Effect of H to F bioisosteric modification on the cytotoxicity of a 2,4,6-trimethoxychalcone (
Abstract
Chalcones in their various guises have been considered either valid and critically important lead compounds in the development of novel anticancer agents or as pan assay interference compounds, PAINS. Medicinal chemistry is replete with exemplars from both “camps” progressing to clinical utility. Chalcones offer a simple starting point for the development of specific compounds with high levels of activity toward key biological targets. Chalcones have been shown to display a wide array of anticancer compounds. This chapter seeks to offer an overview of key examples in an effort to encourage further reading and research in development in this intriguing space.
Keywords
- chalcones
- biologically active
- cancer
- structure activity relationship data
1. Introduction
Arguably, cancer represents one of the most serious threats to human health. Its incidence is on the rise, and while there have been an increasing number of new drugs and new targets over the past 50 or so years, it is still responsible for multiple deaths across the globe [1]. The advent of targeted therapies arguably commenced with the discovery and clinical use of the protein kinase inhibitor imatinib [2]. Since this first report, there have been multiple novel protein kinase inhibitor-based drugs entering clinical use [3]. More recently, there has been a significant shift in treatment paradigms to the use of mono-clonal antibodies, with this market predicted to be >$US300 billion by 2030 [4]. Despite this, the survival rates for metastatic breast cancer (Stage IV, 5-year survival is <25%), for pancreatic cancer this is a more dire 7% [5]. Treatment of glioblastoma and other neurological cancers has not advanced in the past 3–4 decades [6, 7].
2. Biological activity of chalcones
Chalcones or analogues or derivatives of (
Despite the numerous examples of clinically used chalcones, they are often overlooked for lead development as a function of PAINS filtering [11]. We note the key role here of the medicinal chemist in understanding both the limitations of the lead scaffold, potential promiscuity and the nature of the biological screening conducted. If the scaffold limitations are understood, there is limited rationale in excluding a whole compound class, especially given the current utility of these analogues. However, vigilance is required in SAR examinations. We recommend the removal of PAINS filters from preliminary screening cascades and the introduction of robust orthogonal assay procedures to enable rapid identification of true lead compounds [12, 13]. In so doing, we believe that this will increase the attractiveness of chalcones as leads; potentially matching their use will greatly increase the attractiveness of chalcones as potential starting points for drug discovery [9, 14].
Historically, chalcones, for example
Being able to switch between two chalconoid structures (
Despite the PAINS expectation, there have been a large number of chalcones reported to elicit anticancer activity via specific cell signaling pathways. Of note are those analogues (
A key feature of chalcone
Within the NF-κB activation pathway the Toll-like receptor 4 (TLR4) and myeloid differentiation 2 (MD2) regulate the downstream signal transduction, such as MAPK phosphorylation. In a LPS-acute lung injury model chalcone
The removal of purported PAINS is more frustrating with recent examples where promiscuous inhibitors were not removed or the filters demonstrated an oversensitivity toward key compound types. That is, these filters may reject non-promiscuous compounds [12, 29].
The use of bioisosteric replacements with chalcones has high prevalence. Commencing with 2,4,6-trimethoxychalcone (
Isosteric replacements have not been limited to simple Grimm’s isosteres, but they have been explored in nonclassical isostere space with the replacement of the central olefin with a small heterocyclic compound, such as the thiophene analogues shown in Table 2. These modified chalcones, for example,
2.1 Chalcone hybrids
The biological activity of chalcones, and study thereof is not limited to the parent structure, but has recently expanded to encapsulate hybrid (chimeric) molecules. These chimeras combine the cytotoxicity of the parent chalcone (
Chalcones themselves are known to inhibit several anticancer targets, including thioredoxin reductase [21], and tubulin polymerization [37, 38]. Based on this there was an expectation (upheld) that chimeric molecules possessing a N-aryl piperazine and chalcone moieties would show higher potencies in the cell lines examined. Indeed, with these molecules considerable synergy arising from the combination of both partners was observed. Of the analogues reported, hybrid
The introduction of an active warhead has been accomplished through the synthesis of a α-bromoacryloylamido chalcones (Figure 6). Analogues of this nature are expected to act as covalent modifiers of their target protein [39]. Intriguingly, this combines the once thought of anathema of a covalent inhibitor with a compound classified as a PAINS [11, 24]. Yet, compounds
Chalcones have been hybridized via an ethylene glycol (or related diol linker) linker (often used in medicinal chemistry to enhance solubility) (Figure 7) [41, 42]. Analogues such as the 1,4-dihydropyridyl-chalcones (
Access to chalcones can be via traditional solution phase synthesis approaches, but in some instances there are reports of the use of solid supports. With
While amide linages have been reported in the development of chalcone hybridism, the use of an ester moiety has the added advantage of allowing a cellular esterase cleavage of the hybrid to afford the two parent drugs. In principle, this may allow the presentation of three different biologically active compounds simultaneously: the hybrid, the chalcone, and the co-drug. The ester approach to coupling compound pharmacophores has been elegantly demonstrated with chalcone hybrids leveraging the often-present hydroxyl moiety. This approach, obviously, can also afford the corresponding ether (versus ester) linked analogue, which is significantly more cleavage resistant. Within this coupled pharmacophore environment, chalcone-amidobenzothiazole chimeras
