The syntheses, the biological evaluation, and the structure-activity relationships of a novel series of l,8-dihydroxy-9(10H)-anthracenones bearing acyl-, alkyl-, or alkylidene-linked aromatic substituents in the 10-position are described. The phenylacyl and phenylalkylidene analogs were far more potent inhibitors of 5-lipoxygenase (5-LO) from bovine polymorphonuclear leukocytes (IC50 values in the 10 -7 M range) than the antipsoriatic drug anthralin, whereas phenylalkyl analogs were only weak inhibitors. Among the active compounds were both potent generators of hydroxyl radicals, as determined by deoxyribose degradation, and strong reducers of the stable free radical 2,2-diphenyl-l-picrylhydrazyl (DPPH). However, several derivatives of this series maintained 5-LO inhibitory activity but did not generate hydroxyl radicals and were not reactive with DPPH. In particular, phenylacyl analogs were also 6 times more efficient in inhibition of lipid peroxidation in model membranes than anthralin. Structure-activity relationships have shown that the presence of free phenolic groups in the attached aromatic ring is beneficial but not required for 5-LO inhibitory potency. The inhibitory potency in the 10-phenylacyl series increased with the length of the acyl chain with three methylene units being the optimum, suggesting a specific enzyme interaction which would not be expected for nonspecific redox inhibitors.Psoriasis is a widespread, chronic inflammatory and scaling skin disease, mainly characterized by increased cell proliferation of the epidermis.
The 8-alkyl- (3-6), 8-phenyl- (7), 12-bromo- (8), 8-alkyl-12-bromo- (9-12), and 12-bromo-8-phenyl- (13) berberine derivatives were prepared and tested for their antimicrobial activity in vitro to evaluate structure-activity relationships. Introduction of the alkyl or phenyl group and the bromine atom into the C-8 and C-12 positions of berberine (1), respectively, led to significant increases of the antimicrobial activity. In both the 8-alkyl- and 8-alkyl-12-bromo-berberines (3-6 and 9-12, respectively), the antibacterial activity increased as the length of the aliphatic chain increased. The exception was the activity against Candida albicans and Escherichia coli, which did not always increase as the alkyl side chain lengthened. Among the compounds tested, 12-bromo-8-n-hexylberberine (12) was 64, 256, 128, 16, and 32 times more active against Staphylococcus aureus, Bacillus subtilis, Salmonella enteritidis, E. coli, and C. albicans, respectively, in comparison to the clinically used berberine. Compound 12 was also found to be 8, 16, and 128 times more active against S. aureus, S. enteritidis, and C.albicans, respectively, than kanamycin sulfate, but was of the same order of activity against B. subtilis, and only one-fourth as active against E. coli.
A number of lapacho compounds, representing the most common constituents of the inner bark of Tabebuia impetiginosa, together with some synthetic analogues, were evaluated in vitro against the growth of the human keratinocyte cell line HaCaT. With an IC(50) value of 0.7 microM, beta-lapachone (4) displayed activity comparable to that of the antipsoriatic drug anthralin. 2-Acetyl-8-hydroxynaphtho[2,3-b]furan-4,9-dione (7), which was prepared in a four-step synthesis from 2,8-dihydroxy-1, 4-naphthoquinone, was the most potent inhibitor among the known lapacho-derived compounds and inhibited cell growth with an IC(50) value of 0.35 microM. Furthermore, other active constituents of lapacho inhibited keratinocyte growth, with IC(50) values in the range of 0.5-3.0 microM. However, as already observed with anthralin, treatment of HaCaT cells with these potent lapacho compounds also caused remarkable damage to the plasma membrane. This was documented by leakage of lactate dehydrogenase into the culture medium, which significantly exceeded that of the vehicle control. Because of their potent activity against the growth of human keratinocytes, some lapacho-derived compounds appear to be promising as effective antipsoriatic agents.
The reaction of peri-substituted anthracenediones with sodium dithionite in dimethylformamide and water has been investigated. The system selectively reduces the carbonyl group flanked by the peri substituents of the anthracenediones to give the corresponding 4,5-disubstituted 9(10H)-anthracenones and thus provides a route to anthracenones which are otherwise difficult to obtain. Many functional groups can be tolerated, the reaction is compatible with the presence of peri alkoxy groups and unsaturated side chains of the starting anthracenediones, and the reduction does not go beyond the anthracenone stage. However, the formation of anthracenones depends on the nature of the peri substituents. No products were obtained from the 1,8-dimethyl-substituted anthracenedione and the parent compound with no substituents.
