Showing papers in "Journal of Medicinal Chemistry in 1984"

Functional-Group Contributions to Drug Receptor Interactions

Abstract: The binding constants and structural components of 200 drugs and enzyme inhibitors have been used to calculate the average binding energies of 10 common functional groups. As expected, charged groups bind more strongly than polar groups, which in turn bind more tightly than nonpolar groups. The derived intrinsic binding energies (in kcal/mol) are (i) charged groups, CO-2, 8.2; PO2-4, 10.0; N+, 11.5; (ii) polar groups, N, 1.2; OH, 2.5; CO, 3.4; O or S ethers, 1.1; halogens, 1.3; (iii) nonpolar groups, C (sp2), 0.7; C (sp3), 0.8. These values may be used to determine the goodness of fit of a drug to its receptor. This is done by comparing the observed binding constant to the average binding energy calculated by summing the intrinsic binding energies of the component groups and then subtracting two entropy related terms (14 kcal/mol for the loss of overall rotational and translational entropy and 0.7 kcal/mol for each degree of conformational freedom). Drugs that match their receptors exceptionally well have a measured binding energy that substantially exceeds this calculated average value--examples include diazepam and biotin. Conversely, if the observed binding energy is very much less than the calculated average value, then the drug apparently matches its receptor less well than average. Examples of this type include methotrexate and buprenorphine.

Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]-phenyl]methanone hydrochloride (LY156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity.

Abstract: In an effort to prepare nonsteroidal antiestrogens demonstrating greater antagonism and less intrinsic estrogenicity than those currently available, a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives was synthesized. These compounds were prepared by Friedel-Crafts aroylation of appropriate O-protected 2-arylbenzo[b]thiophene nuclei with basic side-chain-bearing benzoyl chlorides followed by removal of the protective groups to provide the desired compounds containing both hydroxyl and basic side-chain functionality. A particularly useful method for the cleavage of aryl methoxy ethers without removal of (dialkylamino)ethoxy side chain functionality elsewhere in the molecule was found to be AlCl3/EtSH. The benzothiophene derivatives were tested for their ability to inhibit the growth-stimulating action of estradiol on the immature rat uterus. Seemingly minor changes in the side-chain amine moiety were found to have profound effects on the ability of the compounds to antagonize estradiol. Analogues having basic side chains containing cyclic (pyrrolidine, piperidine, and hexamethyleneamine) moieties were found to have less intrinsic estrogenicity and to antagonize estradiol action more completely than their noncyclic counterparts. The most effective antiestrogen in the series, compound 44, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone, elicited a modest uterotropic activity that did not increase with increasing dose. In antagonism of estradiol, 44 exhibited a degree of inhibition surpassing that of tamoxifen at any dose tested. The new benzothiophene antiestrogen was also shown to have high affinity for rat uterine cycloplasmic estrogen receptor and to be an inhibitor of the growth of DMBA-induced rat mammary tumors.

Studies on heterocyclic compounds. 6. Synthesis and analgesic and antiinflammatory activities of 3,4-dimethylpyrano[2,3-c]pyrazol-6-one derivatives.

Abstract: A series of new 1- and 2-substituted 3,4-dimethylpyrano[2,3-c]pyrazol-6-one derivatives and 1-substituted 1,6-dihydro-4-methyl-6-oxopyrano[2,3-c]pyrazole-3-acetic acids were synthesized and examined for their analgesic and antiinflammatory activities. Most of these compounds showed more prominent analgesic activities than antiinflammatory activities, and this result was similar to that of aminopyrine. Among these compounds, 1,3,4-trimethylpyrano[2,3-c]pyrazol-6(1H)-one and 2,3,4-trimethylpyrano[2,3-c]pyrazol-6(2H)-one showed more potent analgesic activity than aminopyrine.

Interactions of antitumor drugs with natural DNA: 1H NMR study of binding mode and kinetics.

