Biomedical subjects
Publications and source records attributed to F Tillequin.
A new phenylpropanoid glycoside, ballotetroside, has been isolated from the aerial parts of Ballota nigra. On the basis of chemical and spectral data, its structure has been established as (3,4-dihydroxyphenyl)-2-ethyl[alpha-L-arabinopyranosyl-(1-->2)-alp ha- L-rhamnopyranosyl-(1-->3)]-beta-D-apiofuranosyl-(1-->6)-4-O- caffeoyl-beta-D-glucopyranoside.
Seven 1,2-dihydroxy-1,2-dihydroacronycine and 1,2-dihydroxy-1,2-dihydro-6-demethoxyacronycine esters and diesters were synthesized via osmic oxidation of acronycine or 6-demethoxyacronycine followed by acylation. The 6-demethoxyacronycine derivatives were found to be inactive, whereas in contrast, all of the acronycine derivatives were more potent than acronycine itself when tested against L1210 cells in vitro. Four selected acronycine derivatives (17,19, 21, and 22) were evaluated in vivo against murine P388 leukemia and colon 38 adenocarcinoma implanted in mice. All compounds were markedly active against P388 at doses 4-16-fold lower than acronycine itself. Against the colon 38 adenocarcinoma, the three compounds 17, 21, and 22 were highly efficient. 1,2-Diacetoxy-1,2-dihydroacronycine (17) was the most active, all the treated mice being tumor-free on day 23.
Reported herein is the X-ray crystallographic structure of a novel 10-oxygenated secotrinervitane diterpene, 3 alpha, 10 alpha-diacetoxy-7,16-secotrinervita-7,11,15(17)-triene (4), from soldiers of the endemic Madagascan termite Nasutitermes canaliculatus, which was compared with an energy-minimized structure obtained by computer molecular modeling. We also report 1H- and 13C-NMR and MS data for this new diterpene.
PURPOSE: Combination of the acronycine pharmacophore with various sugar units appeared of interest, since numerous anticancer agents possess a sugar moiety, which strongly influence both their bioavailability and their selective toxicity towards tumor cells. METHODS: A series of 2-hydroxy-1,2-dihydroacronycine glycosides were synthetized, by condensation of the racemic aglycone with appropriate glycoside donors. Their effect on the inhibition of L1210 cell proliferation were evaluated. RESULTS: Compounds 6a, 6b, 11a, 11b, and 12a, 12b, including a halogenated sugar moiety displayed activities of the same order of magnitude as acronycine itself. Compounds 7a, 7b, and 8a, 8b, bearing a 2.3.6-trideoxy-3-azido-L-lyxo- and L-arabino-hexopyranose unit respectively, were significantly more potent than acronycine in inhibiting cell proliferation. CONCLUSIONS: The activity of 2-hydroxy-1,2-dihydroacronycine glycosides seems to be related to the lipophilicity of the sugar unit.
Nitration of acronycine (1) and 6-demethoxyacronycine (3) afforded 2-nitroacronycine (2) and 2-nitro-6-demethoxyacronycine (4), respectively. Reduction of 2-nitroacronycine yielded, depending on the conditions, 2-nitro-1,2-dihydroacronycine (5), 2-oxo-1,2-dihydroacronycine oxime (7) or 2-amino-1,2-dihydroacronycine (6). This latter was readily converted into 2-dimethylamino-1,2-dihydroacronycine (8), 2-acetylamino-1,2-dihydro-acronycine (9) and 2-benzoylamino-1,2-dihydroacronycine (10). The cytotoxicity of these compounds was evaluated against L1210 leukemia cells. Compounds 2 and 7 were 300- and 10-fold more potent than acronycine in inhibiting L1210 cell proliferation, respectively. Compound 2 was devoid of antitumor activity against P388 leukemia and C38 colon adenocarcinoma.
The two novel prodrugs 4 and 11 have been prepared from tetra-O-acetyl-D-galactopyranose and doxorubicin in three and six steps, respectively. Their low cytotoxicity, high stability in plasma and, in the case of 11, efficient hydrolysis in the presence of alpha-galactosidase, fulfill preliminary conditions for their use in combination with monoclonal antibody-enzyme conjugates.
Three new labdane diterpenes, 12 alpha,17-epoxy-3 beta-hydroxy-8(9),13- labdadien-16,15-olide (aulacocarpinolide) [1], methyl 8 beta,17:14 zeta,15-diepoxy-3 beta-hydroxy- 12E-labden-16-oate (aulacocarpin A) [2], and methyl 8 beta,17:14 zeta,15-diepoxy-3 beta,6 beta- dihydroxy-12E-labden-16-oate (aulacocarpin B) [3] have been isolated from the Cameroonian spice, Aframomum aulacocarpos, and their structures elucidated using spectroscopic techniques. The known bioactive diterpene dialdehyde, 8 beta,17-epoxy-12E-labdene-15,16-dial (aframodial) [4] was also isolated. Compounds 1-3 showed weak antimicrobial and cytotoxic activities.