Like a significant number of other chimeric compounds, “click-approaches” have also been applied in the development of a series of chalcone-coumarin chimeras, for example,
Within this subset of click conjugates,
Continuation of the click-linked chalcone hybrids with β-lactams [51] revealed
Loch-Neckel et al. reported a further investigation of the mechanism of an analogue (
Several hybrids besides those discussed above have also been reported to exhibit potent anticancer activities (Figure 11). For example, β-carboline−chalcone (
2.2 Inhibition of tubulin
Clinically, targeting microtubules—the multifunctional cytoskeletal proteins comprising α- and β-tubulin heterodimers—has provided considerable success in the treatment of multiple cancers. Archetypal microtubule-targeting compounds include the taxanes used in the treatment of metastatic pancreatic cancer [59], and vinca alkaloids in the treatment of hematological and lymphatic neoplasms [60]. However, the continued use of these agents, like a significant number of anticancer drugs, is limited by toxicity (here neurotoxicity) and drug resistance [61, 62]. In this target space, multiple natural and synthetic chalcones (
Given the current toxicity and resistance issues with the taxanes and vinca alkaloids, in combination with the decorated microtubule activity of chalcones, it is not surprising that the hybridization of these compound classes has been explored. Some groups have attempted to develop these combination drugs using rational drug design approaches. Niu approached this via molecular docking and high-correlation quantitative pharmacophore models (40 compounds with experimental data and 800 decoys to discriminate active versus inactive molecules) were generated using the SAR of known tubulin inhibitors [63]. Model validation followed by virtual screening identified ca. 1000 drug-like molecules that were pharmacophore matched. Ultimately, five differentially substituted (
Isolated from
Other hybrids, for example, anthraquinone-chalcone (
Chalcone modification afforded the amino-substituted
Isolated from
Novel o-aryl chalcone (
Confirmation of the tubulin-binding target has been obtained with TUB091 (
2.3 Miscellaneous chalcones
Chalcone-benzoxaborole (
2.4 Selected mechanism of action studies
Ducki et al. predicted tubulin to be the target of chalcone due to the similarity between chalcone and the β-tubulin inhibitor combretastatin A4 [81]. A 5D-QSAR model was used to conclude that the methyl group at the α-position made a sizable difference in the preferred conformation from s-cis (
2.5 Targeting topoisomerase
Critically, the correct assembly of DNA is essential for cellular function. This assembly is in part governed by a series of topoisomerases (TOPOs), including TOPO-I and TOPO-II, which are responsible for the winding and unwinding of DNA. TOPO function is a critical process for DNA transcription and replication, and has been targeted as an anticancer strategy [91]. Several chalcones have shown TOPO inhibitory activity [92]. Chalcone
2.6 Estrogen receptor
In many cancers, the hormone receptor status is a governing factor in determining the treatment protocols. For example, in breast cancer key treatment drivers relate to the presence (or absence) of the estrogen, progesterone, and HER receptor subtypes. The first two receptors are sex-linked and act as transcription factors guiding the interplay between endogenous ligands such as 17β-estradiol. There are multiple clinical drugs that target aberrant ER activity to alleviate the symptoms of menopause, inflammation, and cancer [95].
Chalcone isoliquiritigen in (
Gan et al. reported that chalcones
2.7 Targeting CYPs
The parent analogue, ANF (
Of the modified ANF analogues reported,
Examination of these analogues against MCF-7, MDA-MB-231, LCC6/P-gp, and MCF-7/1B1 revealed the 2-pyridyl chalcone analogue to be broad-spectrum active in both the wild type (MCF-7 and MDA-MB-231 cells) and also in the drug-resistant cells (LCC6/P-gp and MCF-7/1B1) (Table 3). Replacement of the phenyl moiety with a tetramethoxynaphthalene resulted in a drop in CYP1B1 activity (IC50 > 1000 nM), but the MCF-7 and LCC6/P-gp cytotoxicity increased. This presumably is a consequence of increased cellular uptake [99] (Table 4).
IC50 values (μM) | ||||
---|---|---|---|---|
Compound | MCF-7 | MDA-MB-231 | LCC6/P-gp | MCF-7/1B1 |
ANF ( | 80.7 ± 7.6 | >100 | 82.3 ± 8.5 | >100 |
25.9 ± 3.2 | 46.2 ± 5.3 | >100 | 32.3 ± 4.5 | |
48.1 ± 3.7 | 79.6 ± 4.9 | 48.6 ± 2.9 | >100 | |
43.4 ± 1.6 | 75.3 ± 6.8 | 43.9 ± 4.4 | >100 | |
7.6 ± 0.7 | 19.8 ± 2.8 | 8.0 ± 2.3 | 12.7 ± 1.7 | |
6.3 ± 1.4 | 15.8 ± 2.2 | 9.6 ± 1.3 | 15.1 ± 1.8 | |
46.8 ± 4.7 | 48.9 ± 4.1 | >100 | 20.4 ± 3.3 |
3. Conclusions
The medicinal chemistry landscape is a mobile one. Approaches that were viewed as unviable mere 5- to 10-years ago are now gaining traction. The introduction of PAINS filters has stymied some areas of medicinal chemistry development, correctly; but in other areas, the changing paradigms may necessitate a reexamination of the type of screening filters applied. This is especially relevant to the potential development of chalcones in the anticancer drug space. It has been consistently shown that not only do these agents possess high levels of antiproliferative activity as single agents, they synergise well across a significant number of clinically used anticancer drugs.
As this field progresses, careful reevaluation of off-target effects, compound specificity, and promiscuity will remain key, but there is significant potential for transformation of chalcones into true clinical compounds. It is worth noting that it is the role of the medicinal chemist to modulate the unfavorable effects of lead compounds in the development of clinical candidates. This, perhaps though is best left in an academic environment until “compound cleaning” to a true development candidate can be achieved.
Acknowledgments
AM is the recipient of NH&MRC project funding targeting the development of novel anticancer agents. CCR and AM are recipients of funding from the University of Newcastle Priority Research Centre for Drug Development.
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