Abstract: 1H NMR has been used to study the interactions of over 70 clinical and experimental antitumor drugs with DNA. Spectra of the low-field (H-bonded imino proton) resonances of DNA were studied as a function of drug per base pair ratio. From the spectral changes observed, it was possible to distinguish three modes of drug binding (intercalation, groove binding, and nonspecific outside binding), to determine the kinetics of drug binding (approximate lifetime of the bound drug), and, in favorable cases, to determine the specificity of the drugs for A X T or G X C base pairs. This method is a useful assay for general drug-binding characteristics. For the intercalating compounds there appears to be a correlation between drug-binding kinetics and useful antitumor activity.

Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins.

Abstract: The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants has prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy. The potential role of derangements of 5-HT pathways in the etiology of depression has long been suspected and has given impetus to the development of newer compounds that accentuate inhibition of serotonin reuptake. This paper presents structure-activity relationships for a series of cis-1-amino-4-(substituted-aryl)tetralins, which are surprisingly potent and selective inhibitors of serotonin uptake in in vitro models. These compounds are pharmacologically distinct from corresponding members of the trans series, which also potently block uptake of dopamine and norepinephrine. The activity in both cis and trans series is stereospecific, being restricted to the cis-(1S,4S) and the trans-(1R,4S) enantiomers.

Antitumor imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one , a novel broad-spectrum antitumor agent.

Abstract: Interaction of 5-diazoimidazole-4-carboxamide and alkyl and aryl isocyanates in the dark affords 8-carbamoyl-3-substituted-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-on es. In cold methanol or ethanol, the 3-(2-chloroethyl) derivative 7a decomposes to afford 2-azahypoxanthine (14) and methyl and ethyl N-(2-chloroethyl)carbamates, respectively. Compound 7a has curative activity against L-1210 and P388 leukemia and may act as a prodrug modification of the acyclic triazene 5-[3-(2-chloroethyl)triazen-1-yl]imidazole-4-carboxamide (MCTIC), since it ring opens to form the triazene in aqueous sodium carbonate.

Inhibition of aminopeptidases by amastatin and bestatin derivatives. Effect of inhibitor structure on slow-binding processes.

Abstract: Amastatin [(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl-L-valyl-L-valyl-L- aspartic acid] and bestatin [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-L-leucine] are slow-binding, competitive inhibitors of aminopeptidase M (AP-M) with net inhibition constants (Ki) of 1.9 X 10(-8) and 4.1 X 10(-6) M, respectively. The effect of inhibitor structure on net Ki and on slow-binding inhibition was evaluated for analogues of both inhibitors on AP-M and leucine aminopeptidase (LAP). The (2S)-hydroxyl group contributes to the stabilization of a collision complex [EI], which is formed rapidly. In contrast, increasing the peptide chain length of the inhibitor produces more potent inhibitors as a consequence of a slower binding process. A statine analogue of amastatin [(3S,4S)-Sta-Val-Val-Asp] stimulated rather than inhibited LAP. AP-M binds tri- and tetrapeptide inhibitors more strongly than dipeptide inhibitors, whereas LAP binds dipeptide inhibitors more strongly. The difference in binding can be used to distinguish cytosolic from membrane-bound aminopeptidases.

Azasteroids as inhibitors of rat prostatic 5 alpha-reductase.

Abstract: A series of A-ring heterocyclic steroids has been prepared and tested for inhibition of rat prostatic steroid 5 alpha-reductase in vitro. Strikingly high inhibitory activity was found with a group of 17 beta-substituted 4-methyl-4-aza-5 alpha-androstan-3-ones. These compounds were prepared from 3-keto-delta 4-precursors by oxidative (O3 or NaIO4-KMnO4) A-ring cleavage followed, in turn, by ring closure with an amine and hydrogenation over platinum catalyst. Other A-ring azasteroids were made by Beckmann rearrangement of oximes of 2-oxo-A-nor, 3-oxo- and 4-oxo-5 alpha-androstanes. An A-nor-2-oxo-3-azasteroid was prepared by oxidative decarbonylation of a precursor 2,3-dioxo-4-azasteroid with m-chloroperbenzoic acid. A-ring modifications of the 4-azasteroids included delta 1-unsaturation, 2- and 4-substituents, and 3-carbonyl replacements. Side chains at the 17-position were varied with an emphasis on carboxylate derivatives (salts, esters, and amides).

