ABSTRACT
3-Ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (2) was converted to 6-carbethoxymethyl-3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (6) through an oxalyl derivative. Treatment of 6 with ammonia gave the corresponding amide 7 which on sodium borohydride reduction and subsequent dehydration yielded 6-carbamylmethyl-3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (9). The analogous ester 10 was similarly obtained from 6. Numerous attempts to dealkylate the 3-ethoxy group of 9 or 10 failed. However, 6 coould easily be dealkylated on heating with 25% hydrochloric acid in a sealed tube.The ester, 6-carbethoxymethyl-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinoline-3(2H),5-dione (11), so obtained was converted to the corresponding amide 12 which on reduction with sodium borohydride and subsequent dehydration afforded the desired compound, 6-car-bamylmethyl-8-methyl-7(5)H-cyclopental[f]isoquinolin-3-(2H)-one (1). 1 was found to be mildly cytotoxic againstL5178Y mouse leukemia cells in culture.1 was also found to bind to native calf thymus DNA. 1 inhibited RNA synthesis by a DNA-dependent RNA polymerase and a higher inhibition of RNA synthesis was observed when poly(dG-dC) was used as a template than when poly(dA-dT) was used. A significant increase of thermal transition temperature of calf thymus DNA and poly(dG)-poly(dC) was observed in the presence of 1. The accumulated evidence demonstrates that 1 interacts weakly with calf thymus DNA and interacts preferentially with poly(deoxyribonucleotides)-containing GC pairs.
Subject(s)
Cyclopentanes/analogs & derivatives , DNA , Deoxyribonucleotides , Isoquinolines/chemical synthesis , Polynucleotides , Animals , Binding Sites , Cattle , Cyclopentanes/chemical synthesis , Cyclopentanes/pharmacology , DNA Nucleotidyltransferases/metabolism , Depression, Chemical , Escherichia coli/enzymology , Hot Temperature , Isoquinolines/pharmacology , Nucleic Acid Denaturation , Spectrophotometry, Ultraviolet , Templates, GeneticABSTRACT
Simplified prostaglandin analogs were prepared and tested for inhibition of gastric acid secretion. An alkyl moiety of 1-8 carbon atoms was substituted for the C-13 to C-20 chain of the PG's. Analog variations included shortened and lengthened acid side chains, beta-oxidation blockage, beta-ketol, Falpha-hydroxyl, and cyclohexanone substitution. Maximal inhibitory activity was obtained with the shorter alkyl moieties.
Subject(s)
Cyclopentanes/analogs & derivatives , Gastric Juice/metabolism , Prostaglandins/chemical synthesis , Animals , Chromatography, Gas , Cyclopentanes/chemical synthesis , Cyclopentanes/pharmacology , Depression, Chemical , Gastric Mucosa/metabolism , Male , Prostaglandins/pharmacology , Pylorus/physiology , Rats , StereoisomerismABSTRACT
By the use of space-filling models, a novel compound, 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3-(2H)-one was devised which would be expected to hydrogen bond specifically to GC pairs in the major groove of the double helix such that (i) the amino group of the cytosine molecule donates a hydrogen bond to the C-3 carbonyl of the isoquinoline moiety and (ii) the amide proton of the side chain donates a hydrogen bond to the N-7 of guanine. 3-Ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4) which constitutes the basic ring system of 1 was synthesized in a multistep procedure starting from m-methyl-N-acetylbenzylamine (5). Friedel-Crafts reaction of 5 led to 2,4-bis(chloromethyl)-5-methyl-N-acetylbenzylamine (6) which on treatment with KCN, hydrolysis of the resultant nitrile, and subsequent esterification afforded 6-carbethoxymethyl-7-methyl-1,2,3,4-tetrahydroisoquinolin-3-one (9). Treatment of 9 with triethyloxonium fluoborate followed by dehydrogenation of the product gave 6-carbethoxy-methyl-3-ethoxy-7-methylisoquinoline (14). Chain extension of 14 followed by cyclization led to 3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (19) which on reduction and subsequent dehydration yielded 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4).
Subject(s)
Cyclopentanes/analogs & derivatives , DNA , Isoquinolines/chemical synthesis , Binding Sites , Cells, Cultured , Cyclopentanes/chemical synthesis , Cyclopentanes/pharmacology , HeLa Cells , Isoquinolines/pharmacology , Lymphoma/metabolism , Magnetic Resonance Spectroscopy , Models, Structural , Neoplasms, Experimental/metabolism , Nucleic Acid Conformation , Spectrophotometry, UltravioletABSTRACT
Insertion of a Silastic-PVP implant containing 150 mug PGF2alpha into one of the uterine horns or administration of a single subcutaneous injection of 4 mug of Depo-Estradiol Cypionate (ECP) did not induce abortion in pregnant rats. However, a combined treatment with 150 mug of PGF2alpha in a Silastic-PVP implant and 4 mug of ECP induced abortion in all treated rats. Apparently, ECP stimulated endogenous production of PGF and consequently enhanced the effect of the administered 150 mug of PGF2alpha. The release of 3H-PGF2alpha from Silastic-PVP implants was faster after intrauterine or intraperitoneal than after subcutaneous insertion. The release rate of 3H-PGF2alpha from Silastic-PVP implants in vitro was comparable to that observed after subcutaneous placement of similar implants. It is suggested that administration of estrogen combined with PGF2alpha might shorten the interval between treatment with PGF2alpha and abortion. Moreover, a Silastic-PVP implant would lend itself as a better method of administration, releasing PGF2alpha locally, slowly, and continuously.
