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. 2023 Jul 3;14(7):955-961.
doi: 10.1021/acsmedchemlett.3c00141. eCollection 2023 Jul 13.

Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1

Samuël Demin  1 , Aldo Peschiulli  1 , Adriana I Velter  1 , Ann Vos  1 , Benoît De Boeck  1 , Bradley Miller  2 , Frederik J R Rombouts  1 , Tristan Reuillon  1 , William Lento  2 , Maria Dominguez Blanco  1 , Matthieu Jouffroy  3 , Helena Steyvers  1 , Mariette Bekkers  1 , Cristina Altrocchi  1 , Beth Pietrak  2 , Seong Joo Koo  1 , Lawrence Szewczuk  2 , Ricardo Attar  2 , Ulrike Philippar  1
Affiliations

Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1

Samuël Demin et al. ACS Med Chem Lett. .

Abstract

Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds (Ra)-10 and (Ra)-15, possessing remarkable cellular potency and properties.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Examples of MCL-1 inhibitors tested in clinical trials.
Figure 2
Figure 2
Novel macrocyclic C4-linked isomeric pyrazoles.
Figure 3
Figure 3
Co-crystal structure of (Ra)-10 (green) with MCL-1 structure (purple) (PDB 8SVY) at 1.47 Å. Main binding interactions for (Ra)-10 with MCL-1: carboxylic acid forming hydrogen bonds and a salt bridge with Arg263, pyrazole nitrogen establishes a water-mediated hydrogen bond with His224, and two π–π stacking interactions between Phe270 and both naphthyl part and indole scaffold. *The methoxyethoxymethyl side chain adopts two conformations in the crystal lattice.
Scheme 1
Scheme 1. Synthesis of Compound (Ra)-10
Reagents and conditions: (a) BH3.THF, THF, 50 °C, 16 h, 86%; (b) TBDMSCl, imidazole, DMAP, DCM, rt, 16 h, 59%; (c) CPhos-Pd-G3, K2CO3, 1,4-dioxane/water (10:1), 40 °C, 3 h; (d) MeI, Cs2CO3, DMF, rt, 2 h, 39%; (e) DDQ, DCM/water (10:1), 2 h, rt, 98%; (f) DIPEA, MsCl, DCM, 0 °C, 30 min; then KSAc, DMF, rt, 16 h, 82%; (g) MeOH/THF (3:1), K2CO3, rt, 48 h; (h) p-TsOH, MeOH, rt, 1 h, 69% (2 steps); (i) DTBAD, PPh3, toluene/THF (5:1), 70 °C, 4 h, 60%; (j) Chiral SFC separation, 25%; (k) LiOH, MeOH/THF/water (1:1:1), 60 °C, 3 h, 88%.
Scheme 2
Scheme 2. Synthesis of Compound (Ra)-15
Reagents and conditions: (a) PdCl2(dtbpf), K3PO4, toluene, 125 °C, 16 h, 78%; (b) DDQ, DCM/water (9:1), rt, 30 min, 58%; (c) DIPEA, MsCl, DCM, 0 °C, 10 min.; then KSAc, DMF, rt, 15 min, 64%; (d) MeOH/THF (2:1), K2CO3, rt, 1 h, 39%; (e) p-TsOH, MeOH, rt, 30 min, 98%; (f) DTBAD, PPh3, toluene/THF (20:1), 70 °C, 10 min.; (g) Chiral SFC separation, 14% (from 31); (h) 4-(2-bromoethyl)morpholine hydrobromide, Cs2CO3, DMF, 60 °C, 16 h; (i) LiOH, water/MeOH/THF (1:2:2), 60 °C, 3 h, 37% (2 steps).
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