No description available.

<p>Histone deacetylases (HDACs) have been shown to play key roles in tumorigenesis, and</p><p>have been validated as effective enzyme target for cancer treatment. Largazole, a marine natural</p><p>product isolated from the cyanobacterium Symploca, is an extremely potent HDAC inhibitor that</p><p>has been shown to possess high differential cytotoxicity towards cancer cells along with excellent</p><p>HDAC class-selectivity. However, improvements can be made in the isoform-selectivity and</p><p>pharmacokinetic properties of largazole.</p><p>In attempts to make these improvements and furnish a more efficient biochemical probe</p><p>as well as a potential therapeutic, several largazole analogues have been designed, synthesized,</p><p>and tested for their biological activity. Three different types of analogues were prepared. First,</p><p>different chemical functionalities were introduced at the C2 position to probe the class Iselectivity profile of largazole. Additionally, docking studies led to the design of a potential</p><p>HDAC8-selective analogue. Secondly, the thiol moiety in largazole was replaced with a wide</p><p>variety of othe zinc-binding group in order to probe the effect of Zn2+ affinity on HDAC</p><p>inhibition. Lastly, three disulfide analogues of largazole were prepared in order to utilize a</p><p>different prodrug strategy to modulate the pharmacokinetic properties of largazole.</p><p>Through these analogues it was shown that C2 position can be modified significantly</p><p>without a major loss in activity while also eliciting minimal changes in isoform-selectivity. While</p><p>the Zn2+-binding group plays a major role in HDAC inhibition, it was also shown that the thiol</p><p>can be replaced by other functionalities while still retaining inhibitory activity. Lastly, the use of</p><p>a disulfide prodrug strategy was shown to affect pharmacokinetic properties resulting in varying</p><p>functional responses in vitro and in vivo.</p><p>v</p><p>Largazole is already an impressive HDAC inhibitor that shows incredible promise.</p><p>However, in order to further develop this natural product into an anti-cancer therapeutic as well as</p><p>a chemical probe, improvements in the areas of pharmacokinetics as well as isoform-selectivity</p><p>are required. Through these studies we plan on building upon existing structure–activity</p><p>relationships to further our understanding of largazole’s mechanism of inhibition so that we may</p><p>improve these properties and ultimately develop largazole into an efficient HDAC inhibitor that</p><p>may be used as an anti-cancer therapeutic as well as a chemical probe for the studying of</p><p>biochemical systems.</p> / Dissertation

La réaction de métathèse a connu un essor considérable au cours de ces dernières années et le prix Nobel décerné aux chimistes Yves Chauvin, Robert H. Grubbs et Richard R.Schrock est venu récompenser ce travail. Cette réaction a été impliquée pour la synthèse de molécules naturelles d’origine marine. Les thiocyanatines A et B isolées en 2001 ont été ainsi préparées en utilisant la réaction de métathèse croisée. Il s’agit du premier exemple de métathèse en présence de groupements thiocyanates. De plus, ces deux synthèses utilisent la technologie micro-ondes. Le largazole, isolé en 2008, est une cible synthétique très important du fait de son activité anticancéreuse. Ce manuscrit retrace la synthèse d’une partie de cette molécule mais également une étude méthodologique pour la formation de motifs thiazoles par micro-ondes. Enfin, la rugulactone, isolée en 2009, a été préparée selon une stratégie tandem de métathèse cyclisante / métathèse croisée et cette dernière a été appliquée à la synthèse d’analogues. / The metathesis realized an important development during the last few years and the Nobelprize given to the chemists Yves Chauvin, Robert H. Grubbs et Richard R. Schrock came toreward this work. This reaction has been involved for the synthesis of natural molecules of marine origin. Thiocyanatines A and B, isolated in 2001, have been so prepared by using the reaction of cross metathesis. This is the first example of metathesis with the presence ofthiocyanates groups. Moreover, these two syntheses are using the microwave technology. Largazole, isolated in 2008, is a very important synthetic target because of its anticancerous activity. This manuscript is explaining the synthesis of one part of this molecule but it also provides a methodological study for the formation of thiazoles motives by microwave. Then,Rugulactone, isolated in 2009, has been prepared with a tandem strategy of ring clossing metathesis / cross metathesis and this one has been applied to the synthetis of analogues.

<p>Part I: Extensive studies for treating hypercholesterolemia, one of the major causes of human morbidity throughout the world, have led to the development of statin drugs-the most prevalent drug prescribed today. In addition to statins, SCH 351448 has attracted considerable interest from many synthetic groups as it is the only selective activator of low-density lipoprotein receptor (LDL-R) containing structural features such as a C2-symmetry and 2,6-cis-tetrahydropyrans. Even though direct dimerization has been the most efficient method for the construction of C2-symmetric macrodiolides, total syntheses of SCH 351448 were only achived by stepwise dimerizations. In this chapter, attempts were made to exploit the inherent C2-symmetric macrodioloide via direct dimerization using various single monomeric units, but they did not prove to be viable. Therefore, formal synthesis of SCH 351448 was accomplished through two tandem sequences; cross-metathesis/conjugate addition and allylic oxidation/conjugate addition reactions, to stereoselectively construct 2,6-cis-tetrahydropyrans embedded in SCH 351448. The 1,4-syn aldol and the Suzuki coupling reactions were effective for the construction of the monomeric units. This convergent route should be broadly applicable to the synthesis of a diverse set of analogues of SCH 351448 for further biological studies.</p><p>Part II: Histone deacetylases (HDACs) play a significant role in tumorigenesis and have been recognized as one of the target enzymes for cancer therapy. Extensive studies in small molecules inhibiting HDAC enzymes have resulted in pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and class I HDAC inhibitor FK228, approved by FDA in 2006 and 2009, respectively. Recently, largazole, a natural product was isolated from Symploca sp. presented HDAC inhibitory activity. Due to its unique differential cytotoxicity, potency, and class selectivity, structure-activity relationship (SAR) studies of largazole have been achieved to improve the potency and class selectivity. In addition to such biological activities, pharmacokinetic characteristics and isoform selectivity should be improved for the therapeutic potential of cancer therapy. In this chapter, two types of largazole analogues were synthesized by a convergent route that involved an efficient and high yielding multistep sequence. The synthesis of three disulfide analogues to improve pharmacokinetics and five linker analogues to enhance HDAC isoform selectivity is disclosed. The evaluation of biological studies is in progress.</p> / Dissertation

No description available.