Chiral Analogues of PFI-1 as BET Inhibitors and Their Functional Role in Myeloid Malignancies

Luo²,

et al. 2022

Acta Pharmacol Sin

BRD4 plays a key role in the regulation of gene transcription and has been identified as an attractive target for cancer treatment. In this study, we designed 26 new compounds by modifying 3-ethyl-benzo[d]isoxazole core with sulfonamides. Most compounds exhibited potent BRD4 binding activities with Δ T m values exceeding 6 °C. Two crystal structures of 11h and 11r in complex with BRD4(1) were obtained to characterize the binding patterns. Compounds 11h and 11r were effective for BRD4(1) binding and showed remarkable anti-proliferative activity against MV4-11 cells with IC 50 values of 0.78 and 0.87 μM. Furthermore, 11r (0.5−10 μM) concentration-dependently inhibited the expression levels of oncogenes including c-Myc and CDK6 in MV4-11 cells. Moreover, 11r (0.5−10 μM) concentration-dependently blocked cell cycle in MV4-11 cells at G 0 /G 1 phase and induced cell apoptosis. Compound 11r may serve as a new lead compound for further drug development.

Section: Introductionmentioning

confidence: 99%

Design, synthesis and pharmacological characterization of N-(3-ethylbenzo[d]isoxazol-5-yl) sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia

Luo²,

et al. 2022

Acta Pharmacol Sin

Photochem & Photobiology

“…The functional group, when added to lead compounds for generating analogues, has shown to increase chemical and metabolic stability and improve solubility (1,2,5). The focus on synthetically incorporating sulfoximine in drug molecules has resurfaced due to recent viable and safe methods described in the literature (8)(9)(10)(11)(12)(13)(14)(15)(16). Reactive intermediates in the context of sulfoximine have been often profiled in the discussion of synthesizing them (17)(18)(19)(20)(21)(22), but recently focus has also shifted in analyzing reactive intermediates as a by-product of their degradation through S-heteroatom bond cleavages (23).…”

Section: Introductionmentioning

confidence: 99%

Photochemistry of N‐Phenyl Dibenzothiophene Sulfoximine^†

Isor

Hommelsheim

Cone

et al. 2021

Self Cite

Sulfoximines are popular scaffolds in drug discovery due to their hydrogen bonding properties and chemical stability. In recent years, the role of reactive intermediates such as nitrenes has been studied in the synthesis and degradation of sulfoximines. In this work, the photochemistry of N-phenyl dibenzothiophene sulfoximine [5-(phenylimino)-5H-5k 4dibenzo[b,d]thiophene S-oxide] was analyzed. The structure resembles a combination of N-phenyl iminodibenzothiophene and dibenzothiophene S-oxide, which generate nitrene and O ( 3 P) upon UV-A irradiation, respectively. The photochemistry of N-phenyl dibenzothiophene sulfoximine was explored by monitoring the formation of azobenzene, a photoproduct of triplet nitrene, using direct irradiation and sensitized experiments. The reactivity profile was further studied through direct irradiation experiments in the presence of diethylamine (DEA) as a nucleophile. The studies demonstrated that Nphenyl dibenzothiophene sulfoximine underwent S-N photocleavage to release singlet phenyl nitrene which formed a mixture of azepines in the presence of DEA and generated moderate amounts of azobenzene in the absence of DEA to indicate formation of triplet phenyl nitrene.

“…In light of our ongoing studies of the N-functionalization of sulfoximines and bioactive compounds based on such entities, we became interested in the synthesis of 2-sulfoximidoyl acetic acids 4 as potential building blocks, which could be useful in the construction of highly complex sulfoximidoyl-containing scaffolds such as compound 3 , a candidate for an IRAK4 (interleukin-1 receptor-associated kinase 4) inhibitor . Retrosynthetic analysis (Scheme B) of the 2-sulfoximidoyl acetic acid scaffold 4 suggests a multicomponent Petasis reaction as an elegant way to access these structures.…”

mentioning

confidence: 99%

2-Sulfoximidoyl Acetic Acids from Multicomponent Petasis Reactions and Their Use as Building Blocks in Syntheses of Sulfoximine Benzodiazepine Analogues

et al. 2021

Self Cite

Upon application of a multicomponent Petasis reaction, a broad range of NH-sulfoximines and boronic acids react with glyoxalic acid to afford the corresponding 2-substituted acetic acids with N-bound sulfoximidoyl groups. The protocol features excellent yields under ambient, metal-free conditions and short reaction times. Furthermore, the applicability of 2-sulfoximidoyl acetic acids as building blocks for synthesizing sulfoximine-based benzodiazepine analogues was demonstrated.