Biomedical subjects
Publications and source records attributed to F Tillequin.
A new 4(1H)-quinolinone alkaloid, sarcomejine (1), has been isolated from the bark of Sarcomelicope megistophylla. Its structure has been elucidated on the basis of MS and NMR data and especially with a long-range (1)H-(15)N correlation NMR spectrum at natural abundance.
Octandrenolone (1) was prepared in high yield by condensation of 2', 4',6'-trihydroxyacetophenone with 3-chloro-3-methylbut-1-yne in the presence of a catalytic amount of copper(I) iodide. Methylation of 1 afforded O-methyloctandrenolone (2). Oxidation of 2 with m-chloroperoxybenzoic acid followed by hydrolysis gave the racemic trans-(+)-1-(9,10-dihydro-9,10-dihydroxy-5-methoxy-2,2,8, 8-tetramethyl-2H,8H-benzo[1,2-b:3,4-b']dipyran-6-yl)ethanone (3), which confirmed the structure of the natural product previously isolated from Melicope erromangensis.
Two new alkaloids, megistophylline I (1) and megistophylline II (2), were isolated from the bark of Sarcomelicope megistophylla. Their structures have been elucidated on the basis of MS and NMR data.
Ballota nigra is a European plant known for its neurosedative properties. In this study, the ability of five phenylpropanoids (verbascoside, forsythoside B, arenarioside, ballotetroside, and caffeoyl malic acid) isolated from a hydroalcoholic extract, to bind to benzodiazepine, dopaminergic, and morphinic receptors was investigated. To carry out these studies, affinity tests with rat striata, entire brains and receptor rich preparations were employed. In addition, the phenolic aspect of these five phenylpropanoid esters led to investigate antioxidant activities using cell-free experiments and cellular experiments including isolated polymorphonuclear neutrophils (PMN). Effects of phenylpropanoid esters against reactive oxygen species as superoxide anion, peroxide hydrogen, hypochlorous acid and hydroxyl radical were tested. These molecules are liberated by PMN during inflammatory disorders, so that reproduction of this process in vitro stimulating PMN by chemical stimulants was undertaken. Results show that four of the five compounds are able to bind to the studied receptors. Inhibitory concentrations at 50% were determined and vary from 0.4 to 4.7 mg/ml. This may be in relation with the Ballota nigra known neurosedative activities. Results concerning antioxidant investigations evidence an ability to scavenge reactive oxygen species. Inhibitory concentrations at 50% obtained are comparable to those of known antioxidant drugs (mesna or N-acetyl cysteine). Moreover, the use of different stimuli having various pathways of action on PMN oxidative metabolism permits to establish that each phenylpropanoid ester has its own particular way of action by using proteine kinase C or phospholipase C pathways.
Two new alkaloids, megistonine I (1) and megistonine II (2), were isolated from the bark of Sarcomelelicope megistophylla. Their structures, which are derived from the 3-methoxy-4-quinolone basic skeleton, were elucidated on the basis of MS and extensive NMR studies.
In addition to the previously isolated phenylpropanoid glycosides verbascoside 1, forsythoside B 2, arenarioside 3 and ballotetroside 4, another four compounds were isolated from generative aerial parts of Ballota nigra: three phenylpropanoid glycosides, alyssonoside 5, lavandulifolioside 6 and angoroside A 7 and a non-glycosidic derivative (+)-(E)-caffeoyl-L-malic acid 8. The antibacterial activity of the five major compounds (1-4 and 8) was tested against gram-positive and gram-negative bacteria. Three of them (1-3) exhibited a moderate antimicrobial activity against Proteus mirabilis and Staphylococcus aureus including one methicillin-resistant strain.
Two new alkaloids, megistosarcimine and megistosarconine, were isolated from the aerial parts of Sarcomelicope megistophylla. Their structures have been elucidated on the basis of their spectral data and molecular modeling.
Sharpless asymmetric dihydroxylation of acronycine (1) gave (1R, 2R)-1,2-dihydroxy-1,2-dihydroacronycine (2) and (1S,2S)-1, 2-dihydroxy-1,2-dihydroacronycine (3), which allowed determination of the absolute configuration of natural cis-1,2-dihydroxy-1, 2-dihydroacronycine as 1R,2R. The cis isomer had been previously isolated from various Sarcomelicope species. Benzylic reduction of isomers 2 and 3 gave the alcohols 4 (2R) and 5 (2S), respectively. Acetylation of 2 and 3 afforded the corresponding esters 6 and 7. No significant difference of cytotoxicity was observed between these (1R,2R)- and (1S,2S)-enantiomers and the recently described, highly active racemic cis-1,2-diacetoxy-1,2-dihydroacronycine, when tested against L-1210 cells in vitro.
Selective deprotection of peracetylaucubin (3) by use of KCN led to 6-O-acetylaucubin (4), which was readily converted into 2',3',4',6', 10-penta-O-benzoylaucubin (7). Configuration inversion performed on 7, using a modified Mitsunobu reaction, followed by deprotection, afforded 6-epi-aucubin (2).