A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria

Abstract: Steroid glycosides and the unique glycosidase activity of the colonic microflora form the basis of a new colon-specific drug-delivery system. Drug glycosides are hydrophilic and, thus, poorly absorbed from the small intestine. Once such a glycoside reaches the colon it can be cleaved by bacterial glycosidases, releasing the free drug to be absorbed by the colonic mucosa. This concept was illustrated with dexamethasone 21-beta-D-glucoside (1) and prednisolone 21-beta-D-glucoside (2), two prodrugs that may be useful in treating inflammatory bowel disease. Hydrolysis of the prodrugs by beta-glucosidase and fecal homogenates in vitro released the free steroids. Glucosides 1 and 2 were administered to rats intragastrically to determine when and where the free steroids were released. Unmodified dexamethasone (3) and prednisolone (4) were also given to rats intragastrically to compare absorption of the glucosides with the free steroids. Both glucosides were found to reach the rat lower intestine in 4-5 h, where they were rapidly hydrolyzed, releasing the free steroids. Delivery of steroid 3 (via glucoside 1) was more specific than that of steroid 4 (via glucoside 2): nearly 60% of an oral dose of glucoside 1 reached the cecum, whereas less than 15% of glucoside 2 reached the cecum. When free steroids 3 and 4 were administered orally, they were almost exclusively absorbed in the small intestine: less than 1% of an oral dose of each reached the cecum.

Synthesis and evaluation of radioiodinated terminal p-iodophenyl-substituted alpha- and beta-methyl-branched fatty acids.

Abstract: Methods have been developed for the preparation of terminal p-idophenyl-substituted alpha- and beta-methyl-branched long-chain fatty acids. The syntheses and physical properties of 14-(p-iodophenyl)-2(RS)-methyltetradecanoic acid and 15-p-iodophenyl)-3(RS)-methylpentadecanoic acid are described. The radioiodinated agents are of interest as a result of the expected pronounced uptake and prolonged myocardial retention that may result from the inhibition of fatty acid metabolism. Tissue distribution studies in rats with 14-(p-(125I)iodophenyl)-2(RS)-methyltetradecanoic acid and 15-(p-(125I)iodophenyl)-3(RS)-methylpentadecanoic acid show significant heart uptake and prolonged retention accompanied by low in vivo deiodination and high blood levels. A comparison of the heart uptake of the radioiodinated methyl-branched fatty acids and their unbranched analogues has demonstrated a greater myocardial retention of the methyl-branched fatty acids than the unbranched analogues. These results suggest that the mechanism of myocardial retention results from steric or chemical inhibition of the metabolism of these fatty acids by the presence of the methyl group.

Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones.

Abstract: A series of novel triazol-3-ones have been synthesized, and their in vitro and in vivo antifungal properties are reported. Compound 68 (itraconazole), which displays a pronounced oral activity against vaginal candidosis in rats and against microsporosis in guinea pigs, has been selected for clinical evaluation.

Intensely potent morpholinyl anthracyclines.

Abstract: 3'-Deamino-3'-(3-cyano-4-morpholinyl)doxorubicin is a new analogue that is 100 to 1000 times more potent than doxorubicin against tumors in cell culture or in mice, that is active by intraperitoneal, intravenous, or oral dosing, and that does not produce chronic myocardial lesions in mice. This analogue was encountered in studies on the reductive alkylation of doxorubicin and daunorubicin with 2,2' - oxybis [acetaldehyde], which constructs a morpholino ring incorporating the amino N. The morpholinyl nitrile byproducts are separated by virtue of their nonbasicity from the expected morpholino derivatives. The 13-dihydro and 5-imino derivatives are also described in this important new class of anthracyclines.

beta-Lapachone: synthesis of derivatives and activities in tumor models.

Abstract: In order to find a 3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione more potent than the naturally occurring 2,2-dimethyl derivative [beta-lapachone (10a)], we synthesized a series of analogous compounds with modifications at position 2 of the pyran ring or at positions 8 and 9 of the benzene ring. Of the compounds tested in vitro for inhibition of RNA-dependent DNA polymerase and in mice infected with Rauscher leukemia, all retained good enzyme activity. Inhibition of the reverse transcriptase activity of the 2,2-substituted derivatives 10b-e was as strong as 10a. However, only the 2-methyl-2-phenyl derivative 10e proved to be about as potent as the 2,2-dimethyl reference compound 10a in prolonging the mean survival time of mice with Rauscher leukemia virus induced leukemia.

