Correction to 3-Thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1) Based Molecules as Potent, Dual Inhibitors of B-Cell Lymphoma 2 (Bcl-2) and Myeloid Cell Leukemia Sequence 1 (Mcl-1): Structure-Based Design and Structure–Activity Relationship Studies

Abstract

Page 1102. In Scheme 1, the structures of 3 (S1) and 6a−i should be corrected as follows:

Proteolysis Targeting Chimeras for the Selective Degradation of Mcl-1/Bcl-2 Derived from Nonselective Target Binding Ligands

“…Herein, we selected two Bcl-2 family inhibitors, S1-6 and Nap-1 (Figure a), whose opposite binding orientations to the BH3 groove of Bcl-2 proteins have been identified by two-dimensional and three-dimensional (3D) NMR in our previous studies. − For S1-6 , the solvent-exposed 3-cyano group located in the P3 pocket of the BH3 groove provides a suitable point for linker attachment without tethering the binding properties (Figure b, top). We then replaced the cyano group with the 3-aminopropanoic acid methyl ester group, which yielded compound 1 (Figure a).…”

“…To achieve the desired ligands, a generally applicable three-step synthetic strategy was devised (Scheme ). First, intermediate compounds 1 and 2 were synthesized according to earlier reported routes. − Second, the linkers bearing a free amine group at one end and a Boc-protected amine group at the other end were attached to the pomalidomide via nucleophilic aromatic substitution reactions . In the third step, deprotection of the Boc-protected amine and subsequent hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU)-mediated amide bond formation with the carboxylic acid in intermediate molecules 1 and 2 afforded the desired PROTAC compounds, respectively.…”

“…In this article, we constructed two series of PROTACs, H1 – H5 , and C1 – C6 , by introducing the E3 ligase cereblon (CRBN)-binding ligand pomalidomide to Bcl-2/Mcl-1 dual inhibitors S1-6 − and Nap-1 (Figure a), which exhibit a lower M w (approximately 500) and a lower binding affinity for both targets in the micromolar range, via alkyl and PEG linkers of different lengths. Among them, PROTACs C3 and C5 were observed to potently and selectively induce the ubiquitination and proteasomal degradation of Mcl-1 and Bcl-2 in cellulo, respectively, by hijacking a CRBN ubiquitin ligase to form a ternary complex with the target protein.…”

Bcl-2 Family Proteins Are Involved in the Signal Crosstalk between Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Tumor Chemotherapy Resistance

“…Studies based on two-dimensional nuclear magnetic and fluorescence polarization experiments show that S1 has a high affinity for Bcl-2 and Mcl-1. S1 can therefore interfere with the interactions of Bcl-2/Bax or Mcl-1/Bak, thus inducing apoptosis in various tumor cells [ 43 ], including liver and breast cancer [ 44 ]. Our recent study shows that S1 can also induce apoptosis in glioma U251 cells, accompanied by upregulation of the expression of the autophagy marker protein LC3-II and ER stress marker protein PDI.…”

Another structural correction for 1‐oxo‐1H‐phenalene‐2,3‐dicarbonitriles: Synthesis of a potent BCL‐2 inhibiting 7‐phenoxy derivative

“…Despite numerous studies describing physicochemical and biological properties of 8‐oxo‐8 H ‐acenaphtho[1,2‐ b ]pyrrole‐9‐carbonitrile ( A ) derivatives, it was only in 2013/2014 when the original authors published two separate corrigendum papers, [ 21,22 ] in which the core structure A was revised. They used two‐dimensional (2D) nuclear magnetic resonance (NMR) techniques to reassign the molecule as 1‐oxo‐1 H ‐phenalene‐2,3‐dicarbonitrile (scaffold B , Figure 1).…”