3-deazaadenosine (6a) and 2,8-diaza-3-deazaadenosine (6b), were very slowly reacting substrates and weak inhibitors of bovine adenosine deaminase, whereas the inosine analogues were highly resistant to human purine nucleoside phosphorylase. The 4-benzylamino derivatives were weak inhibitors of adenosine transport into human erythrocytes. The inosine, adenosine, and selected N4-substituted analogues exhibited no in vitro toxicity toward murine L1210 leukemia and B16 melanoma cells.
Adenosine Deaminase Inhibitors↗