2-Phenylindoles. Relationship between structure, estrogen receptor affinity, and mammary tumor inhibiting activity in the rat

Abstract: A number of 2-phenylindole derivatives with one hydroxy group in the meta or para position of the phenyl ring and a second one in position 5, 6, or 7 of the indole nucleus were synthesized. In addition, different alkyl groups were introduced into positions 1 and 3 of the heterocycle. The influence of these structural variations on the binding affinity for the calf uterine estrogen receptor was studied. A prerequisite for the binding is the presence of an alkyl group at the nitrogen. Favorable are a hydroxy group located in the para position of the phenyl ring and short alkyl chains both in position 1 and 3 of the indole. The highest relative binding affinity (RBA) values (e.g., 33 for 20b, 21 for 24b, 23 for 35b) are close to that of hexestrol (RBA = 25, estradiol = 100). Depending on the positions of the oxygen functions and size of the alkyl residues, the indole derivatives behaved as strong estrogens (20c, 24c, 35c) or impeded estrogens with antagonistic activity (23c, 29c, 30c, 31c, 40c, 44c) in the immature mouse. Some of these derivatives (20c, 23c, 24c, 29c, 30c, 31c) were tested for their inhibitory effect on dimethylbenzanthracene-induced hormone-dependent mammary tumors of the rat. Both types exhibited a strong growth inhibition with a reduction of the average tumor area at appropriate dosage. A mode of action involving the estrogen receptor system is assumed.

Preparation and antibacterial activities of new 1,2,3-diazaborine derivatives and analogues.

Abstract: 1,2-Dihydro-1-hydroxy-2-(organosulfonyl)areno[d] [1,2,3]diazaborines 2 (arene = benzene, naphthalene, thiophene, furan, pyrrole) were synthesized by reaction of (organosulfonyl)hydrazones of arene aldehydes or ketones with tribromoborane in the presence of ferric chloride. The activities of 2 against bacteria in vitro and in vivo (Escherichia coli) were determined and structure-activity relationships are discussed. Included in this study are 2,3-dihydro-1-hydroxy-2-(p-tolylsulfonyl)-1H-2,1-benzazaborole+ ++ (3) and 1-hydroxy-1,2,3,4-tetrahydro-2-(p-tolylsulfonyl)-2,1-benzazabor ine (4) as well as the carbacyclic benzodiazaborine analogue 4-hydroxy-3-(p-tolylsulfonyl)isoquinoline (7). The nature of the active species is briefly discussed.

2-Substituted thiazolidine-4(R)-carboxylic acids as prodrugs of L-cysteine. Protection of mice against acetaminophen hepatotoxicity

Abstract: A number of 2-alkyl- and 2-aryl-substituted thiazolidine-4(R)-carboxylic acids were evaluated for their protective effect against hepatotoxic deaths produced in mice by LD90 doses of acetaminophen. 2(RS)-Methyl-, 2(RS)-n-propyl-, and 2(RS)-n- pentylthiazolidine -4(R)-carboxylic acids (compounds 1b,d,e, respectively) were nearly equipotent in their protective effect based on the number of surviving animals at 48 h as well as by histological criteria. 2(RS)-Ethyl-, 2(RS)-phenyl-, and 2(RS)-(4-pyridyl)thiazolidine-4(R)-carboxylic acids (compounds 1c,f,g) were less protective. The enantiomer of 1b, viz., 2(RS)- methylthiazolidine -4(S)-carboxylic acid (2b), was totally ineffective in this regard. Thiazolidine-4(R)-carboxylic acid (1a), but not its enantiomer, 2a, was a good substrate for a solubilized preparation of rat liver mitochondrial proline oxidase [Km = 1.1 x 10(-4) M; Vmax = 5.4 mumol min-1 (mg of protein)-1]. Compound 1b was not a substrate for proline oxidase but dissociated to L-cysteine in this system. At physiological pH and temperature, the hydrogens on the methyl group of 1b underwent deuterium exchange with solvent D2O (k1 = 2.5 X 10(-5) s), suggesting that opening of the thiazolidine ring must have taken place. Indeed, 1b labeled with 14C in the 2 and methyl positions was rapidly metabolized by the rat to produce 14CO2, 80% of the dose being excreted in this form in the expired air after 24 h. It is suggested that these 2-substituted thiazolidine-4(R)-carboxylic acids are prodrugs of L-cysteine that liberate this sulfhydryl amino acid in vivo by nonenzymatic ring opening, followed by solvolysis.

