Pre-mRNA Splicing-Modulatory Pharmacophores: The Total Synthesis of Herboxidiene, a Pladienolide–Herboxidiene Hybrid Analog and Related Derivatives

Abstract

Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This activity makes herboxidiene a valuable starting point for the development of anticancer drugs. Here, we report an improved enantioselective synthesis of herboxidiene and the first report of its biologically active totally synthetic analog: 6-norherboxidiene. The synthesis of the tetrahydropyran moiety utilizes the novel application of inverse electron-demand Diels-Alder chemistry and the Ferrier-type rearrangement as key steps. We report, for the first time, cytotoxicity IC50s for synthetic herboxidiene and analogs in human tumor cell lines. We have also demonstrated that synthetic herboxidiene and its analogs can potently modulate the alternate splicing of MDM-2 pre-mRNA.

The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action

“…Moreover, the diene pharmacophore would clash with the BPA, consistent with a model in which the compound locks SF3B1 in an open conformation and competes for the same binding site as the BPA. agrees with the reported SAR for the herboxidiene analogs that lose about threefold activity when this carboxylate is methylated (Lagisetti et al 2014). Similarly, we show that modification at this C3 hydroxyl (compound 3) also leads to a significant drop in activity.…”

An unexpected tandem cycloaddition reaction of α,β-unsaturated acid chloride with amines: Synthesis of dihydropyrancarboxamide derivatives and biological activity

“…The inhibition zones were more evident since the concentration of 250 μg/mL and the severe inhibitory effect was recorded at the concentration of 500 μg/mL with all tested compounds. Our results were concordance with that cited in the literature [27][28][29][30][31][32][33][34][35][36][37][38][39].…”

“…The various biological activities of tetrahydropyran [29][30][31][32], thiazole [33][34][35][36], benzthiazole [37][38][39] and benzimidazole derivatives [40,41] and other hetertocyclic compounds [42,43] prompted us to study the antimicrobial activities of our newly synthesized products. The in vitro antibacterial activities of compounds 9 and 10a-10f were evaluated against Gram positive and Gram negative bacteria (S. aureus, B. subtilis, E. coli and B. cereus) and fungus (Candida albicans) are reported in Table 5.…”

Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages

“…Structure-activity relationship (SAR) data for the three compounds and related molecules have been steadily emerging (Sakai et al 2002;Mizui et al 2004;Lagisetti et al 2008Lagisetti et al , 2013Lagisetti et al , 2014Albert et al 2009;Fan et al 2011;Gundluru et al 2011;Muller et al 2011;Villa et al 2012Villa et al , 2013Gao et al 2013;Ghosh and Chen 2013;Arai et al 2014;Effenberger et al 2014;Ghosh et al 2014a,b,c;He et al 2014). SSA (1), which is similar to FR901464 (Nakajima et al 1996b), meayamycin (Albert et al 2009), thailanstatins (Liu et al 2013), and sudemycins (Fan et al 2011), differs in structure relative to the other two compounds.…”