Total Syntheses of Pladienolide-Derived Spliceosome Modulators

Abstract

Pladienolides, an emerging class of naturally occurring spliceosome modulators, exhibit interesting structural features, such as highly substituted 12-membered macrocycles and epoxide-containing diene side chains. The potential of pladienolides as anti-cancer agents is confirmed by H3B-8800, a synthetic analog of this natural product class, which is currently under Phase I clinical trials. Since its isolation in 2004 and the first total synthesis in 2007, a dozen total syntheses and synthetic approaches toward the pladienolide class have been reported to date. This review focuses on the eight completed total syntheses of naturally occurring pladienolides or their synthetic analogs, in addition to a synthetic approach to the main framework of the natural product.

Stereochemical Control of Splice Modulation in FD-895 Analogues

“…As described herein, these studies offer an insight into how nature can uniquely adapt stereochemistry for such a wide variety of downstream targets. Most critically, this updated SAR data (SAR map 17 provided in the Table of Contents graphic) provides a resource to guide the identification of analogues with single-digit nanomolar activity 34 as well as guide the design of linkages for ADC applications. 35 ■ EXPERIMENTAL SECTION General Experimental Methods.…”

“…17 The importance of these classes of SPLMs is now well recognized through significant synthetic efforts, including that on the FD-895 (1), pladienolides (2a, Figure 1), and spliceostatins including FR901464 (2b), meayamycin (2c), thailanstatin A (2d), and herboxidiene (2e), as recently reviewed. 18,19 These studies have led to a remarkable level of structure−activity relationship (SAR) data that defines how each of these molecules adopts a consensus motif that uniquely positions itself into the core SF3B complex of the spliceosome. 20,21 Recognized since their discovery, the high potency and tumor cell selectivity of these analogues has ultimately led to the entry of two Phase I clinical trials on semi-synthetic analogues E7107 (3a, Figure 2) and H3B-8800 (3b).…”

Special Issue “Feature Review Papers in Organic Synthesis”

“…The total synthesis of natural products is represented by the review of Sim et al [ 8 ], which shows a series of syntheses of naturally occurring pladienolides or analogues. These compounds are naturally occurring spliceosome modulators that exhibit interesting structural features and are potential anti-cancer agents.…”