ABSTRACT
The posttranslational addition of a farnesyl moiety to the Ras oncoprotein is essential for its transforming activity. Cell-active inhibitors of the enzyme that catalyzes this reaction, protein farnesyltransferase, have been shown to selectively block ras-dependent transformation of cells in culture. Here we describe the protein farnesyltransferase inhibitor 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl] pentyloxy-3-phenylpropionylmethioninesulfone methyl ester (L-739,749), which suppressed the anchorage-independent growth of Rat1 cells transformed with viral H-ras and the human pancreatic adenocarcinoma cell line PSN-1, which harbors altered K-ras, myc, and p53 genes. This compound also suppressed the growth of tumors arising from ras-transformed Rat1 cells in nude mice by 66%. Under the same conditions, doxorubicin inhibited tumor growth by 33%. Control tumors formed by v-raf- or v-mos-transformed Rat1 cells were unaffected by L-739,749. Furthermore, mice treated with L-739,749 exhibited no evidence of systemic toxicity. This is a demonstration of antitumor activity in vivo using a synthetic small molecule inhibitor of protein farnesyltransferase.
Subject(s)
Alkyl and Aryl Transferases , Cell Transformation, Viral , Genes, ras , Oligopeptides/pharmacology , Transferases/antagonists & inhibitors , Animals , Genes, mos , Mice , Mice, NudeABSTRACT
A general route for preparing side chain ether analogues of lovastatin is presented. These analogues proved to be weaker inhibitors of HMG-CoA reductase than the corresponding side chain ester analogues. Interestingly, inhibitory potency was enhanced markedly when the 4-fluoro group was incorporated in the aromatic moiety of the side chain benzyl group of 2d.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Lovastatin/analogs & derivatives , Chemical Phenomena , Chemistry , Esters , Ethers , Lovastatin/chemical synthesis , Lovastatin/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
The syntheses of a series of 7-(3,5-disubstituted [1,1'-bephenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactones are reported. Intrinsic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity is enhanced markedly when the biphenyl moiety is substituted by chloro or methyl groups at positions 3 and 5 and a fluoro group at position 4'. These substitutions, followed by resolution, provided compounds 100(+) and 110(+) with 2.8 times the intrinsic inhibitory activity of compactin. Compound 100(+) was shown to possess the same chirality in the lactone ring as compactin by single-crystal X-ray crystallography.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Animals , Lactones/pharmacology , Rats , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
Chain modification of a thiazolidinone prostaglandin isostere has led to the production of 4-[3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl] benzoic acid (5b) which at 1 mg/kg po in the conscious dog causes a 70% increase in renal blood flow over control values with a duration of action exceeding 5 h. Preliminary testing indicates that 5b has a relatively specific action on the vasculature of the kidney. The enantiomers of 5b have been separated and the renal vasodilatory activity has been found to be entirely a property of the R-(+) enantiomer.
Subject(s)
Kidney/blood supply , Thiazoles/pharmacology , Vasodilation/drug effects , Animals , Dogs , Female , Models, Molecular , Regional Blood Flow/drug effects , Stereoisomerism , Thiazolidines , Vascular Resistance/drug effects , X-Ray DiffractionABSTRACT
5-(2,4-Difluorophenyl)salicylic acid, diflunisal (25), is the best compound, in terms of both efficacy and safety, from over 500 salicylates investigated in our laboratories. It is a chemically distinct, nonacetylating salicylic acid, more active than aspirin as an analgesic and antiinflammatory agent and superior in duration of action and therapeutic index. Some recent clinical and biochemical observations are briefly discussed.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Salicylates/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Dogs , Rats , Salicylates/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis of a series of 8-acetyl- (or 1-hydroxyethyl-) 12-hydroxy-13-aryloxytridecanoic acids and their sulfonamide isosteres is described. These compounds are formally derived from members of earlier reported series of modified secoprostaglandins by replacing the omega-butyl chain termini by substituted aryloxy groups. A number of these compounds are potent inhibitors of collagen-induced blood platelet aggregation in guinea pigs on oral administration.
Subject(s)
Platelet Aggregation/drug effects , Prostaglandins, Synthetic/chemical synthesis , Animals , Cyclic AMP/metabolism , Decanoic Acids/chemical synthesis , Decanoic Acids/pharmacology , Female , Guinea Pigs , In Vitro Techniques , Male , Mice , Ovary/drug effects , Ovary/metabolism , Prostaglandins E/pharmacology , Prostaglandins, Synthetic/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
A series of 7-(N-alkylmethanesulfonamido) heptanoic acids has been prepared which represents an extension of our 8-aza-11,12-secoprostaglandin studies. The studies. The compounds mimic the natural prostaglandins in that they markedly stimulate cAMP formation in the mouse ovary assay.
Subject(s)
Heptanoic Acids/chemical synthesis , Prostaglandins, Synthetic/chemical synthesis , Animals , Cyclic AMP/biosynthesis , Female , Heptanoic Acids/pharmacology , In Vitro Techniques , Mice , Ovary/drug effects , Ovary/metabolism , Prostaglandins E/pharmacology , Prostaglandins, Synthetic/pharmacology , Structure-Activity RelationshipSubject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Salicylates/chemical synthesis , Acetylation , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aspirin/pharmacology , Chemistry, Pharmaceutical/history , Fluorobenzenes/chemical synthesis , Fluorobenzenes/pharmacology , History, 20th Century , Salicylates/pharmacology , Structure-Activity Relationship , United StatesABSTRACT
A series of N-acyl-N-alkyl-7-aminoheptanoic acids has been prepared and evaluated for their ability to mimic the natural prostaglandins in certain biological systems. These compounds can be regarded as 8-aza-11,12-secoprostaglandins and, indeed, most of them stimulate cAMP formation in the mouse ovary assay, just as is observed with the natural prostaglandins. Selected compounds from this series also have been studied and shown to have prostaglandin-like effects in vivo.
Subject(s)
Fatty Acids/chemical synthesis , Prostaglandins , Acylation , Alkylation , Animals , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Chemical Phenomena , Chemistry , Cyclic AMP/biosynthesis , Fatty Acids/pharmacology , Female , Mice , Ovary/drug effects , Ovary/metabolism , Prostaglandins/pharmacology , StereoisomerismABSTRACT
A series of (diacylvinylaryloxy)acetic acids was synthesized and tested in dogs for saluretic and diuretic activity. Several compounds exhibit a high order of activity, the most active being [2,3-dichloro-4-(2,2-diacetylvinyl)-phenoxy]acetic acid (3). This compound is about three times as potent as [2,3-dichloro-4-(2-methylenebutyryl)-phenoxy]acetic acid (ethacrynic acid) but is qualitatively similar in causing a prompt increase in the excretion of water and in the excretion of sodium and chloride ions in approximately equimolar amounts. Saturation of the double bond of 3 virtually abolishes activity lending support to the hypothesis that the saluresis induced by these compounds, like that of ethacrynic acid, is related at least in part to a chemical reaction with protein-bound sulfhydryl groups. Four mercaptan adducts of 3 were prepared; these probably function as prodrugs in producing saluresis. The adduct with mercaptoacetic acid is as active as 3 itself.
