Regiospecific synthesis of pyrido[3,4-b]- and pyrido[4,3-b]carbazole-5,11-dione derivatives. Evaluation of their in vitro antifungal or antiprotozoological activities.

Hetero Diels-Alder reactions between 2- or 3-bromocarbazolequinones 1a or 1b and azadiene 5 afford regiospecifically pyrido[3,4-b]- and pyrido[4,3-b]carbazole-3,5,11-triones 6a and 6b. The regiochemistry of the cycloadditions is controlled by the position of the bromine atom at C-2 or C-3 of the bromoquinone. The corresponding N- and O-methyl derivatives 7 and 8 are prepared. Structural assignment of the regioisomers is made by 1H-NMR nuclear Overhauser effect difference experiments performed on a diacetoxy derivative of pyrido[4,3-b]carbazole 9b. The in vitro antifungal and antiprotozoological activities of some prepared derivatives have been evaluated against Candida albicans, Candida krusei, Cryptococcus neoformans and Trichomonas vaginalis. None of the tested compounds have shown significant activity towards the yeasts or protozoa.

Synthesis of furonaphth[1,3]oxazine and furo[1,3]oxazinoquinoline derivatives as precursors for an o-quinonemethide structure and potential antitumor agents.

The synthesis of dihydro furonaphth[1,3]oxazine derivatives 3 was performed through a Mannich-type condensation between 2-cyano-5-hydroxy-3-methylnaphtho[1,2]furan 2a, 1.5 eq of a primary amine and 3 eq of formaldehyde. Similarly, 2-cyano-5-hydroxy-3-methylfuro[2,3-f]quinoline 2b gave the dihydro furo[1,3]oxazino-quinoline compounds 4. Heating a mixture of the naphthofuran 2a, tert-butylamine and formaldehyde at toluene reflux led to the furonaphthoxazine 3e, which decomposes to afford an o-quinonemethide intermediate 5. The latter was trapped with 1-morpholinopropene to give a dihydro furonaphthopyran derivative 6. All compounds 2, 3, 4 and 6 were assayed for in vitro cytotoxic activity toward L 1210, MDA-MB 231 and PC tumor cells. Among them, furonaphth[1,3]oxazines 3b, 3c, and furo[1,3]oxazinoquinolines 4c, 4d showed significant activity against L 1210 cells, while furoquinoline 2b was the most cytotoxic compound towards all three cell lines.

Synthesis of Mannich bases of 5-hydroxynapthalene-1,8-carbolactone as potential antifungal or antitumor agents.

Mannich bases of 5-hydroxynaphthalene-1,8-carbolactone 1 were prepared from various secondary amines or bulky primary amines and formaldehyde. They were isolated in almost all cases as hydrochlorides. These derivatives were submitted to in vitro antifungal and cytotoxic assays. The antifungal assays were performed against three strains of yeasts and five strains of human pathogenic fungi. Two of the tested compounds, 2i and 2j, exhibited interesting antifungal activities against Candida albicans and Candida tropicalis. The cytotoxic activity was evaluated towards L 1210 leukemia cells. Almost all of the Mannich bases had shown significant activity against this tumor cell line as values of IC50 less than or equal to 4 micrograms/ml are considered interesting. Only one derivative 2 developed better cytotoxicity than the parent compound 1.

[Excitability cycle of the soleus motor nucleus during synergistic conditioning in man]. / Cycle d'excitabilité du noyau moteur soléaire en conditionnement synergiste chez l'homme.

Electrical stimulation of medial or lateral gastrocnemius nerve modulates the H reflex of the soleus muscle in a well defined sequence of inhibitory and facilitatory phases the amplitude of which depends on the strength of the conditioning stimulus. This method of investigation of the soleus monosynaptic reflex pathway avoids the disadvantages of homonymous conditioning. Discussion of our results points to the roles of Ib and Renshaw cells inhibitions in the early phases of the recovery cycle, and to the roles of reafferents, disinhibition of Renshaw cells, presynaptic inhibition and muscarinic discharge of Renshaw cells for the late phases.

[Proprioceptive proximo-distal relationships between the quadriceps and soleus muscles in man]. / Liaisons proprioceptives proximodistales entre muscles quadriceps et soléaire chez l'homme.

Electrical stimulation of femoral nerve modulates voluntary tonic activity o of ipsilateral soleus muscle. Stimulus time-locked inhibitory and facilitatory phases can be distinguished. EMG temporal analysis suggests that early perturbations are correlated with spinal effects of centripetal electrical activity. The inhibitory effects which momentarily abolish voluntary soleus activity are thought to result from quadriceps Ib fibres recruitment. While no heteronymous activity is induced at rest, femoral nerve Ia fibres activation can produce soleus muscle reflex when soleus motor nucleus excitability is increased by voluntary command. Recurrent discharge resulting from soleus reflex response enhances inhibition initially due to quadriceps Ib volley. Secondary effects of isometric quadriceps contraction (and soleus contraction when the femoral stimulus elicits a reflex in this muscle) have their own effects later. These findings suggest that proprioceptive relationships of the two muscular groups are efficient during tonic isometric voluntary command.