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The palladium(II)-catalyzed oxidation of alpha,beta-unsaturated cyclic acetals derived from mono- and disaccharides leads in appreciable yields to new aldehydo acetals which, overall, results in an anti-Markovnikov addition.
Transacetalation of fully 6-O-pivaloylated alpha-, beta-, and gamma-cyclodextrins with benzaldehyde dimethylacetal in the presence of (+)-10-camphorsulfonic acid gave monobenzylidene acetals (4, 5, 6) in moderately good yields. Benzylation of the beta-cyclodextrin derivative 5 followed by acid-catalyzed hydrolysis of the benzylidene group and acetylation afforded a di-O-acetyl-non-adeca-O-benzyl derivative 9. NMR spectroscopic analysis of 9, including two-dimensional HOHAHA and 1H-(13)C correlation experiments revealed that the benzylidene group bridged the O-2 and O-3 positions of contiguous D-glucopyranosyl residues. Reductive ring-opening of the benzylidene acetal with lithium aluminum hydride/aluminum chloride afforded predominantly a 2(1)-O-unprotected derivative 10 in good yield.
Medroxyprogesterone acetate (MPA) is currently used therapeutically in the treatment of mammary and endometrial carcinomas. In order to develop a more potent and useful drug, we synthesized the novel compound, 9alpha-fluoromedoroxyprogesterone acetate (FMPA), by fluorinating MPA, and we also previously reported that FMPA displays more potent anti-angiogenic activity in the chorioallantoic membrane assay than MPA. In the present study, we investigated (1) the effects of FMPA on rat mammary carcinomas induced by dimethylbenz[a]anthracene (DMBA) to determine the anti-tumor activity, (2) the effect on angiogenesis in rabbit corneal assays, and (3) compared these results with those for MPA. FMPA inhibited the growth of mammary carcinomas in a dose-dependent manner (7.5, 30 and 120 mg/kg). Almost complete involution of the carcinomas was observed at doses of 30 and 120 mg/kg. MPA also inhibited the growth of carcinomas at doses of 30 and 120 mg/kg, but no involution of carcinomas was observed even at 120 mg/kg. FMPA significantly and MPA to a lesser degree inhibited carcinogenesis at 120 mg/kg within their treatments. In rabbit corneal assays, FMPA significantly inhibited angiogenesis (IC50 value=0.085 microg/pellet). MPA also significantly inhibited angiogenesis (IC50 value=0.60 microg/pellet). From these results, we conclude that FMPA is potentially more effective in the treatment of mammary carcinomas than MPA.
A series of non acetal-type analogs of artemisinin containing C-C bond at position-12 have been found to be 15-22 times more stable than acetal(C-O)-type prodrugs of artemisinin in simulated stomach acid.
The synthesis and in vitro and in vivo activities of a series of cephalosporins having side chains derived from 2-[(2,2,2-trifluoroethyl)thio]acetic acid or 2-(cyanomethylthio)acetic acid and with acetoxymethyl or 3-heterocyclic thiomethyl substituents at the 3 position are described. In both series, increasing the oxidation state of the side-chain sulfur atom from sulfide to sulfoxide/sulfone decreased the in vitro gram-positive activity, but the effect on gram-negative activity was variable and less pronounced. The protective effectiveness in mice infected with Escherichia coli increased as the oxidation level of the side-chain sulfur was raised from sulfied to sulfoxide/sulfone. Replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in overall improvement of activity both in vitro and in vivo for all oxidation states.
The discovery of the (acryloylaryloxy)acetic acids as a new class of potent diuretics prompted the investigation of related bicyclic compounds. Annelated analogues of the parent series, the (2-alkyl- and 2,2-dialkyl-1-oxo-5-indanyloxy)acetic acids, were the subjects of this study. Those compounds, unlike the monocyclic parent compound, lacked the double bond adjacent to the carbonyl group. More importantly, they possessed both saluretic and uricosuric properties. The optimal single 2-substituents for maximal saluretic and uricosuric activity were determined. In general, better activity was observed when a second 2-alkyl substituent (especially methyl) was present in the molecule. Replacement of the carboxy substituent by 5-tetrazolyl generally resulted in a reduction in activity.
