L’identification d’une substance naturelle, produite par un organisme vivant n’est que l’une des toutes premières étapes du développement d’un nouveau médicament. Beaucoup de molécules à visée thérapeutique développées par des sociétés pharmaceutiques ont en fait été découvertes dans des laboratoires académiques. C’est toujours un continuum de la recherche fondamentale vers la recherche appliquée, souvent de la recherche publique vers la recherche privée, qui aboutit à la mise au point d’un médicament. Leur fabrication, directement à partir de substances naturelles, pose fréquemment le problème de l’approvisionnement en matière première. De nombreuses équipes du monde entier se heurtent aux difficultés de synthèse de ces molécules naturelles complexes. Ce travail de thèse retrace l’histoire des travaux majeurs sur la recherche de molécules naturelles d’intérêt médical à travers les succès et les échecs de chercheurs ayant mis leur énergie, leur imagination, leur ténacité et leur patience au service de la science pour surmonter les obstacles et découvrir de nouvelles molécules de grand intérêt thérapeutique. Elle présente également un travail complémentaire de mise au point d’une base de données regroupant un certain nombre de plantes utiles dans la lutte contre le cancer dans le cadre d’un projet de vulgarisation scientifique. La discussion est consacrée à la question de la place du hasard dans les découvertes scientifiques à travers l'exemple de Pierre Potier. / Identifying a natural substance produced by a living organism is only one of the very first steps towards the development of a new drug. Many molecules which were aimed at therapeutic goals and developed by pharmaceutical companies have in fact been discovered in academic research laboratories. The elaboration of a new drug is always a continuum from basic research toward applied research, and often from public research toward private research. Making these drugs straight from natural substances frequently confronts us with the problem of finding the raw materials. Numerous teams all over the world are facing the difficulties linked to the synthesis of these complex natural molecules.This PhD thesis relates the story of the milestones in the research of natural molecules for medicine through the successes and failures of scientists who put their energy, imagination, tenacity and patience into Science in order to overcome obstacles and discover new molecules for therapeutic use.It also presents a complementary work which consists in developing a database of useful plants in cancer fighting as part of a project of scientific vulgarisation. The discussion is about the part of chance in scientific discovery through the example of Pierre Potier.

Agelanthus dodoneifolius est une plante de la pharmacopée africaine utilisée en médecine traditionnelle pour le traitement de pathologies cardiovasculaires. Un fractionnement bioguidé a permis d'isoler une nouvelle dihydropyranone : baptisée Dodonéine (Ddn), elle possède des propriétés hypotensives et vasorelaxantes chez le rat.L'objectif de la thèse est de caractériser la ou les cible(s) moléculaire(s) de la Ddn dans le système cardiovasculaire et d'identifier un dérivé plus sélectif.Nos résultats montrent que la Ddn bloque le courant calcique de type L des cardiomyocytes ventriculaires de rat et des cellules musculaires lisses vasculaires, d'environ 30% avec une IC50 de l'ordre du µM. La Ddn apparaît comme un nouveau bloqueur des canaux calciques de type L avec des propriétés électrophysiologiques qui lui sont propres. Une étude biochimique a montré que l'anhydrase carbonique (CA) est également inhibée par la Ddn, et nous avons caractérisé l'expression de plusieurs isoformes au sein de muscle lisse vasculaire : CA II, III, XIII et XIV. Nos travaux précisent que leur inhibition augmente le pH intracellulaire, pouvant conduire à l'activation des canaux KCa. Ainsi, la Ddn induit un effet vasorelaxant en inhibant deux protéines: les canaux calciques et l'anhydrase carbonique. Nous avons ensuite démontré que les dérivés de la Ddn nouvellement synthétisés sont aussi vasorelaxants ; toutefois, le plus efficace, la Ddn-Bicyclique-OH, ne concurrence pas les bloqueurs calciques utilisés en clinique. Cependant, l'effet vasorelaxant de la Ddn et Ddn-Bc-OH caractérisé sur des artères systémiques humaines est en accord avec l'utilisation de la plante en médecine traditionnelle. / Agelanthus dodoneifolius is one of the medicinal plants used in African pharmacopeia and traditional medicine for the treatment of cardiovascular diseases. Bioguided fractionation has allowed isolating one of its main active principles named Dodoneine (Ddn). It is a new dihydropyranone which exerts hypotensive and vasorelaxant effects on rat.The aim of this work is to characterize the molecular(s) target(s) of Ddn on cardiovascular system and identify the most selective and effective Ddn's derivative.Electrophysiological studies revealed that Ddn blocks L-type calcium current density of about 30% with an IC50 value of about 2 µM on cardiac myocytes and on vascular smooth muscle cells. Ddn appears as a new natural calcium channel blocker which has its own electrophysiological properties. As it has been shown, by biochemical study, that carbonic anhydrase is a potential target for Ddn, we have demonstrated that isozymes II, III, XIII are present on vascular smooth muscle cells and inhibited by Ddn. This inhibition resulted in a rise in pHi of about 0.31, leading to KCa channel activation. Interestingly, Ddn induced vasorelaxation by targeting two proteins: calcium channel and carbonic anhydrase. Then, we demonstrated that Ddn's derivatives newly synthetized have also vasorelaxant properties via the inhibition of L-type calcium current. Among them, Ddn-Bicyclique-OH is the most effective but appears not to be a better pharmacological tool compared to the calcium channel blockers already use in clinical. However, in accordance to the use of the plant in traditional medicine, our results clearly show that Ddn and Ddn-Bc-OH induce a vasorelaxant effect on human systemic artery.