The present listing includes emetine and emetine analogs, all of which incorporate as part of their structures a top isoquinoline portion originating from tyrosine and a lower portion of monoterpenoidal origin. Tubulosine and related bases are also included; these consist of a top isoquinoline portion, a middle portion of monoterpenoidal origin, and a lower pendant indole system originating from tryptophan.The last alkaloid to be mentioned is the recently characterized bharatamine (30), which occupies an anomalous position. Biogenetically, it is related to emetine (1) because its upper moiety emanates from tyrosine and its lower half is very probably of terpenoidal derivation. From a purely structural aspect, however, this compound may be considered a protoberberine, even though it lacks the two oxygenated substituents always present in ring D of the protoberberines. Because of this ambiguity, bharatamine is included in this listing and will also be mentioned in a forthcoming review of the protoberberines.Emetine and emetine analogs occur with certainty in only three plant families: Alangiaceae, Icacinaceae, and Rubiaceae. Psychotria ipecacuanha Stokes (Rubiaceae) is one of the main sources for emetine and its analogs. The name of this plant is synonymous with Cephaelis ipecacuanha Rich, and also with Uragoga ipecacuanha Baill. Similarly, Psychotria granadensis Benth. ex Oerst is synonymous with Uragoga granadensis.Uv data are in nm, and log e values are quoted between parentheses. Ir frequencies are in cm-1. Nmr spectra are at low resolution in CDC13, unless stated otherwise.Chemical shifts are in units. Whenever two or more references are cited, it is usually the first reference that is actually quoted in the tables.The numbering system for emetine (1) is as given below. Several reviews or listings of the emetine alkaloids have appeared in the literature (la-o).
In vitro cytotoxic activities of 24 quaternary protoberberine alkaloids related to berberine have been evaluated using a human cancer cell line panel coupled with a drug sensitivity database. Extending the alkyl chain at position 8 or 13 strongly influenced the cytotoxic activity, that is, relative lipophilicity as well as the size of the substituent affects cytotoxicity. The highest level of activity was observed in 8- or 13-hexyl-substituted derivatives of berberine. Structure-activity relationships are described.
Methoxy-indolo[2,l-a]isoquinolines 8a-f and their dihydroderivatives 7a-f were synthesized by Bischler-Napieralski reaction of the (bromomethoxyphenyl)-[2-(methoxyphenyl)-ethyl]acetamides 4a-f, reduction, subsequent cyclization and dehydrogenation. They were tested for cytostatic activity in vitro using P388 D x leukemia and MDA MB 231 mammary tumor cells. The trimethoxy-5,6-dihydroindoloisoquinoline 7d and the tetramethoxyindoloisoquinoline 8f showed an inhibition of cellproliferation of about 70 % at a concentration of 10" 5 molar. The aim of our investigations is the synthesis of cytostatic compounds with binding affinity for the estrogen receptor, that can be used for the selective treatment of hormone dependent mammary tumors. Suitable structures for this approach are tetracyclic N-heterocycles, which are known to intercalate into the DNA 1 ) and are able to bind to the estrogen receptor 2 ).Based on these findings, we synthesized a number of indolo[2,l-a]isoquinolines 8a-f and their dihydro analogues 7a-f. Cytostatic activity of these compounds was evaluated in vitro using MDA-MB 231 mammary tumor cells and P388 D 1 leukemia cells. ChemistryThe synthesis was performed as outlined in scheme 1. The starting methyl bromophenylacetates 2a-c were synthesized by bromination of the corresponding phenylacetic acids and conversion to the methyl esters. The 2-phenylethylamine 3a was obtained directly by LiAlH 4 reduction of the 3-methoxy-ß-nitrostyrene 3) or, in better yield, in two steps with NaBH 4 followed by LiAlH 4 . The best method was the hydrogenation of the 3-methoxy-phenylacetonitrile with Rh/C.The reaction of the bromo-phenylacetates 2a-c with the 2-phenylethylamines 3a and 3b afforded the corresponding amides 4a-f. Cyclisation to the 3,4-dihydroisoquinolines was accomplished by a modified Bischler-Napieralski method using POCl 3 in CH 3 CN. The crude products were treated with NaBH 4 to give the 1,2,3,4-tetrahydro-l-benzylisoquinolines 5a-f. In the case of 4c (2-Bromo-4,5-dimethoxyphenyl)-(3,4-dihydro-6-methoxyisoquinolyl-l)-ketone was formed as a byproduct, probably by air oxidation 4) . The correct substitution pattern in the isoquinoline ring was confirmed by ^-NMR spectroscopy.The benzylisoquinolines 5a-f were converted into the tetracyclic indolo[2,l-a]isoquinolines by treatment with NaH in DMSO. This reaction must involve a benzyne intermediate 5) because both bromo compounds 5a and 5b led to the same structure. The reaction mixture contained two products
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