Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold

doi:10.1016/j.bmcl.2017.11.023

Bioorganic & Medicinal Chemistry Letters

Volume 28, Issue 3, 1 February 2018, Pages 523-528

https://doi.org/10.1016/j.bmcl.2017.11.023 Get rights and content

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Inspired by a rhodanine-based dual inhibitor of Bcl-x_L and Mcl-1, a focused library of analogues was prepared wherein the rhodanine core was replaced with a less promiscuous thiazolidine-2,4-dione scaffold. Compounds were initially evaluated for their abilities to inhibit Mcl-1. The most potent compound 12b inhibited Mcl-1 with a K_i of 155 nM. Further investigation revealed comparable inhibition of Bcl-x_L (K_i = 90 nM), indicating that the dual inhibitory profile of the initial rhodanine lead had been retained upon switching the heterocycle core.

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Acknowledgements

We thank the University of Maryland School of Pharmacy and the Center for Biomolecular Therapeutics, University of Maryland School of Medicine for financial support of this research.

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Thiazolidinedione (TZD) is one of the privileged heterocyclic rings and has shown many biological applications in medicinal chemistry and drug discovery. This review covers the synthetic approaches of TZD and its derivatives, different synthetic techniques for affording the desired regioselectivity and stereoselectivity, and the techniques that would enhance reaction conditions such as microwave, one‐pot, or ultrasound synthesis. It focuses on synthetic challenges of glitazones and the transformation of other heterocycles to TZD. Moreover, the chemical and biological behavior of TZD through the substitution in the N3 position, modification of the C5 position, annealing in complex heterocyclic systems, and hybridization with other pharmacologically attractive moieties are discussed. All reactions mentioned are provided as possible with different reaction conditions, mechanisms, derivatives scope, yield and clarified by applications of such reactions in the construction of potential medicinal agents. The review also answers questions about rapid racemization of glitazones, their toxicity, considering TZD as pan‐assay interference compounds (PAINS) or not, and the influence of saturation of 5‐position of TZD in their biological activities. This review is a comprehensive guide to make informed decisions for construction of TZD derivatives with biological potentials.
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Cancer is amongst the deadliest and most disruptive disorders, having a much higher death rate than other diseases worldwide. Human cancer rates continue to rise, thereby posing the most significant concerns for medical health professionals. In the last two decades, researchers have gone past several milestones in tackling cancer while gaining insight into the role of apoptosis in cancer or targeting various biomarker tools for prognosis and diagnosis. Apoptosis which is still a topic full of complexities, can be controlled considerably by B-cell lymphoma 2 (BCL-2) and its family members. Therefore, targeting proteins of this family to prevent tumorigenesis, is essential to focus on the pharmacological features of the anti-apoptotic and pro-apoptotic members, which will help to develop and manage this disorder. This review deals with the advancements of various epigenetic regulators to target BCL-2 family proteins, including the mechanism of several microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Similarly, a rise in natural and synthetic molecules’ research over the last two decades has allowed us to acquire insights into understanding and managing the transcriptional alterations that have led to apoptosis and treating various neoplastic diseases. Furthermore, several inhibitors targeting anti-apoptotic proteins and inducers or activators targeting pro-apoptotic proteins in preclinical and clinical stages have been summarized. Overall, agonistic and antagonistic mechanisms of BCL-2 family proteins conciliated by epigenetic regulators, natural and synthetic agents have proven to be an excellent choice in developing cancer therapeutics.
2-Oxy-3-phenylacrylic acid derivatives as potent Mcl-1 inhibitors for treatment of cancer
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Citation Excerpt :
Among various classes of Mcl-1 inhibitors, thiazoles derivatives were exploited for their Mcl-1-inhibiting activities [20]. Representative examples of this kinds including the rhodanine derivatives developed by Chai group and 2-thioxo-4-thiazolidinone compounds reported by Fletcher and Fang independently (Fig. 1), which indicated the high potential of these heterocycles as Mcl-1 inhibitors [21–24]. Along our ongoing research towards development of Mcl-1 inhibitors, we have previously discovered a kind of novel potential Mcl-1 inhibitor Compound 1 with thiazolone as a key structural core, which exhibited a Ki value of 0.3 μM for Mcl-1 and showed good anti-proliferative activities towards several solid tumor cells [25].
Myeloid cell leukemia-1 (Mcl-1) is a crucial member of Bcl-2 family protein and is recognized as a promising therapeutic target for cancer treatment. Here, based on the lead compound we reported earlier, a focused library of analogues was designed, synthesized and evaluated for the inhibitory activity against Mcl-1. 2-oxy-3-phenylacrylic acid derivative III-2, turned out to be the most potent compound with good binding affinity for Mcl-1 and anti-proliferative activities. In addition, the effective inhibition of cell migration, the improvement of apoptosis and the decreased expression of Mcl-1 by compound III-2, as well as the molecule docking elucidated its mechanism of action. Taken together, 2-oxy-3-phenylacrylic acid derivatives may represent a new class of Mcl-1 inhibitors and deserve further study.
