Calyculins and Related Marine Natural Products as Serine- Threonine Protein Phosphatase PP1 and PP2A Inhibitors and Total Syntheses of Calyculin A, B, and C

Abstract

Calyculins, highly cytotoxic polyketides, originally isolated from the marine sponge Discodermia calyx by Fusetani and co-workers, belong to the lithistid sponges group. These molecules have become interesting targets for cell biologists and synthetic organic chemists. The serine/threonine protein phosphatases play an essential role in the cellular signalling, metabolism, and cell cycle control. Calyculins express potent protein phosphatase 1 and 2A inhibitory activity, and have therefore become valuable tools for cellular biologists studying intracellular processes and their control by reversible phosphorylation. Calyculins might also play an important role in the development of several diseases such as cancer, neurodegenerative diseases, and type 2-diabetes mellitus. The fascinating structures of calyculins have inspired various groups of synthetic organic chemists to develop total syntheses of the most abundant calyculins A and C. However, with fifteen chiral centres, a cyano-capped tetraene unit, a phosphate-bearing spiroketal, an anti, anti, anti dipropionate segment, an α-chiral oxazole, and a trihydroxylated γ-amino acid, calyculins reach versatility that only few natural products can surpass, and truly challenge modern chemists’ asymmetric synthesis skills.

Lithistid Sponges Derived Compounds and Their Importance in Biological Research - A Review

“…Moto purines and congeners are protein phosphatase inhibitors [27]. The complex polyketide swinholide A and bistheonellide A are biologically active metabolites that show nanomolar potent against tumor cells [6,7].…”

“…Neopeltotide [60,61] has potency again tumor cells and involves in energy production (ATP synthesis). Other organisms collected at the same site had none of these compounds [26][27][28][29][30].…”

“…It has been shown that discodermolide shows its synergistic activity with paclitaxel both in vitro and in vivo showing that in combination therapeutic rules that would reduce toxicity than the paclitaxel treatment [49,57,58]. Discodermolide was evaluated in phase 1 clinical trials for solid tumor malignancies at the cancer therapy and research center in San Antonio, Texas, using molecular mechanics calculation and NMR methods [25][26][27][28][29]. The various compounds derived from lithistid sponges are illustrated in Fig.…”

A Short and Efficient Synthesis of (2S,3S,4S)-tert-Butyl 3,4-Dihydroxy-2-(methoxymethyl)-5-oxopyrrolidine-1-carboxylate

“…We then turned our focus to Lewis acidic conditions. Thus, trimethylaluminum gave lactam 15 in 35% yield, and (Bu 2 ClSn) 2 O in benzene at reflux provided 15 in 73% yield, while the milder (Bu 3 Sn) 2 O did not persuade the adduct to cyclize at all. 16 The enantiopurity of lactam 15 was determined by chiral GC analysis to be 96% ee.…”

“…Since the isolation of calyculin A in 1986 by Fusetani and co-workers 1a and, a few years later, calyculins B, C, and D by the same group, 1b their highly complex structures and role as protein phosphatase inhibitors (PP1 and PP2A) has attracted both synthetic chemists and biologists. 2 The first synthesis of ent-calyculin A was published by Evans and co-workers in 1992, 3a and thus far a total of six syntheses of different calyculins have been published. [3][4][5] Calyculin C (1) contains four different structural regions: C1-C9 tetraene, C10-C25 dipropionate spiroketal, C26-C32 oxazole and C33-C37 amino acid subunits (Figure 1).…”