A presente pesquisa tem como objetivo desenvolver um estudo acerca da noção aristotélica de constituição orgânica, no qual procurarei propor um exame da filosofia da natureza de Aristóteles referente ao aspecto, atribuído ao organismo, de ser substância natural no seu mais elevado grau, estabelecendo uma análise comparativa entre os compostos elementares, os compostos homogêneos inanimados e os compostos orgânicos. Para tanto, pretendo, primeiramente, promover uma análise a respeito do caráter substancial dos organismos vivos. Em seguida, delimitar uma investigação em torno dos tipos de composições naturais, levando em conta a maneira pela qual a necessidade natural estaria envolvida no processo constitutivo de tais composições. E, por fim, oferecer uma interpretação relativa ao capítulo 12 do livro IV dos Meteorológicos, a qual tem por base discernir a natureza formal associada, por um lado, às propriedades características dos corpos homogêneos em geral, considerados em si e por si mesmos, e, por outro, às propriedades características da constituição orgânica, de modo a precisar as diferenças entre elas. Penso que, com este estudo, também será possível compreender de um modo claro o motivo pelo qual, nesta concepção de natureza, toma-se o organismo vivo como o paradigma de substâncias (ousiai) naturais. / This research aims to develop a study on the aristotelian notion of organic constitution, which seek to propose an examination of the natural philosophy of Aristotle concerning the aspect, assigned to the body, to be natural substance in its highest degree, establishing an analysis comparative between elementary compounds, inanimate homoeomerous compounds and organic compounds. Therefore, I intend, first, to promote an analysis regarding the substantial nature of living organisms. Then delimit an investigation around the kinds of natural compositions, taking into account the way in which natural necessity would be involved in the constitutive process of such compositions. And finally, offer an interpretation relating to Chapter 12 of De Caelo IV, which relies on discerning the formal nature associated, on the one hand, the characteristic properties of homoeomerous bodies generally considered in themselves and for themselves, and, on the other hand, the characteristic properties of the organic constitution in order to clarify the differences between then. I think that, with this study, also will be possible understand in a clearly way the reason, in this conception of nature, it takes the living organism as the paradigm of natural substances (ousiai).

A presente pesquisa tem como objetivo desenvolver um estudo acerca da noção aristotélica de constituição orgânica, no qual procurarei propor um exame da filosofia da natureza de Aristóteles referente ao aspecto, atribuído ao organismo, de ser substância natural no seu mais elevado grau, estabelecendo uma análise comparativa entre os compostos elementares, os compostos homogêneos inanimados e os compostos orgânicos. Para tanto, pretendo, primeiramente, promover uma análise a respeito do caráter substancial dos organismos vivos. Em seguida, delimitar uma investigação em torno dos tipos de composições naturais, levando em conta a maneira pela qual a necessidade natural estaria envolvida no processo constitutivo de tais composições. E, por fim, oferecer uma interpretação relativa ao capítulo 12 do livro IV dos Meteorológicos, a qual tem por base discernir a natureza formal associada, por um lado, às propriedades características dos corpos homogêneos em geral, considerados em si e por si mesmos, e, por outro, às propriedades características da constituição orgânica, de modo a precisar as diferenças entre elas. Penso que, com este estudo, também será possível compreender de um modo claro o motivo pelo qual, nesta concepção de natureza, toma-se o organismo vivo como o paradigma de substâncias (ousiai) naturais. / This research aims to develop a study on the aristotelian notion of organic constitution, which seek to propose an examination of the natural philosophy of Aristotle concerning the aspect, assigned to the body, to be natural substance in its highest degree, establishing an analysis comparative between elementary compounds, inanimate homoeomerous compounds and organic compounds. Therefore, I intend, first, to promote an analysis regarding the substantial nature of living organisms. Then delimit an investigation around the kinds of natural compositions, taking into account the way in which natural necessity would be involved in the constitutive process of such compositions. And finally, offer an interpretation relating to Chapter 12 of De Caelo IV, which relies on discerning the formal nature associated, on the one hand, the characteristic properties of homoeomerous bodies generally considered in themselves and for themselves, and, on the other hand, the characteristic properties of the organic constitution in order to clarify the differences between then. I think that, with this study, also will be possible understand in a clearly way the reason, in this conception of nature, it takes the living organism as the paradigm of natural substances (ousiai).