A series of (E)-[4-(3-oxo-1-alkenyl)phenoxy]acetic acids was synthesized and tested in dogs for saluretic and diuretic properties. Several compounds exhibited noteworthy activity, e.g., (E)-[2,3-dichloro-4-(3-oxo-1-butenyl)phenoxy]acetic acid (3a). While possessing only half of the dose potency of ethacrynic acid (2), the active compounds act similarly to this diuretic in causing a prompt increase in the excretion of water and in the excretion of sodium and chloride ions in approximately equimolar amounts. Potassium ion excretion is increased but less markedly than sodium excretion.
A series of [(2-nitro-1-alkenyl)aryloxy]acetic acids was synthesized and tested in dogs for saluretic and diuretic activity. A number of these compounds exhibit a high order of activity on iv or po administration; representative of these is (E)-[2,3-dichloro-4-(2-nitropropenyl)phenoxy]acetic acid (5). The most highly active compounds are qualitatively similar in action to [2,3-dichloro-4-(2-methylenebutyryl)phenoxylacetic acid (ethacrynic acid) in causing a prompt increase in the excretion of water and of sodium and chloride ions in approximately equimolar amounts but are three to five times as potent. Potassium ion excretion is increased but less markedly than sodium excretion.
A series of 5-aryl-2H-tetrazoles, 5-aryl-2H-tetrazole-2-acetic acids, and [(4-phenyl-5-aryl-4H-1,2,4-triazol-3-yl)thio]acetic acids were synthesized and tested in vitro for superoxide scavenging activity, in vivo in the carrageenan-induced rat paw edema assay, and in the reverse passive Arthus reaction. The hydroxy-substituted compounds were effective as in vitro scavengers of superoxide but were not effective as in vivo antiinflammatory agents.
[formula: see text] The reactions of glycals with ceric(IV) ammonium nitrate and sodium iodide in the presence of acetic acid provides 2-deoxy-2-iodo-alpha-mannopyranosyl acetates with good stereoselectivity. In the majority of the cases examined, the selectivity was considerably better than that from reactions using N-iodosuccinimide and HOAc.
PURPOSE: To investigate the effect of two doses of megestrol acetate (MA) compared with placebo on quality of life (QoL) and nutritional status (NS) in patients with advanced endocrine-insensitive cancer. PATIENTS AND METHODS: Two hundred forty patients were randomised to double-blind MA 480 mg/day, MA 160 mg/day, or matching placebo for 12 weeks. Nutritional status (including weight, skinfold thickness and midarm circumference) and QoL (using 6 linear analogue self-assessment (LASA) scales) were assessed at randomisation and after four, eight and 12 weeks. A QoL ranking incorporating QoL and death was also used ranging from 1 = dead to 5 = much better QoL. RESULTS: One hundred seventy-four patients were assessable at week four, 136 at week eight and 103 patients at week 12. Patients receiving MA reported substantially better appetite (P = 0.001), mood (P = 0.001) and overall quality of life (P < 0.001), and possibly less nausea and vomiting (P = 0.08) than patients receiving placebo, based on a test for trend. A larger benefit was seen with the higher dose which (unlike the lower dose) was significantly better in pairwise comparisons with placebo for appetite, mood and overall QoL (each P < or = 0.001). Despite some missing data on QoL scores, QoL ranking was available on 227 (95%) of patients with significantly higher QoL ranking associated with MA (P = 0.002). Improvements in QoL occurred early within four weeks and were sustained. No statistically significant differences were observed in NS measurements, including weight (P = 0.29). Side effects of therapy were minor and did not differ significantly across treatments. CONCLUSION: Megestrol acetate given at 480 mg/day is useful palliation in patients with endocrine-insensitive advanced cancer. It improves appetite, mood and overall quality of life in these patients, although not through a direct effect on nutritional status.
The copper(II) acetate monohydrate- or manganese(III) acetate dihydrate-mediated reaction of [60]fullerene with beta-keto esters 1a-1c or with beta-diketones 1d,1e in the presence of 4-dimethylaminopyridine afforded only dihydrofuran-fused C60 derivatives 2a-2e. However, aromatic methyl ketones 3a-3c gave two kinds of products: methanofullerenes 4a-4c and dihydrofuran-fused C60 derivatives 5a,5b. Possible reaction mechanisms are proposed.