Synthesis and antifungal activity of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine (SF 86-327) and related allylamine derivatives with enhanced oral activity

Abstract: The allylamine derivatives are a new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. A new subclass, which features an acetylene group conjugated with the allylamine double bond, is characterized by enhanced antifungal activity, especially on oral treatment of guinea pig dermatophytoses. Increased branching of the alkyl group next to the triple bond led to the tert-butylacetylene derivative SF 86-327, a compound with strikingly increased activity in vitro and in vivo, which is now under clinical evaluation. Versatile synthetic routes, comparative biological data, and structure--activity relationships are presented.

Parasite enzymes as potential targets for antiparasitic chemotherapy

Abstract: I have thus far listed a total of 10 potential targets for antiparasitic chemotherapeutic consideration. This is by no means a completed list. Many more will be added to it with time and with more future findings. Among these 10 targets (summarized in Table I), however, one may gain some insight and see a few interesting general trends: (1) Nucleic acid metabolism and carbohydrate-energy metabolism in protozoan parasites appear to be targets for fruitful chemotherapeutic attacks. Their being useful targets results generally from the deficient metabolism in the protozoan parasites. Thus, the main vulnerability among the protozoan parasites is closely associated with their parasitic nature. (2) Microtubules and nervous systems appear to be the main chemotherapeutic targets in helminths. They differ from those in the host not because of their parasitic nature but, more likely, because of the evolutionary distance separating the mammalian hosts and the primitive metazoa. Thus, free-living nematodes, such as Caenorhabditis elegans, have their microtubules just as susceptible to the benzimidazole anthelmintics as those from the parasitic worms. The motoneuronal map of C. elegans is identical with that of Ascaris lumbricoides. Both worms are similarly immobilized by levamisole, piperazine, avermectins, etc. The dual insecticidal and antiexoparasite activities found in the avermectins and milbemycins may also suggest that the free-living insects and the ticks and lice may have the same GABA nervous system. This main discrepancy between protozoan parasites and metazoan parasites may be partly attributable to the higher mutation rates and higher frequencies of genetic recombination among the protozoa, evidenced by the higher rates of development of drug resistance among them. The fast adaptation to a new environment may be essential for survival, but it would also lead to metabolic deficiencies after the protozoa lived in a luxurious environment for a while. This revelation may suggest that future chemotherapeutic studies on parasitic helminths can utilize free-living helminths as models to eliminate many unnecessary technical difficulties. Also, there perhaps could be a further classification among the parasites to term the protozoa "true parasites" and the helminth "pseudo-parasites" from the viewpoint of chemotherapy.

Synthesis 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 as possible superoxide scavengers and antiinflammatory agents

Abstract: 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.

2-Acetylpyridine thiosemicarbazones. 9. Derivatives of 2-acetylpyridine 1-oxide as potential antimalarial agents

Abstract: In view of the antimalarial activity in mice of 2-acetylpyridine thiosemicarbazones, a series of analogous 1-oxides was prepared for evaluation. Their synthesis was achieved by the reaction of 2-acetylpyridine 1-oxide with methyl hydrazinecarbodithioate to give methyl 3-[1-(2-pyridinyl 1-oxide)ethylidene]hydrazinecarbodithioate (II). Reaction of the latter intermediate with secondary amines afforded the desired 2-acetylpyridine 1-oxide thiosemicarbazones (III). Reduction of the azomethine linkage of II with NaBH4 gave methyl 3-[1-(2-pyridinyl 1-oxide)ethyl]-hydrazinecarbodithioate (IV) whose S-methyl group was then displaced by amines to give a 1-[1-(2-pyridinyl 1-oxide)ethyl]thiosemicarbazide, V. Antimalarial activity of III was evaluated against both Plasmodium berghei in the mouse and Plasmodium falciparum in an automated in vitro test system. In both cases, 2-acetylpyridine 1-oxide thiosemicarbazones were found to be less active than the corresponding de-1-oxide analogues. When compounds V were evaluated against Plasmodium berghei in the mouse, a diminution of activity was similarly seen in comparison to the analogues not bearing the 1-oxide moiety.

