A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
New spiro-indeno[1,2-b]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights (2023)
Barakat, A., Alshahrani, S., Al-Majid, A. M., Alamary, A. S., Haukka, M., Abu-Serie Marwa, M., Domingo, L. R., Ashraf, S., Ul-Haq, Z., Nafie, M. S., & Teleb, M. (2023). New spiro-indeno[1,2-b]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights. Journal of Enzyme Inhibition and Medicinal Chemistry, 38, Article 1. https://doi.org/10.1080/14756366.2023.2281260
JYU-tekijät tai -toimittajat
Julkaisun tiedot
Julkaisun kaikki tekijät tai toimittajat: Barakat, Assem; Alshahrani, Saeed; Al-Majid, Abdullah Mohammed; Alamary, Abdullah Saleh; Haukka, Matti; Abu-Serie Marwa, M.; Domingo, Luis R.; Ashraf, Sajda; Ul-Haq, Zaheer; Nafie, Mohamed S.; et al.
Lehti tai sarja: Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366
eISSN: 1475-6374
Julkaisuvuosi: 2023
Ilmestymispäivä: 23.11.2023
Volyymi: 38
Artikkelinumero: 1
Kustantaja: Informa Healthcare
Julkaisumaa: Britannia
Julkaisun kieli: englanti
DOI: https://doi.org/10.1080/14756366.2023.2281260
Julkaisun avoin saatavuus: Avoimesti saatavilla
Julkaisukanavan avoin saatavuus: Kokonaan avoin julkaisukanava
Julkaisu on rinnakkaistallennettu (JYX): https://jyx.jyu.fi/handle/123456789/92273
Tiivistelmä
Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-b]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost‐effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC50 = 177 nM) was comparable to roscovitine (IC50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids.
YSO-asiasanat: molekyylidynamiikka; inhibiittorit; kasvaimet; keuhkosyöpä
Vapaat asiasanat: spiro-indeno[12-b]quinoxalines; molecular electron density theory; lung cancer; CDK2; molecular dynamics
Liittyvät organisaatiot
OKM-raportointi: Kyllä
Raportointivuosi: 2023
JUFO-taso: 1