Subject(s)
Abortifacient Agents/pharmacology , Abortion, Veterinary/chemically induced , Estradiol/analogs & derivatives , Fetus/drug effects , Pregnancy, Animal/drug effects , Prostaglandins/pharmacology , Abortion, Induced/veterinary , Animals , Cyclopentanes/administration & dosage , Cyclopentanes/analogs & derivatives , Drug Synergism , Estradiol/administration & dosage , Female , In Vitro Techniques , Pregnancy , Pregnancy Trimester, Second/drug effects , Propionates/administration & dosage , Prostaglandins/administration & dosage , Rats , Rats, Inbred Strains , Silicones , Time Factors , TritiumABSTRACT
A rapid and precise method for evaluating the miotic activity of cholinergic drugs has been developed based on Long's method for measuring the rate of mydriasis. The rate of reversal of mydriasis developed previously in the intact mouse eye by a mild mydriatic (phenycyclidine) is used to evaluate the miotic activity. The method provides a useful tool for measuring and comparing the miotic activity of acetylcholine agonists and cholinesterase inhibitors.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Miotics/pharmacology , Mydriatics/pharmacology , Parasympathomimetics/pharmacology , Pupil/drug effects , Amides/pharmacology , Animals , Arecoline/pharmacology , Atropine/pharmacology , Cyclopentanes/analogs & derivatives , Dimethylamines/pharmacology , Drug Interactions , Lighting , Methods , Mice , Microscopy , Phencyclidine/pharmacology , Phenylacetates/pharmacology , Pyridines/pharmacology , Time FactorsSubject(s)
Diazoxide/pharmacology , Glucose/pharmacology , Insulin/biosynthesis , Islets of Langerhans/metabolism , Sulfonylurea Compounds/pharmacology , Animals , Cyclohexanes/analogs & derivatives , Cyclohexanes/pharmacology , Cyclopentanes/analogs & derivatives , Cyclopentanes/pharmacology , Glucose/metabolism , Hormones/biosynthesis , In Vitro Techniques , Leucine/metabolism , Oxidation-Reduction , Peptide Biosynthesis , Proinsulin/biosynthesis , Pyrazines/pharmacology , Pyrroles/pharmacology , Rats , Tolbutamide/pharmacologyABSTRACT
Renal tubular reabsorption of cycloleucine (1-amino-cyclopentane carboxylic acid) was studied in vivo et situ by continuous microperfusion of single proximal tubules of the rat. The results show: a) cycloleucine is reabsorbed rapidly compared with other amino acids b) this reabsorption is saturable and can be inhibited by oligomycin c) cycloleucine inhibits tubular reabsorption of L-arginine, glycine, and of L-phenylalanine. Mutual reciprocal inhibition occurs only with L-phenylalanine (and perhaps also with glycine). A maximal possible permeability coefficient for cycloleucine (less than 6 times 10--5 cm times sec--1) was calculated. Assuming simple 2-parameter kinetics, Vmax and Km for tubular reabsorption of cycloleucine were estimated. It can be concluded from the present results that cycloleucine is reabsorbed by a mechanism that transports L-phenylalanine, but not by the system shared by dibasic amino acids.
Subject(s)
Amino Acids/metabolism , Antineoplastic Agents/metabolism , Cyclopentanes/analogs & derivatives , Kidney Tubules, Proximal/metabolism , Absorption , Animals , Arginine/metabolism , Biological Transport/drug effects , Cell Membrane Permeability , Cyclopentanes/metabolism , Cyclopentanes/pharmacology , Glycine/metabolism , Kinetics , Male , Oligomycins/pharmacology , Perfusion , Phenylalanine/metabolism , RatsABSTRACT
The anal gland secretions of dolichoderine ants in the genus Azteca are fortified with cyclopentyl ketones. Since these compounds, 2-methylcyclopentanone, cis-1-acetyl-2-methylcyclopentane, and 2-acetyl-3-methylcyclopentene, release sustained alarm behavior in ant workers, they constitute a new chemical class of insect pheromones. The ketones probably also function as defensive compounds and thus are part of the ants' alarm-defense system.