6-Methylangelicins: a new series of potential photochemotherapeutic agents for the treatment of psoriasis.

Abstract: The possible presence of methylpsoralens as undesired inquinants in synthetic methylangelicins has been avoided through a synthetic pathway starting from umbelliferones carrying a methyl group in the 6-position The new 6-methylangelicins show a high affinity toward DNA, forming in the dark a molecular complex; the complexed angelicins under UV-A irradiation photobind effectively to the macromolecule, forming only monoadducts The new compounds show an evident antiproliferative activity by inhibiting DNA synthesis on Ehrlich cells; great differences, however, can be seen between the various compounds All the compounds are lacking of skin erythemogenic activity Some of the new 6-methylangelicins, evaluated in terms of mutagenic activity, demonstrate to be less effective than 8-methoxypsoralen (8-MOP), used for a comparison On the basis of antiproliferative activity, lack of skin phototoxicity, and low mutagenicity, two compounds have been chosen for clinical evaluation The compounds tested on seven psoriatic patients by topical application and UV-A irradiation proved to be more effective than 8-MOP, used in the same conditions

Selective delivery of cytotoxic compounds to cells by the LDL pathway

Abstract: Cancer cells need cholesterol to make new membrane. They get it either by de novo synthesis or from low-density lipoprotein (LDL), or both. Some types of cancer have very high LDL requirements. LDL particles, which circulate in the blood, contain a cholesteryl ester core surrounded by a phospholipid coat containing apoproteins that are recognized by LDL receptors on cell surfaces. After attachment to cells, LDL is endocytosed into lysosomes, where the core is exposed and hydrolyzed. A technique is known whereby LDL can be isolated, its core removed and replaced by a compatible lipophilic substance, and then reconstituted into intact LDL particles that are recognized and internalized by cells in the normal manner. A series of cytotoxic compounds has been synthesized, designed to be compatible with reconstituted LDL, and directed against cancers that copiously internalize LDL. They were evaluated by measuring the toxicity of reconstituted LDL toward test cells bearing LDL receptors. Selectivity was determined by comparison, either with mutant cells with few LDL receptors or with reconstituted methylated LDL (which is not recognized by LDL receptors) on normal cells. Two compounds, 19 and 25, were found that reconstitute well, kill or arrest the test cells at reasonably low concentrations, and are completely selective, suggesting that they are delivered to cells exclusively via the LDL pathway.

N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]- N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor

Abstract: Synthese a partir de l'acide (methoxy-6 trifluoromethyl-5) naphtoique-1 et du N-methyl glycinate de methyle

A novel peptide delivery system involving peptidase activated prodrugs as antimicrobial agents. Synthesis and biological activity of peptidyl derivatives of 5-fluorouracil

Abstract: As an approach to the development of antimicrobial agents, a novel peptide carrier system was designed, based on the chemical instability of alpha-substituted glycine analogues, with the explicit intent of actively transporting therapeutically useful compounds into microbial cells. Peptides containing 5-fluorouracil (5-FU) linked to the peptide backbone were selected to test the feasibility of this new delivery system. These peptide conjugates were designed such that they would be substrates for both the microbial peptide permeases and peptidases. After entry into cells, enzymatic hydrolysis of the peptide generates an unstable alpha-(5-FU)-glycine that spontaneously decomposes to release 5-FU. The 5-FU-peptide conjugates were tested for antifungal (Candida albicans) and antibacterial (Escherichia coli) activity and were found to have antimicrobial activities comparable to free 5-FU. Noninhibitory peptides antagonized the antimicrobial activities of the 5-FU-peptide conjugates but not of free 5-FU, a result consistent with peptide transport mediated entry of the peptide conjugates into cells. Further support for this conclusion was provided by the finding that biological activities were dependent upon peptide stereochemistry.