The effect of acetate dialysis (AD), bicarbonate dialysis (BD), and acetate-free biofiltration (AFB) on nitric oxide (NO) synthesis and the implications for dialysis hypotension was studied. The finding that uremic plasma is a potent inducer of NO synthesis by endothelial cells in vitro suggested that the cardiovascular instability of dialysis patients might result from excessive NO formation. Cardiovascular instability is more frequent in patients undergoing AD than BD. To see whether these differences were attributable to NO, we studied the NO synthetic pathway ex vivo in patients undergoing different dialysis procedures. Five patients were treated, in a random order, with AD, BD, and AFB, a technique using a buffer-free dialysate and postdilution of a sterile bicarbonate solution. Each type of dialysis was used for 1 week, comprising three dialysis sessions. A polyacrylonitrile dialyzer was used for all three methods. Before and after the third dialysis, plasma was collected, added to [3H]L-arginine, and incubated with human umbilical vein endothelial cells (HUVECs) for 24 hours. NO synthesis was evaluated as [3H]L-citrulline formation. Plasma concentrations of interleukin-1beta (IL-1beta), a potent inducer of inducible NO synthase (iNOS) in endothelial cells, were also measured. Plasma collected from patients after AD stimulated endothelial NO synthesis more than plasma from the same patients before the dialysis session (pre-AD, 0.173+/-0.028 nmol/10(5) cells v post-AD, 0.280+/-0.093 nmol/10(5) cells; P < 0.05). A slight, although not significant, increase was also observed when HUVECs were incubated with plasma drawn after BD (pre-BD, 0.151+/-0.014 nmol/10(5) cells; post-BD, 0.230+/-0.055 nmol/10(5) cells). AFB did not aggravate the stimulatory effect of uremic plasma on endothelial NO synthesis (pre-AFB, 0.184+/-0.038 nmol/10(5) cells; post-AFB, 0.189+/-0.040 nmol/10(5) cells). Plasma IL-1beta was greater (P < 0.01) after AD than after BD and AFB (post-AD, 0.234+/-0.028 pg/mL; post-BD, 0.124+/-0.019 pg/mL; post-AFB, 0.120+/-0.013 pg/mL). With AD, there was a greater intradialytic decrease in systolic blood pressure than with BD or AFB. Weight and blood volume loss and sodium balance were similar in AD, BD, and AFB. These data were consistent with the possibility that NO and cytokines, released in excessive amounts during AD, may contribute to hemodynamic instability.
A single i.p. injection in rats of 20 microgram 12-O-tetradecanoylphorbol-13-acetate (TPA) or 100 mg phenobarbital (PB)/kg body weight resulted in a transient increase in liver ornithine decarboxylase (ODC) activity. Maximal stimulation of ODC activity was observed approximately 4 h after application of TPA and 4-6 h after treatment of PB. Six hours after TPA injection and greater than 8 h after treatment with PB the ODC activity had returned to control level. ODC activity induction occurred in a dose dependent manner, maximal stimulation was obtained with 20-100 microgram TPA and 100 mg PB/kg body weight, respectively. At higher doses the tumor promotors became increasingly inhibitory. The in vivo induction of rat liver ODC activity by TPA appeared to be under transcriptional control since administration of 2 mg actinomycin D/kg body weight or 50 mg cycloheximide/kg body weight 1 h prior to application of the tumor promotor prevented the increase of ODC activity. Furthermore the TPA-stimulated ODC induction was shown to be very sensitive to retinyl-acetate (RA). An i.p. dose of RA of 0.2 microgram/kg body weight applied 1 h before TPA inhibited ODC induction by 35%. Increasing the dose of RA to 20 microgram/kg body weight completely prevented the stimulation of ODC activity by TPA.
