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A methodology was studied to set up the benzo[a]fluorene skeleton, which provides a potential route to the total synthesis of isoprekinamycin (IPK) (1-112) and analogues of this natural product that contains an unusual diazo group so as to study the relationship of the structure and bioactivities. Basically the strategy involved a Suzuki coupling between the bromoindenone 2-64 as an AB ring building block and the pinacol boronate 2-89 as a D ring building block to generate a diaryl intermediate 2-90 that incorporates the A, B and D ring of isoprekinamycin. The diaryl intermediate was cyclized via a Dieckmann-like reaction to provide the full ABCD benzo[a]fluorene ring system that incorporates a cyano group at the carbon atom intended to become the carbon of the diazo group in the final structure. This intermediate was subjected to a sequence of reactions involving hydrolysis of the cyano group to the amide followed by a modified Hofmann rearrangement that provided the C-N bond at the correct position for creation of the diazo group in a three step sequence. This methodology provided a model of IPK 2-58 with the longest linear path of the synthesis being thirteen steps and in a 7% yield overall. A total synthesis of IPK which followed the method developed in the model synthesis was then attempted. In this IPK synthesis, the key Dieckmann-like cyclization that proceeded very selectively in the model synthesis proved to be problematic as a result of a competing aldol reaction involving the B-ring ketone group. This problem was eventually solved by reducing the ketone with LiAlH(n-Bu)(i-Bu)2 to produce a reduced aluminate intermediate which served as a protecting group through several steps to the full benzo[a]fluorene system that provided a sample of IPK, after appropriate functional group modification. The synthetic compound was shown to be identical with a sample of the natural product. The synthesis represents the first total synthesis of IPK and was achieved with an overall yield of 6% and the longest linear path being fourteen steps. An examination of the crystallographic data for the model compound 2-58 and IPK provided structure confirmation of the proposal that the diazonium ion character of the diazo group in IPK is enhanced by the presence of intramolecular H-bonding An analogue of IPK was designed, incorporating a side chain at C3 of the D ring in order to improve solubility and potentially the affinity of the molecule for DNA. An intermediate 4-74 that contains a carbamate group intended to serve as the precursor of the diazo group of the IPK analogue, was synthesized using the same strategy as the model of IPK through eleven steps in 14% yield overall. Another benzo[a]fluorene 5-28 was synthesized in 6% overall yield, via an eleven steps sequence initiated from commercial available 3-methylsalicylic acid. This benzo[a]fluorene is intended to be a key intermediate for the total synthesis of fluorostatin A and for the synthesis of analogues of IPK with a side chain at the C4 of the D ring. A discussion of potential significance of the proposed analogues and how they might be best achieved synthetically from the intermediates prepared in this study is provided.

The aim of the project was to synthesize linear anthrasteroid analogues of testosterone, 19-nortestosterone and estradiol. A total synthesis of (+/-)-7,11-cyclo-8,9-seco-19-nor-testosterone, (+/-)-7,11-cyclo-8,9-secoestradiol and (+/-)-1beta-t-butoxy-9a,11abeta-dimethyl-1,2,3, 3aalpha, 4, 4aalpha, 5,8,9, 9a,10,10alphabeta,11,11a-tetradecahydro-7-cyclopent[b]anthrac-enone was accomplished. The synthesis presented provides a short, direct route to linear anthrasteroid analogues. This compares favourably with the synthesis reported by S. Aoyama and K. Sasaki, which involves complex transformations of steroids. The synthetic route involved the synthesis of the trans-bicyclic hydrindan, (+/-)-1beta-t-butoxy-7abeta-methyl-3aalpha,4,7,7a-tetrahydro-5(6H)-indanone, using the synthetic pathway developed by Z.G. Hajos and D.R. Parrish. This intermediate was regiospecifically annulated to give the novel tricyclic enone, (+/-)-1beta-t-butoxy-9abeta-methyl-l,2,3,3aalpha,4,7,8,8abeta,9,9a-decahydro-6-benz[f]indenone via two different routes. Thestereochemistry of the new ring junction was elucidated by using H n.m.r. spectroscopy and the lanthanide shift reagent Eu(FOD)[3].Further regiospecific annulation of the tricyclic enone gave the novel linear tetracyclic compound, (+/-)-1beta-t-butoxy-lla-methyl-1,2,3,3abeta,4,4abeta,5,8,9,9abeta,10,10abeta,11,11a-tetradecahydro-7-cyclopent[b]anthracenone. The t-butyl group of this compound was removed to give (+/-)-7,11-cyclo-8,9-seco-19-nortestosterone, or the A-ring was aromatized and the t-butyl group cleaved to give (+/-)-7,11-cyclo-8,9-seco estradiol. The synthesis of linear anthrasteroid analogues of testosterone was accomplished by regiospecific methylation of the tricyclic enone to give the novel compound (+/-)-1betat-butoxy-7,9abeta-dimethyl-1,2,3,3a?,4,7,8,8abeta,9,9a-decahydro-6-benz[f]indenone. Regiospecific annulation of this compound gave a mixture of stereoisomers,(+/-)-1beta-t-butoxy-9abeta,11aB-dimethyl-1,2,3,3abeta,4,4a,5,8,9,9a,10,10abeta, 11, 11a-tetradecahydro-7-cyclopent[b]anthracenone and (+/-)-1beta-t-butoxy-9ad, 11abeta-di-methy 1-1,2,3,3aA, 4,4aA, 5,8,9,9a,10,10abeta,11, 11a-tetra-decahydro-7-cyclopent[b]anthracenone.

