Antitumor Compounds Based on a Natural Product Consensus Pharmacophore

Abstract

We report the design and highly enantioselective synthesis of a potent analog of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous novel analogs. We present results on the in vitro activity for this compound against several tumor cell lines.A novel mechanism of anti-tumor activity was recently elucidated for two structurally distinct fermentation products (see Figure 1) 1 and pladienolide 2 (actually a set of closely related compounds that have been designated pladienolides A-G, isolated from Streptomyces platensis) 3 and FR901464 (isolated from Pseudomonas sp. No 2663). 4-6 These natural products have previously been reported to have a similar novel effect on the cell cycle in mammalian cell lines; cell cycle arrest at the G1 and G2/M phases. 3, 4 . This effect on the cell cycle distinguished these compounds from other anti-tumor agents that also inhibit proliferation in tumors and act at previously identified molecular targets. 3-5 This interaction with the spliceosome leads to the inhibition of mRNA splicing and the translation of unspliced mRNA, which ultimately results in the observed effects on the cell cycle. 2, 7 The first of these natural products to be discovered, FR901464, showed activity in in vivo cancer animal models, but showed a relatively narrow therapeutic window. 4 On the other hand pladienolide-based compounds (first reported in 2004) have shown a very broad therapeutic window. 2 Of the seven pladienolides, pladienolide B was reported to have the most promising anti-cancer activity in vivo, and it has recently been reported that a derivative of pladienolide B has entered human clinical trials for cancer. 2Motivated by the recognition that FR901464 and pladienolide have a very similar (or possibly identical) mechanism of action, we compared overlays of molecular models of the two natural products. Upon inspection of these overlays we recognized that despite the gross dissimilarities *To whom correspondence should be addressed. . E-mail: E-mail: thomas.webb@stjude.org. Supporting Information Available: The supporting information includes the general experimental methods, procedures for the synthesis of 9-13 and 15-18, as well as full experimental methods for the cell cycle analysis and the in vitro cytotoxicity assays. This material is available free of charge via theInternet at http://pubs.acs.org. between FR901464 and pladienolide, both molecules share certain common key features (which are known to be critical to their activity) that can overlap in low energy conformations in three dimensions (see Figure 2). It is known from previous studies that the orientation of the acetyl group and the presence of the epoxide are important in conferring activity to FR901464 analogs, 8, 9 but that the glycosidic hydroxyl group...

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

“…We also found that SSA (1), PB (2), and HB (3) very likely interact with the same site on SF3B1, which strongly supports the presence of a common pharmacophore between the compounds, as predicted by Webb and co-workers (Lagisetti et al 2008, although the full features of the pharmacophore are still not fully apparent. PB (2) and HB (3) resemble each other with a side chain linked to a ring structure.…”

“…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.…”

“…PB (2), which is related to E7107 and FD-895 (Kotake et al 2007;Villa et al 2012), and HB (3), a member of GEX1 family (Sakai et al 2002), share a similar side chain, but have different ring structures (macrolide vs. tetrahydropyran). A common pharmacophore for the three types of inhibitors has been suggested (Lagisetti et al 2008, but no shared feature has been shown to be critical for activity. It is important to know how these compounds individually interact with SF3B1 and how these interactions interfere with its activity.…”

“…Microarray analysis of 2000 splicing events from nearly 500 genes suggested that SSA affects alternative splicing of introns with weak branch points (Corrionero et al 2011). The selective effect of SF3B1 inhibitors on a limited set of gene transcripts presumably results in tumor cells showing higher sensitivity than healthy cells (Lagisetti et al 2008), but what triggers changes in particular splicing events as a result of SF3B1 inhibition remains to be determined. At some level, pre-mRNA sequence must play a role, but how that sequence information is communicated to the spliceosome is poorly understood.…”

Synthesis of ethyl-3-amino-1-aryl-1H-benzo[f]chromeme-2-carboxylate derivatives promoted by DMAP

“…Chromenes derivatives significant heterocycles that are known to have multiple biological activities 1 for instance, antibacterial, 2 antitumor, 3 sex pheromonal, 4 antimicrobial, 5 TNF-a inhibitory, 6 anticancer, 7 antifungal, 8 estrogenic, 9 antiviral 10 and anti-HIV. 11 Such compounds have also been applied in pigments, and insecticides 12 and therefore, a number of methods and catalysts have been reported for the synthesis of chromene derivatives such as, a [1-(n-butyl)-3-methylimidazolium hydroxide ( 31 Many of the above methods have their own advantages.…”