Development of Mcl-1 inhibitors for cancer therapy
2021, European Journal of Medicinal Chemistry
Citation Excerpt :
Encouraged by inhibitory data found for WL-276, Fang’s group (at the School of Pharmacy, Shandong University, China) implemented the structure-based design to form the 2-thioxo-4-thiazolidinone heterocyclic core derivatives, which were pan-Bcl-2 inhibitors (3a-d) [70], as shown in Fig. 9. While the Fletcher group at the School of Pharmacy, University of Maryland, revealed thiazolidine-2,4-dione as a moderate inhibitor (4a) which was later optimized to attain the potent Mcl-1 inhibitor (4b) [71], as shown in Fig. 9. In 2010, Feng et al. discovered a thiazolo [3,2-a]pyrimidinone molecule (2.1.5) from a virtual database screening as a pan-Bcl-2 inhibitor [72], as shown in Fig. 10.
The myeloid leukemia cell differentiation protein (Mcl-1) is an anti-apoptotic protein of the B-cell lymphoma 2 (Bcl-2) family, which regulates cellular apoptosis. Mcl-1 expression plays a key role in survival of cancer cells and therefore serves as a promising target in cancer therapy. Besides, its importance as a cancer target, various peptides and small-molecule inhibitors have been successfully designed and synthesized, yet no Mcl-1 inhibitor is approved for clinical use. However, recent development on the understanding of Mcl-1’s role in key cellular processes in cancer and an upsurge of reports highlighting its association in various anticancer drug resistance supports the view that Mcl-1 is a key target in various cancers, especially hematological cancers. This review compiles structures of a variety of inhibitors of Mcl-1 reported to date. These include inhibitors based on a diverse range of heterocycles (e.g. indole, imidazole, thiophene, nicotinic acid, piperazine, triazine, thiazole, isoindoline), oligomers (terphenyl, quaterpyridine), polyphenol, phenalene, anthranilic acid, anthraquinone, macrocycles, natural products, and metal-based complexes. In addition, an effort has been made to summarize the structure activity relationships, based on a variety of assays, of some important classes of Mcl-1 inhibitors, giving affinities and selectivities for Mcl-1 compared to other Bcl-2 family members. A focus has been placed on categorizing the inhibitors based on their core frameworks (scaffolds) to appeal to the chemical biologist or medicinal chemist.
Leucettamine B analogs and their carborane derivative as potential anti-cancer agents: Design, synthesis, and biological evaluation
2020, Bioorganic Chemistry
Citation Excerpt :
Furthermore, our unpublished results showed that (E)-5-(3-phenylallylidene)pyrimidine-2,4,6(1H,3H,5H)-trione, possessed inhibition activity toward HCC cell lines, HepG2, and Hep3B. In addition to the molecules mentioned above, several other heterocyclic moieties have played pivotal roles in drug development from many decades, such as thiazolidinone [21–30], thioxothiazolidin-4-one [31–35], and hydantoin [36–39]. Among them, thiazolidin-2,4-dione (TZD) scaffold is widely applied in many drugs.
Leucettamine B is a natural product found in marine sponge Leucetta microraphis. Several of analogs of its family, such as aplysinopsine and clathridine, are medicinally active molecules which have applications in many pharmaceuticals and healthcare products; however, thus far, leucettamine B has not been studied. In this report, we describe the synthesis of a new class of analogs of leucettamine B obtained by Knoevenagel condensation using a microwave reactor. The 25 newly synthesized compounds were tested against MDA-MB-468, SW480, and Mahlavu cell lines for anticancer activity. Among them, the carborane-based compound (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)-3-(1-closo-carboranyl)-2-thioxo -thiazolidin-4-one (49) and (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)-3-(2-(pyrrolidin-1-yl)ethyl)-2-thioxothiazolidin-4-one (31) derivatives were found to have the most potential for use against tumor cells. The carborane derivative 49 had the lowest IC₅₀ value against the SW480 cell line (4.7 μM) and the Mahlavu (6.6 μM) cell line. Furthermore, compound 31 also had a low IC₅₀ value against SW480 (7.5 μM). Our research shows that leucettamine B analogs might have potential for use in cancer chemotherapy.
Kröhnke pyridines: Rapid and facile access to Mcl-1 inhibitors
2018, Bioorganic and Medicinal Chemistry Letters
The tumorigenic activity of upregulated Mcl-1 is manifested by binding the BH3 α-helical death domains of opposing Bcl-2 family members, neutralizing them and preventing apoptosis. Accordingly, the development of Mcl-1 inhibitors largely focuses on synthetic BH3 mimicry. The condensation of α-pyridinium methyl ketone salts and α,β-unsaturated carbonyl compounds in the presence of a source of ammonia, or the Kröhnke pyridine synthesis, is a simple approach to afford highly functionalized pyridines. We adapted this chemistry to rapidly generate low-micromolar inhibitors of Mcl-1 wherein the 2,4,6-substituents were predicted to mimic the i, i + 2 and i + 7 side chains of the BH3 α-helix.

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^f: Contributed equally.

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Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold

Abstarct

Graphical abstract

Section snippets

Acknowledgements

Cell

Cell

Mol Cell

Pharmacol Ther

J Med Chem

Cancer Cell

Mol Cancer Ther

Cancer Res

Annu Rep Med Chem

Proc Natl Acad Sci USA

Nat Rev Drug Discov

Nat Rev Mol Cell Biol

Nat Rev Mol Cell Biol

Oncogene

Science

Nat Cell Biol

Science

J Med Chem

Nature

Mol Cell Biol

Proc Natl Acad Sci USA