The leaves of Comptonella microcarpa have yielded one alkaloid, dictamnine, and four known polyoxygenated flavonoids, meliternatin, 3,5,8-trimethoxy-6,7-3',4'-dimethylenedioxyflavone, 7-(3-methylbut-2-enyloxy)-3,5,8-trimethoxy-3', 4'-methylenedioxyflavone (3), 7-hydroxy-3,5,8-trimethoxy-3', 4'methylenedioxyflavone. In addition, two new flavonoids were found whose structures were established on the basis of their spectral data as 7-hydroxy-3,5,6,8-tetramethoxy-3',4'-methylenedioxyflavone (1) and 7-(3-methylbut-2-enyloxy)-3,5,6,8-tetramethoxy-3', 4'-methylenedioxyflavone (2).
Condensation of 2-chloro-3-nitrobenzoic acid with either 5-amino-7-methoxy-2,2-dimethyl-2H-chromene or 5-amino-2,2-dimethyl-2H-chromene afforded diphenylamines 14 and 15. Trifluoroacetic anhydride mediated cyclization gave the corresponding acridones 16 and 17, which were subsequently N-methylated and reduced to 11-aminoacronycine and 11-amino-6-demethoxyacronycine. These two amino compounds, which gave stable water soluble salts, were 2- to 3-fold more potent than acronycine or 6-demethoxyacronycine in inhibiting L1210 cell proliferation.
Sixteen new derivatives of the natural alkaloid acronycine, bearing 1-alkoxy or 1-amino and 2-hydroxy groups, were synthesized in order to clarify the role of the C-1 substitution. Studies on the cytotoxic activity of compounds 4-19 were carried out in vitro on L-1210 cells. Structure-activity relationships are discussed.
New prodrugs consisting of a beta-D-glucuronic acid linked to a MDR reversal agent (verapamil, quinine or dipyridamole) through a self-immolative spacer were synthesized. Four of them were selected for their reduced cytoxicity and beta-glucuronidase enzymatic efficient hydrolysis. Combined use of these prodrugs with a beta-D-glucuronyl-spacer-doxorubicin (HMR1826) according to an ADEPT strategy restored in vitro the sensibility of a MDR resistant strain.
A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CEA-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L1210 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are better substrates for beta-glucuronidase than the corresponding para-substituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected the o-nitro prodrug 25c for clinical trials.
Permanganate oxidation of acronycine (1) led to keto alcohol 4 which could be reduced to trans-1,2-dihydroxy-1,2-dihydroacronycine (3) using NaBH4. Acylation of 3 afforded 12, 13, and 14. These esters (12, 13, and 14) were more potent than 1 when tested against L-1210 cells in vitro. Diacetate 12 was evaluated in vivo against murine P-388 leukemia and was markedly active at a dose 16-fold lower than acronycine itself. Comparison of these results with those recently obtained in the cis-1,2-dihydroxy-1,2-dihydroacronycine series is discussed.
Condensation of 5-amino, 6-amino, 7-amino and 8-amino-2,2-dimethyl-2H-chromenes with either 6-bromoveratraldehyde or 6-chloropiperonal afforded the corresponding Schiff bases, which were subsequently reduced to the corresponding benzylchromenylamines 30-33 and 36-39. Lithium diisopropylamide-mediated cyclization of those amines, followed by spontaneous air oxidation, afforded pyranophenanthridines 3-14. The cytotoxicity of compounds 3-14 was evaluated against L1210 and HT29 cell lines. 9,9-Dimethyl-9H-pyrano[3,2-b]phenanthridines appear to be the most promising compounds of the series, since both the dimethoxy derivative 11 and the methylenedioxy derivative 12 exhibit significant cytotoxic activity. Compound 12 was the most active and induced a massive accumulation of cells in G2 + M phases, suggesting that the cytotoxicity is due to a perturbation of the integrity or function of DNA.
The three new hydrophilic prodrugs 2, 3 and 4 have been prepared from methyl (4-hydroxymethyl-2-nitrophenyl 2,3,4-tri-O-acetyl-beta-D-glucopyranosid)uronate (5) and doxorubicin. Their low cytotoxicity, efficient release of doxorubicin after hydrolysis by beta-D-glucuronidase, and in the cases of 2 and 3 stability at pH 7.2 fulfil the preliminary requirement for their use in antibody-directed enzyme prodrug therapy or prodrug monotherapy.
A preliminary survey of the botanical characters of the species Ballota nigra and of its subspecies is reported. Phytochemical investigation of the flowered aerial parts led us to isolation and structural elucidation of one diterpene (13-hydroxyballonigrinolide) and four phenylpropanoid glycosides reported for the first time from the genus Ballota: verbascoside, forsythoside B, arenarioside and ballotetroside. These compounds appear to be characteristic of this species and could be used for the standardization of the drug. Moreover, the four phenylpropanoid glycosides isolated could justify the use of Ballota nigra as a neurosedative drug.