Development of 3-phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide compounds as inhibitors of antiapoptotic Bcl-2 family proteins.
Antiapoptotic Bcl-2 family proteins, such as Bcl-xL , Bcl-2, and Mcl-1, are often overexpressed in tumor cells, which contributes to tumor cell resistance to chemotherapies and radiotherapies. Inhibitors of these proteins thus have potential applications in cancer treatment. We discovered, through structure-based virtual screening, a lead compound with micromolar binding affinity to Mcl-1 (inhibition constant (Ki )=3 μM). It contains a phenyltetrazole and a hydrazinecarbothioamide moiety, and it represents a structural scaffold not observed among known Bcl-2 inhibitors. This work presents the structural optimization of this lead compound. By following the scaffold-hopping strategy, we have designed and synthesized a total of 82 compounds in three sets. All of the compounds were evaluated in a fluorescence-polarization binding assay to measure their binding affinities to Bcl-xL , Bcl-2, and Mcl-1. Some of the compounds with a 3-phenylthiophene-2-sulfonamide core moiety showed sub-micromolar binding affinities to Mcl-1 (Ki =0.3-0.4 μM) or Bcl-2 (Ki ≈1 μM). They also showed obvious cytotoxicity on tumor cells (IC50 <10 μM). Two-dimensional heteronuclear single quantum coherence NMR spectra of three selected compounds, that is, YCW-E5, YCW-E10, and YCW-E11, indicated that they bind to the BH3-binding groove on Bcl-xL in a similar mode to ABT-737. Several apoptotic assays conducted on HL-60 cells demonstrated that these compounds are able to induce cell apoptosis through the mitochondrial pathway. We propose that the compounds with the 3-phenylthiophene-2-sulfonamide core moiety are worth further optimization as effective apoptosis inducers with an interesting selectivity towards Mcl-1 and Bcl-2.
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Rd, Shanghai 200032 (P. R. China).
Chengwen
C
Yang
Sha
S
Chen
Mi
M
Zhou
Yan
Y
Li
Yangfeng
Y
Li
Zhengxi
Z
Zhang
Zhen
Z
Liu
Qian
Q
Ba
Jingquan
J
Li
Hui
H
Wang
Xiaomei
X
Yan
Dawei
D
Ma
Renxiao
R
Wang
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D009596:Nitrophenols / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry
C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D013876:Thiophenes; D011065:Poly(ADP-ribose) Polymerases; D053453:Caspase 9
Bcl-2 family proteins; antitumor agents; apoptosis; inhibitors; lead optimization; protein-protein interactions