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Open Access Publications from the University of California

Design and synthesis of bioactive macrocyclic natural products

  • Author(s): Singh, Erinprit K.
  • Singh, Erinprit K.
  • et al.

Chapter 1 discusses the background of peptides and their potential as therapeutics; specifically as anti-cancer and antibacterial agents. The synthesis of linear peptides via solution and solid-phase is discussed as well as macrocyclization strategies. Sansalvamide A, a macrocyclic depsipeptide, exhibits micromolar cytotoxicity activity against multiple cancer cell lines. Chapter 2 focuses on the synthesis and structure-activity relationship of Sansalvamide A derivatives. Some of the structural features explored in the SAR include: D-amino acids, N- methyl amino acids, polar amino acids and heterocyclic moieties. This chapter includes a discussion of the synthesis for seven SanA derivatives and structure- activity relationship conclusions drawn from biological testing of these compounds. Chapter 3 discusses the design, synthesis and evaluation of histone deacetylase inhibitors. More than half of all human cancers have non- functioning or mutated genes that are the result of overexpression of histone deacetylases; thus, the development of histone deacetylase inhibitors is critical for combating cancers. Chapter 3 describes the synthesis of six histone deacetylase inhibitors that I contributed to a library of 17 derivatives based on two macrocyclic tetrapeptide natural products: FR235222 and apicidin. Upon biological evaluation of these histone deacetylase inhibitors, a discussion of the structure-activity relationship is presented. Chapter 4 describes the total synthesis of Sanguinamide B. This natural product contains two thiazoles and one oxazole, and is a modified octapeptide macrocycle; unlike other natural products isolated from this sponge, Sanguinamide B contains two proline residues, where these two residues are expected to control the conformation of the macrocycle. The potent cytotoxic and antibiotic properties of other macrolides isolated from the same nudibranch species, and the small microgram quantities of the compound that are available from the natural source, make this natural product very attractive to synthesize. The synthetic strategy to assemble this natural product and conformation of its structure is described in Chapter 4; as well as a discussion of Sanguinamide B's thermodynamic stability and biological activity

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