I. Formal Synthesis of SCH 351448. II. Synthesis and Characterization of Largazole Analogues.
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.
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.
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