The synthesis of quercetin-3-O-beta-D-glucopyranosyl-(1-->2)-beta-D-xylopyranoside [10], a flavonoid recently isolated from Kalanchoe prolifera, has been carried out via orthoester methodology.
The in vitro activities of furo[2,3b]quinoline and acridone alkaloids against Plasmodium falciparum were evaluated by an isotopic semimicrotest. A pyran ring in the furoquinoline nucleus and 2-O-pyranoglycoside and 2-nitro substituents in the acridone nucleus improved the antimalarial activities of the compounds. These findings provide a clue for further chemical modifications.
New prodrugs of daunorubicin, 1c, 1e and 2c, including a galactopyranosyl residue linked to the N-3' of the daunosaminyl moiety through substituted o- or p-benzyloxycarbonyl groups were synthesized. Their low cytotoxicity and high stability in plasma fulfil the conditions for antibody-directed enzyme prodrug therapy (ADEPT). Enzymatic hydrolysis using alpha-D-galactosidase gives rise to daunorubicin by subsequent self-elimination of the spacers. However, elimination clearly depends on the aromatic substitution pattern, as demonstrated especially by comparison with non-substituted analogues.
4'-O-Acetyl-3'-deamino-3'-chloro and 4'-O-acetyl-3'-deamino-3'-bromoepidaunorubicin analogs have been synthesized by condensation of daunomycinone with the corresponding hexopyranosyl chlorides. The glycosides obtained were less potent than adriamycin (ADR) in inhibiting the proliferation of tumor cells in vitro, but they have shown promising activity against a variety of multidrug resistant (MDR) cell lines.
The synthesis of the phenyl beta-glycoside of avobiose, a disaccharide fragment present in the antibiotic avoparcin, is reported. It is based on glycosylation of phenyl 3,4,6-tri-O-benzyl-beta-D-glucopyranoside with 2,3,6-trideoxy-4-O-p-nitrobenzoyl-3-trifluoroacetamido-L-ribo-hex- 1-enitol, a fully protected glycal of L-ristosamine, in the presence of trimethylsilyl triflate.
A novel monoterpene alkaloid, oxerine, has been isolated from the aerial parts of OXERA MORIERI. Its structure 7 has been elucidated on the basis of its spectral data and its sterochemistry established by its synthesis, using harpagide as starting material. Five iridoids and verbascoside have also been isolated from the plant material.
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Two alkaloids (N-methylisosalsoline and carnegine) had been previously described from the aerial parts of Hammada articulata ssp. scoparia. A thorough study of this plant material has now led to the isolation of eight minor alkaloids and one flavonoid. The alkaloids include four isoquinolines (isosalsoline, salsolidine, dehydrosalsolidine and isosalsolidine), one isoquinolone (N-methylcorydaldine), tryptamine, N-omega-methyltryptamine and one beta-carboline (tetrahydroharman). The flavonoid has been identified as isorhamnetin-3-O-beta-D-robinobioside. The structures have been elucidated on the basis of spectral data, mainly mass spectrometry (D-IC) and 1H NMR.
Fractionation of the methanolic extract of Mussaenda arcuata leaves resulted in the isolation of four flavonoid glycosides and of two phenylpropanoid derivatives. The flavonoids were identified as astragalin 2, isoquercitrin 3, kaempferol-3-O-beta-D-rutinoside 5 and rutin 6 and the two phenylpropanoid derivatives as melilotoside 4 and dihydromelilotoside 1. This latter compound is a novel natural product. The structures of compounds 1-6 have been elucidated on the basis of their spectral data and of those of their acetyl derivatives.
Racemic 7-hydroxy-9-oxa-anthracyclinone (5a) has been synthetised in seven steps from quinizarin (6) and its resolution achieved after glycosylation with 3,4-di-O-acetyl-2-deoxy-L-fucose. Chiral pool syntheses of (8S)-8-hydroxymethyl-9-oxa-anthracyclinone (5b) and of (8S,10R) and (8S,10S)-8-hydroxymethyl-10-methyl-9-oxa-anthracyclinones (5c and 5d) have been achieved using (R)-2,3-O-isopropylideneglyceraldehyde (12) and leucoquinizarin (13) as starting materials. Glycosylation of aglycones 5b-5d by either 3,4-di-O-acetyl-2-deoxy-L-fucose or various 3-amino-2,3,6-trideoxy-L-hexoses yielded the corresponding anthracyclines. The synthetic glycosides do not show significant cytotoxic activity at a concentration of 1 microgram/ml against L 1210 cells.