Novel N-hydroxyguanidine derivatives as anticancer and antiviral agents.

Abstract: Hydroxyguanidine contains both features of guanidine and hydroxyurea and has antiviral and anticancer activities both in vitro and in vivo. In order to enhance the antiviral and anticancer activity of this compound, a new series of hydroxyguanidine derivatives with the following structures were synthesized: R = NNHC(= NH)NHOH, where R = aromatic or heterocyclic aldehyde. This series of compounds was prepared in order to alter the lipophilic/hydrophilic balance, as well as the electronic and steric properties of hydroxyguanidine. The anticancer activities of the compounds were tested against cultured L1210 cells. The ID50 values of the above compounds are in the range of 7.80-126 microM. They are about 10-fold more active than hydroxyurea and hydroxyguanidine. The antiviral activities were also tested by assaying the inhibition of transformation of chicken embryo fibroblasts infected with Rous sarcoma virus. The ID50 values of these new compounds are in the range of 2.76-195.2 microM. The most active ones are about 100-fold more active than hydroxyguanidine. At the ID50, no apparent toxicity to the cells was noticed.

A cannabinoid derived prototypical analgesic.

Abstract: The synthesis and analgesic testing of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol (1) are described. Prior (SAR) studies led us to conclude that the pyran ring of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC) was not necessary for the expression of biological activity in this series of cannabinoids. Analysis of models and the use of molecular mechanics calculations suggested that a simpler compound, such as 1, would possess the biological activity of HHC. Compound 1 was prepared in nine steps from [3-(benzyloxy)phenyl]acetonitrile (2). Biological testing in five models of pain shows that compound 1 and morphine are equally potent as analgesics and demonstrates that the pyran ring of HHC is not necessary for biological activity. Further simplification of 1 was pursued by the synthesis of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol (17), but this derivative exhibits significantly reduced analgesic activity.

Potential antitumor agents. 43. Synthesis and biological activity of dibasic 9-aminoacridine-4-carboxamides, a new class of antitumor agent.

Abstract: The synthesis and biological activities of representatives of a new class of antitumor agent, the N-[2-(dialkylamino)ethyl ]-9-aminoacridine-4-carboxamides, are reported. Members of this class are stable and very water soluble with high levels of in vitro and in vivo antitumor activity. The compounds bind tightly to double-stranded DNA by intercalation, but the requirements for antitumor activity are more restrictive. They depend critically on the separation distance, positioning, and pKa values of the two cationic centers. For in vivo activity, significant bulk tolerance exists for lipophilic but not hydrophilic groups about the C-9 acridine position and for both lipophilic and hydrophilic groups on the side-chain cationic moiety. Significant attenuation of the pKa of the side-chain cationic center abolishes activity, as does alteration of either the disposition or separation distance of the side-chain charge with respect to the chromophore.

Antiinflammatory agents. 3. Synthesis and pharmacological evaluation of 2-amino-3-benzoylphenylacetic acid and analogs

Abstract: A series of substituted derivatives of 2-amino-3-benzoylphenylacetic acid (amfenac) has been synthesized and evaluated for antiinflammatory, analgesic, and cyclooxygenase inhibiting activity. Several derivatives including 157 (4'-chloro), 158 (4'-bromo), and 182 (5-chloro, 4'-bromo) were more potent than indomethacin in these assays.

Bis(3,5-diisopropylsalicylato)copper(II), a potent radioprotectant with superoxide dismutase mimetic activity.

Abstract: Superoxide disproportionation may partially account for the noteworthy radioprotectant activity of bis(3,5-diisopropylsalicylato)copper(II) [CuII(3,5-dips)2]. Groups of mice treated with CuII(3,5-dips)2 3 or 24 h before exposure to a lethal dose of gamma-radiation had survival rates of 33% and 58%, respectively. These results suggest that copper complexes might be developed for protection of normal tissues in association with cancer radiotherapy and protection against occupational exposures to hazardous radiation.