A single i.p. injection of 12-O-tetradecanoylphorbol-13-acetate (TPA) induced a transient increase in the levels of rat liver putrescine, spermidine and spermine. These polyamine concentrations continuously increased until 6 h, immediately following administration of the tumor promoter. Phenobarbital (PB) induced an increase of the putrescine and spermidine concentrations during the 8 h post administration studied, while spermine reached a plateau after 4 h. When retinyl-acetate (RA) was injected one hour prior to TPA, the increases of the polyamines were considerably inhibited. This treatment with RA partially inhibited further increase of putrescine and spermine by PB. These findings are discussed in respect to the concomitant ornithine decarboxylase (ODC) activities, we have previously reported. I.p. injection of RA alone caused an elevation of ODC activity as well as putrescine and spermidine concentration within 2 h of exposure.
Diglycerides function as analogs of the phorbol ester tumor promoters. We compare here the activity of glycerol 1-myristate 2-acetate (GMA) with the corresponding phorbol 12-myristate 13-acetate (PMA). GMA inhibited phorbol ester binding to reconstituted protein kinase C, stimulated protein kinase C enzymatic activity, and, upon addition to intact 3T3 cells, inhibited [125I]EGF binding. Its potency was much less than that of PMA, however (2.9 X 10(4)-fold less for phorbol ester binding, greater than 1.2 X 10(5)-fold less for inhibition of EGF binding), and its activity on the intact cells was more transient. The marked difference in potency contrasts with the much smaller differences found previously for the corresponding pairs of dilaurate and dioleate derivatives.
BACKGROUND: The antioestrogen tamoxifen and progestins act via different receptors and may therefore have complementary effects against human breast cancer. This possibility was tested in a randomized study which compared the effects of tamoxifen, standard-dose megestrol acetate, and these two agents in combination, in patients with metastatic breast cancer. PATIENTS AND METHODS: 184 post-menopausal patients with metastatic breast cancer were randomized to initial treatment with either tamoxifen (TAM) 40 mg daily, megestrol acetate (MA) 160 mgm daily, or the combination of the two administered simultaneously. Patients crossed over to the alternative single agent on relapse or disease progression. Patients were evaluated for response, time to initial and ultimate treatment failure, and survival. RESULTS: There were no significant differences between the three groups with respect to response rates, nor the other parameters. Patient survival was significantly associated with age > 60 years, ER positive status, and the absence of visceral metastases. CONCLUSIONS: TAM and MA are both equally effective in response induction as initial treatments and the combination has no advantage. Sequential treatment is still optimal, TAM being the preferred initial agent in view of the reported side effects with MA.
A protocol utilizing both leuprolide acetate (LA) and norethindrone acetate (NETA) in subjects undergoing ovarian suppression prior to follicle aspiration proved more effective than LA alone in reducing the incidence of ovarian cyst formation without affecting clinical outcome. Patients (n = 105) undergoing ovarian stimulation followed by follicle aspiration and in-vitro fertilization (IVF) were prospectively randomized and studied. Study measures included ovarian suppression days, days of human menopausal gonadotrophin (HMG) stimulation, serum oestradiol concentrations, number of cycles developing de novo cysts (>15 mm), number of induced flare responses (day 8 oestradiol >=50 pg/ml), number of office visits, total dose exogenous gonadotrophins, number oocytes retrieved, and clinical pregnancy and delivery rates per retrieval. Patients undergoing IVF received either LA alone (n = 58; controls) or LA and NETA (n = 47; study group) for the first 8 days of their cycle. Results comparing NETA/LA versus LA demonstrated: serum oestradiol 20.7 +/- 3.9 versus 57.3 +/- 9.4 pg/ml respectively on day 8 of ovarian suppression (P P < 0.01); and only three individuals (6.4%) using NETA/LA developed ovarian cysts >15 mm compared to 15 (25.9%) controls (P < 0.01). No differences were observed for days of stimulation, peak oestradiol attained, total dosage of exogenous gonadotrophins, or number of aspirated oocytes. Neither were there differences in the clinical pregnancy (26.8 versus 22.6%) nor in delivery rates (19.5 versus 20. 8%). We conclude that the addition of NETA to LA enhances ovarian suppression and lessens ovarian cyst formation, thereby significantly decreasing the overall cost per cycle.