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La sclérodermie systémique (ScS) est une maladie qui peut engager le pronostic vital des malades de façon très rapide. La pathogénie de la maladie reste encore obscure mais est liée aux atteintes vasculaires probablement en lien avec la fibrose cutanée. La thérapeutique de cette maladie est difficile. Aucun traitement étiologique n'existe et la prise en charge est plutôt axée sur les traitements des différentes atteintes. La iontophorèse cutanée est un dispositif qui permet la diffusion de molécules en solution à travers la peau grâce à une stimulation électrique de manière non invasive. Cette technique a été utilisée initialement comme test physiologique. Notre objectif est d'évaluer et de développer la iontophorèse thérapeutique, notamment avec des molécules vasodilatatrices, pour pouvoir l'utiliser dans des applications thérapeutiques telles que la pris en charge des ulcérations digitales (ou troubles trophiques cutanés) de la ScS. Trois parties ont été développées. La première partie consiste en l'association de deux molécules vasodilatatrices (une per os, le sildenafil, et en iontophorèse, le nitroprussiate de sodium (SNP), en étudiant la tolérance de l'association et son effet sur le flux vasculaire cutané chez le volontaire sain (étude INFLUX-VS). La deuxième partie correspond à un screening de molécules ayant une action vasodilatatrice et étant délivrées en iontophorèse chez le rat : l'étude INFLUX-RAT conclue à l'obtention d'une vasodilatation cutanée chez le rat avec les analogues de la prostacycline. La troisième partie correspond à l'évaluation chez le volontaire sain de la iontophorèse des analogues de la prostacycline : l'étude INFLUX-IT-VS conclue à une dilatation du flux sanguin cutané avec le tréprostinil et avec une bonne tolérance cutanée et systémique. La dernière partie correspond aux avancées parallèles des travaux tant dans le domaine de la reproductibilité des techniques d'acquisition des signaux du flux sanguin cutané que les études réalisées avec les patients sclérodermiques à qui on pourrait espérer un jour voir proposer une iontophorèse thérapeutique. / Systemic scleroderma (ScS) is a rare disease that may be associated with a poor prognosis. The pathogenesis of the disease remains still unclear but comprises vascular abnormalities related to skin fibrosis. ScS disease treatment is difficult. No etiologic therapy is available and patient's management is rather centred on the treatments of the different organs failure symptoms. Skin iontophoresis is a non invasive technique, which allows a transcutaneous diffusion of molecules in solution thanks to an electrical stimulation. This technique was initially used as physiological test. Our objective is to test and to develop therapeutic iontophoresis, in particular with molecules possessing vasodilator properties. The final objective is to use it in therapeutic applications such as the treatment of ScS digital ulcerations. Three parts will be developed in the present work. The first part describes the association of two vasodilatator drugs (sildenafil used per os, associated with sodium nitroprusside used through cathodal iontophoresis. We studied the safety of the association and its effect on the skin vascular flow in healthy volunteers (INFLUX-VS study). The second part describes the screening of vasodilatator drugs delivered through cutaneous iontophoresis in rats (INFLUX-RAT study). The aim of the study was to select the more potent drugs in term of maximal rat skin vasodilatation. The more potent drugs were prostacyclins analogues. The third part describes the iontophoresis of prostacyclins analogues in healthy volunteers: the INFLUX-IT-VS study. The more potent cutaneous vasodilatation was observed with treprostinil, with a good skin and systemic tolerance. The last part decribes the reproducibility of the techniques used to quantify skin blood flow along with studies using these techniques in scleroderma patients. These are required to enable a reproducible evaluation of the effect of skin iontophoresis in patients with scleroderma

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