Kröhnke pyridines: Rapid and facile access to Mcl-1 inhibitors

Evolution in non-peptide α-helix mimetics on the road to effective protein-protein interaction modulators

“…A similar strategy led to the discovery of hydroxynaphthoate-based Mcl-1 inhibitors, exemplified by compound 58 (Figure 12), with nanomolar potency for Mcl-1 and good antiproliferative activity in A375 and SK-MEL-5 melanoma cells, which can be improved by the corresponding acetoxymethyl ester prodrugs [115]. Also focused in the BH3 mimicry, substituents in pyridine derivative 59 (Mcl-1 low micromolar inhibitor) were designed to mimic multi-face i, i+2 and i+7 side chains of the Bak-BH3 α-helix (Figure 12) [116]. A fragment-based approach, using main pockets in the Mcl-1 BH3 groove, facilitated the design of indol-containing Mcl-1 inhibitors, exemplified by compound 60 (Figure 12).…”

1‐Sulfonylated 1,2,3,4‐tetrahydroquinoline‐6‐carboxylic acids as simple, readily‐accessible MCL‐1 inhibitors

“…Furthermore, high expression levels of MCL‐1 are associated with resistance to conventional chemotherapies, as well as to targeted therapies (Wu et al, 2020; Xiang et al, 2018), such as the BCL‐2 inhibitor venetoclax (Bose et al, 2017). Although the development of selective MCL‐1 inhibitors has trailed behind that of its sister proteins BCL‐xL and BCL‐2, owing to the shallow BH3‐binding groove that is largely conserved across the antiapoptotic proteins (Adams & Cory, 2018; Czabotar et al, 2014; Kale et al, 2018), there is now a large number of such compounds that span a range of chemotypes (Abulwerdi, Liao, Liu, et al, 2014; Abulwerdi, Liao, Mady, et al, 2014; Chen et al, 2016; Conlon et al, 2018, 2020; Drennen et al, 2016, 2022; Fletcher, 2019; Friberg et al, 2013; Lanning et al, 2016; Lee et al, 2019; Whiting et al, 2018; Xiang et al, 2018; Yap et al, 2017) (Tron et al, 2018; p. 5) which has almost certainly been fuelled by Stephen Fesik's discovery of the MCL‐1 p2 pocket's plasticity that can mould itself around hydrophobic ligands (Friberg et al, 2013). Whilst a handful of MCL‐1 inhibitors have entered clinical trials, alarmingly several of these have been suspended or even terminated owing to safety concerns (B. Adams, 2021).…”

Synthesis of Asymmetrical 2,6-Diarylpyridines from Linear α,β,γ,δ-Unsaturated Ketones by Addition of Ammonium Formate Followed by Annulation

“…Pyridine is one of the most important heterocycles and the pyridine structures are widely found in many natural products, 1 functional materials, 2 electrochemicals, 3 agrochemicals, 4 pharmaceutical drugs, 5,6 and organocatalysis. 7 As a sequence, the development of effective methods for constructing the pyridine skeleton has attracted considerable attention and a wide range of versatile methods have been developed in the past decades, which include the Hantzsch synthesis, 8 the Vilsmeier-Haack reaction, 9 the Chichibabin reaction, 10 the Bohlmann-Rahtz synthesis, 11 and the Krohnke synthesis.…”

“…7 As a sequence, the development of effective methods for constructing the pyridine skeleton has attracted considerable attention and a wide range of versatile methods have been developed in the past decades, which include the Hantzsch synthesis, 8 the Vilsmeier-Haack reaction, 9 the Chichibabin reaction, 10 the Bohlmann-Rahtz synthesis, 11 and the Krohnke synthesis. 6,12 These methods or their modified procedures are very useful and general for the synthesis of symmetrical pyridines. In addition, more attentions were focused recently on the synthesis of unsymmetrical pyridines and various methodologies such as transitionmetal-catalyzed reaction 13 and metal-free condensation reactions of amines with carbonyl compounds 14,15 have been established.…”

“…The effect of solvents on the reaction was then investigated. Apart from toluene, DMSO, DMF, and N,N-dimethylacetamide (DMAC) were examined and significantly lower yields were achieved compared to that with toluene (entries [6][7][8]. Surprisingly, very low yield of 2a was detected in xylene and chlorobenzene, respectively (entries 9 and 10).…”